WorldWideScience

Sample records for cancer susceptibility loci

  1. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E;

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtype...

  2. Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Stella Koutros

    Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

  3. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

    DEFF Research Database (Denmark)

    Pharoah, Paul D P; Tsai, Ya-Yu; Ramus, Susan J;

    2013-01-01

    Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24...

  4. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

    DEFF Research Database (Denmark)

    Ahmed, Shahana; Thomas, Gilles; Ghoussaini, Maya; Healey, Catherine S; Humphreys, Manjeet K; Platte, Radka; Morrison, Jonathan; Maranian, Melanie; Pooley, Karen A; Luben, Robert; Eccles, Diana; Evans, D Gareth; Fletcher, Olivia; Johnson, Nichola; dos Santos Silva, Isabel; Peto, Julian; Stratton, Michael R; Rahman, Nazneen; Jacobs, Kevin; Prentice, Ross; Anderson, Garnet L; Rajkovic, Aleksandar; Curb, J David; Ziegler, Regina G; Berg, Christine D; Buys, Saundra S; McCarty, Catherine A; Feigelson, Heather Spencer; Calle, Eugenia E; Thun, Michael J; Diver, W Ryan; Bojesen, Stig; Nordestgaard, Børge G; Flyger, Henrik; Dörk, Thilo; Schürmann, Peter; Hillemanns, Peter; Karstens, Johann H; Bogdanova, Natalia V; Antonenkova, Natalia N; Zalutsky, Iosif V; Bermisheva, Marina; Fedorova, Sardana; Khusnutdinova, Elza; Kang, Daehee; Yoo, Keun-Young; Noh, Dong Young; Ahn, Sei-Hyun; Devilee, Peter; van Asperen, Christi J; Tollenaar, R A E M; Seynaeve, Caroline; Garcia-Closas, Montserrat; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Hopper, John L; Southey, Melissa C; Smith, Letitia; Spurdle, Amanda B; Schmidt, Marjanka K; Broeks, Annegien; van Hien, Richard R; Cornelissen, Sten; Milne, Roger L; Ribas, Gloria; González-Neira, Anna; Benitez, Javier; Schmutzler, Rita K; Burwinkel, Barbara; Bartram, Claus R; Meindl, Alfons; Brauch, Hiltrud; Justenhoven, Christina; Hamann, Ute; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; English, Dallas R; Hankinson, Susan E; Cox, David G; Kraft, Peter; Vatten, Lars J; Hveem, Kristian; Kumle, Merethe; Sigurdson, Alice; Doody, Michele; Bhatti, Parveen; Alexander, Bruce H; Hooning, Maartje J; van den Ouweland, Ans M W; Oldenburg, Rogier A; Schutte, Mieke; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Yuqing; Cox, Angela; Elliott, Graeme; Brock, Ian; Reed, Malcolm W R; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Giu-Cheng; Chen, Shou-Tung; Anton-Culver, Hoda; Ziogas, Argyrios; Andrulis, Irene L; Knight, Julia A; Beesley, Jonathan; Goode, Ellen L; Couch, Fergus; Chenevix-Trench, Georgia; Hoover, Robert N; Ponder, Bruce A J; Hunter, David J; Pharoah, Paul D P; Dunning, Alison M; Chanock, Stephen J; Easton, Douglas F

    2009-01-01

    Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage...

  5. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

    Science.gov (United States)

    Eeles, Rosalind A; Olama, Ali Amin Al; Benlloch, Sara; Saunders, Edward J; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Ghoussaini, Maya; Luccarini, Craig; Dennis, Joe; Jugurnauth-Little, Sarah; Dadaev, Tokhir; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Muir, Ken; Giles, Graham G; Severi, Gianluca; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian; Le Marchand, Loic; Lindstrom, Sara; Kraft, Peter; Hunter, David J; Gapstur, Susan; Chanock, Stephen J; Berndt, Sonja I; Albanes, Demetrius; Andriole, Gerald; Schleutker, Johanna; Weischer, Maren; Canzian, Federico; Riboli, Elio; Key, Tim J; Travis, Ruth; Campa, Daniele; Ingles, Sue A; John, Esther M; Hayes, Richard B; Pharoah, Paul DP; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet; Ostrander, Elaine A; Signorello, Lisa B; Thibodeau, Stephen N; Schaid, Dan; Maier, Christiane; Vogel, Walther; Kibel, Adam S; Cybulski, Cezary; Lubinski, Jan; Cannon-Albright; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Spurdle, Amanda B; Clements, Judith A; Teixeira, Manuel R; Dicks, Ed; Lee, Andrew; Dunning, Alison; Baynes, Caroline; Conroy, Don; Maranian, Melanie J; Ahmed, Shahana; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A; Sawyer, Emma J; Morgan, Angela; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas J; Woodhouse, J; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin; Lophatananon, Artitaya; Cox, Angela; Southey, Melissa; Hopper, John L; English, Dallas R; Aly, Markus; Adolfsson, Jan; Xu, Jiangfeng; Zheng, Siqun; Yeager, Meredith; Kaaks, Rudolf; Diver, W Ryan; Gaudet, Mia M; Stern, Mariana; Corral, Roman; Joshi, Amit D; Shahabi, Ahva; Wahlfors, Tiina; Tammela, Teuvo J; Auvinen, Anssi; Virtamo, Jarmo; Klarskov, Peter; Nordestgaard, Børge G; Røder, Andreas; Nielsen, Sune F; Bojesen, Stig E; Siddiq, Afshan; FitzGerald, Liesel; Kolb, Suzanne; Kwon, Erika; Karyadi, Danielle; Blot, William J; Zheng, Wei; Cai, Qiuyin; McDonnell, Shannon K; Rinckleb, Antje; Drake, Bettina; Colditz, Graham; Wokolorczyk, Dominika; Stephenson, Robert A; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Mitev, Vanio; Lose, Felicity; Srinivasan, Srilakshmi; Maia, Sofia; Paulo, Paula; Lange, Ethan; Cooney, Kathleen A; Antoniou, Antonis; Vincent, Daniel; Bacot, François; Tessier; Kote-Jarai, Zsofia; Easton, Douglas F

    2013-01-01

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. PMID:23535732

  6. GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes

    OpenAIRE

    Dai, Jingyao; Gu, Jian; Huang, Maosheng; Eng, Cathy; Kopetz, E. Scott; Ellis, Lee M.; Hawk, Ernest; Wu, Xifeng

    2012-01-01

    Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of colorectal cancer (CRC). However, whether these loci affect clinical outcomes of CRC is not clear. In this study, we genotyped 26 single nucleotide polymorphisms (SNPs) in 10 GWAS-identified CRC susceptibility regions and evaluated their associations with survival and recurrence in 285 stage II and III patients receiving fluorouracil-based adjuvant chemotherapy. Only on...

  7. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki;

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ...

  8. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

    DEFF Research Database (Denmark)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G;

    2011-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of st...

  9. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

    Science.gov (United States)

    Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

    2016-01-01

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID:27117709

  10. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    Science.gov (United States)

    Couch, Fergus J.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A.; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Blank, Stephanie V.; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B. M.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C.; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M.; Eccles, Diana M.; Ehrencrona, Hans; Ekici, Arif B.; Eliassen, Heather; Ellis, Steve; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D.; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D.; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; Gaudet, Mia M.; Gayther, Simon A.; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hansen, Thomas V. O.; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E.; Herzog, Josef; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Humphreys, Keith; Hunter, David J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y.; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G.; Knight, Julia A.; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L.; Makalic, Enes; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W. M.; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L.; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M.; Muranen, Taru A.; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nordestgaard, Børge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Osorio, Ana; Park, Sue K.; Peeters, Petra H.; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M.; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J.; Sanchez, Maria-Jose; Santella, Regina M.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Sinilnikova, Olga M.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I.; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary B.; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E.; Tollenaar, Robert A. E. M.; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H. M.; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N.; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Monteiro, Alvaro A. N.; García-Closas, Montserrat; Easton, Douglas F.; Antoniou, Antonis C.

    2016-01-01

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID:27117709

  11. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E;

    2011-01-01

    were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations......Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes.......016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor...

  12. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

    Science.gov (United States)

    Schumacher, Fredrick R.; Schmit, Stephanie L.; Jiao, Shuo; Edlund, Christopher K.; Wang, Hansong; Zhang, Ben; Hsu, Li; Huang, Shu-Chen; Fischer, Christopher P.; Harju, John F.; Idos, Gregory E.; Lejbkowicz, Flavio; Manion, Frank J.; McDonnell, Kevin; McNeil, Caroline E.; Melas, Marilena; Rennert, Hedy S.; Shi, Wei; Thomas, Duncan C.; Van Den Berg, David J.; Hutter, Carolyn M.; Aragaki, Aaron K.; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Chanock, Stephen J.; Curtis, Keith R.; Fuchs, Charles S.; Gala, Manish; Giovannucci, Edward L.; Gogarten, Stephanie M.; Hayes, Richard B.; Henderson, Brian; Hunter, David J.; Jackson, Rebecca D.; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; LaCroix, Andrea; Laurie, Cathy C.; Laurie, Cecelia A.; Lemire, Mathieu; Levine, David; Ma, Jing; Makar, Karen W.; Qu, Conghui; Taverna, Darin; Ulrich, Cornelia M.; Wu, Kana; Kono, Suminori; West, Dee W.; Berndt, Sonja I.; Bezieau, Stéphane; Brenner, Hermann; Campbell, Peter T.; Chan, Andrew T.; Chang-Claude, Jenny; Coetzee, Gerhard A.; Conti, David V.; Duggan, David; Figueiredo, Jane C.; Fortini, Barbara K.; Gallinger, Steven J.; Gauderman, W. James; Giles, Graham; Green, Roger; Haile, Robert; Harrison, Tabitha A.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jacobs, Eric; Iwasaki, Motoki; Jee, Sun Ha; Jenkins, Mark; Jia, Wei-Hua; Joshi, Amit; Li, Li; Lindor, Noralene M.; Matsuo, Keitaro; Moreno, Victor; Mukherjee, Bhramar; Newcomb, Polly A.; Potter, John D.; Raskin, Leon; Rennert, Gad; Rosse, Stephanie; Severi, Gianluca; Schoen, Robert E.; Seminara, Daniela; Shu, Xiao-Ou; Slattery, Martha L.; Tsugane, Shoichiro; White, Emily; Xiang, Yong-Bing; Zanke, Brent W.; Zheng, Wei; Le Marchand, Loic; Casey, Graham; Gruber, Stephen B.; Peters, Ulrike

    2016-01-01

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. PMID:26151821

  13. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

    Science.gov (United States)

    Eeles, Rosalind A.; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Guy, Michelle; Severi, Gianluca; Muir, Kenneth; Hopper, John L.; Henderson, Brian E.; Haiman, Christopher A.; Schleutker, Johanna; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Stanford, Janet L.; Ostrander, Elaine A.; Ingles, Sue A.; John, Esther M.; Thibodeau, Stephen N.; Schaid, Daniel; Park, Jong Y.; Spurdle, Amanda; Clements, Judith; Dickinson, Joanne L.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Rebbeck, Timothy R.; Cooney, Kathleen A.; Cannon-Albright, Lisa; Chappuis, Pierre O.; Hutter, Pierre; Zeegers, Maurice; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Foulkes, William D.; English, Dallas R.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Morrison, Jonathan; Ardern-Jones, Audrey T.; Hall, Amanda L.; O’Brien, Lynne T.; Wilkinson, Rosemary A.; Saunders, Edward J.; Page, Elizabeth C.; Sawyer, Emma J.; Edwards, Stephen M.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Southey, Melissa C.; Lophatananon, Artitaya; Liu, Jo-Fen; Kolonel, Laurence N.; Le Marchand, Loic; Wahlfors, Tiina; Tammela, Teuvo L.; Auvinen, Anssi; Lewis, Sarah J.; Cox, Angela; FitzGerald, Liesel M.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Kwon, Erika M.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva; McDonnell, Shannon K.; Sellers, Thomas A; Pow-Sang, Julio; Chambers, Suzanne; Aitken, Joanne; Gardiner, R.A. (Frank); Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity; Polanowski, Andrea; Patterson, Briony; Serth, Jürgen; Meyer, Andreas; Luedeke, Manuel; Stefflova, Klara; Ray, Anna M.; Lange, Ethan M.; Farnham, Jim; Khan, Humera; Slavov, Chavdar; Mitkova, Atanaska; Cao, Guangwen; Easton, Douglas F.

    2010-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33). PMID:19767753

  14. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan;

    2015-01-01

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed...... associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded...

  15. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara;

    2015-01-01

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748...

  16. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

    DEFF Research Database (Denmark)

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I;

    2014-01-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer...

  17. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

    Science.gov (United States)

    Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; Spindler, Tassja J; Lin, Yvonne G; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C; Piedmonte, Marion; O'Malley, David M; de la Hoya, Miguel; Caldes, Trinidad; Aittomäki, Kristiina; Nevanlinna, Heli; Collée, J Margriet; Rookus, Matti A; Oosterwijk, Jan C; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N; Caligo, Maria A; Campbell, Ian G; Hogervorst, Frans B L; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaro, Conxi; Pujana, Miquel Angel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Pankratz, Vernon S; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A; Pfeiler, Georg; Berger, Andreas; Singer, Christian F; Tea, Muy-Kheng; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I; Nussbaum, Robert L; Rebbeck, Timothy R; Nathanson, Katherine L; Domchek, Susan M; Lu, Karen H; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Fasching, Peter A; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A; Wicklund, Kristine G; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R; Goodman, Marc T; Thompson, Pamela J; Shvetsov, Yurii B; Runnebaum, Ingo B; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L; Edwards, Robert P; Ness, Roberta B; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Azmi, Mat Adenan Noor; Teo, Soo-Hwang; Woo, Yin-Ling; Fridley, Brooke L; Goode, Ellen L; Cunningham, Julie M; Vierkant, Robert A; Bruinsma, Fiona; Giles, Graham G; Liang, Dong; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W; Terry, Kathryn L; Poole, Elizabeth M; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Krakstad, Camilla; Salvesen, Helga B; Tangen, Ingvild L; Bjorge, Line; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Ji, Bu-Tian; Zheng, Wei; Shu, Xiao-Ou; Gao, Yu-Tang; Rosen, Barry; Risch, Harvey A; McLaughlin, John R; Narod, Steven A; Monteiro, Alvaro N; Chen, Ann; Lin, Hui-Yi; Permuth-Wey, Jenny; Sellers, Thomas A; Tsai, Ya-Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W; Wu, Anna H; Pearce, Celeste L; Coetzee, Gerry; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Gayther, Simon; Pharoah, Paul P; Antoniou, Antonis C; Chenevix-Trench, Georgia

    2015-02-01

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers. PMID:25581431

  18. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD.

    Directory of Open Access Journals (Sweden)

    Robert P Young

    Full Text Available Epidemiological studies show that approximately 20-30% of chronic smokers develop chronic obstructive pulmonary disease (COPD while 10-15% develop lung cancer. COPD pre-exists lung cancer in 50-90% of cases and has a heritability of 40-77%, much greater than for lung cancer with heritability of 15-25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400 subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV(1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV(1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the "risk genotypes" derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70. We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.

  19. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    NARCIS (Netherlands)

    F.J. Couch (Fergus); K.B. Kuchenbaecker (Karoline); K. Michailidou (Kyriaki); G.A. Mendoza-Fandino (Gustavo A.); S. Nord (Silje); J. Lilyquist (Janna); C. Olswold (Curtis); B. Hallberg (Boubou); S. Agata (Simona); H. Ahsan (Habibul); K. Aittomäki (Kristiina); C.B. Ambrosone (Christine B.); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); V. Arndt (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); M. Barile (Monica); R.B. Barkardottir (Rosa); D. Barrowdale (Daniel); L. Beckmann (Lars); M.W. Beckmann (Matthias); J. Benítez (Javier); S.V. Blank (Stephanie); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); S.E. Bojesen (Stig); M.K. Bolla (Manjeet); B. Bonnani (Bernardo); H. Brauch (Hiltrud); H. Brenner (Hermann); B. Burwinkel (Barbara); S.S. Buys (Saundra S.); T. Caldes (Trinidad); M.A. Caligo (Maria); F. Canzian (Federico); T.A. Carpenter (Adrian); J. Chang-Claude (Jenny); S.J. Chanock (Stephen J.); W.K. Chung (Wendy K.); K.B.M. Claes (Kathleen B.M.); A. Cox (Angela); S.S. Cross (Simon); J.M. Cunningham (Julie); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); H. Darabi (Hatef); M. de La Hoya (Miguel); P. Devilee (Peter); O. Díez (Orland); Y.C. Ding (Yuan); R. Dolcetti (Riccardo); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); I. dos Santos Silva (Isabel); M. Dumont (Martine); A.M. Dunning (Alison); D. Eccles (Diana); H. Ehrencrona (Hans); A.B. Ekici (Arif); H. Eliassen (Heather); S.D. Ellis (Steve); P.A. Fasching (Peter); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); A. Försti (Asta); F. Fostira (Florentia); W.D. Foulkes (William); M.O.W. Friebel (Mark ); E. Friedman (Eitan); D. Frost (Debra); M. Gabrielson (Marike); M. Gammon (Marilie); P.A. Ganz (Patricia A.); S.M. Gapstur (Susan M.); J. Garber (Judy); M.M. Gaudet (Mia); S.A. Gayther (Simon); A-M. Gerdes (Anne-Marie); M. Ghoussaini (Maya); G.G. Giles (Graham); G. Glendon (Gord); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); M.J. Gunter (Marc J.); L. Haeberle (Lothar); C.A. Haiman (Christopher A.); U. Hamann (Ute); T.V.O. Hansen (Thomas); S. Hart (Stewart); S. Healey (Sue); T. Heikkinen (Tuomas); B.E. Henderson (Brian); J. Herzog (Josef); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); M.J. Hooning (Maartje); R.N. Hoover (Robert); J.L. Hopper (John); K. Humphreys (Keith); D. Hunter (David); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny N.); C. Isaacs (Claudine); A. Jakubowska (Anna); M. James (Margaret); R. Janavicius (Ramunas); U.B. Jensen; E.M. John (Esther); M. Jones (Michael); M. Kabisch (Maria); S. Kar (Siddhartha); B.Y. Karlan (Beth Y.); S. Khan (Sofia); K.T. Khaw; M.G. Kibriya (Muhammad); J.A. Knight (Julia); Y.-D. Ko (Yon-Dschun); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); A. Kwong (Ava); Y. Laitman (Yael); D. Lambrechts (Diether); C. Lazaro (Conxi); E. Lee (Eunjung); L. Le Marchand (Loic); K.J. Lester (Kathryn); A. Lindblom (Annika); N.M. Lindor (Noralane); S. Lindstrom (Stephen); J. Liu (Jianjun); J. Long (Jirong); J. Lubinski (Jan); P.L. Mai (Phuong); E. Makalic (Enes); K.E. Malone (Kathleen E.); A. Mannermaa (Arto); S. Manoukian (Siranoush); S. Margolin (Sara); F. Marme (Federick); J.W.M. Martens (John); L. McGuffog (Lesley); A. Meindl (Alfons); A. Miller (Austin); R.L. Milne (Roger); P. Miron (Penelope); M. Montagna (Marco); S. Mazoyer (Sylvie); A.-M. Mulligan (Anna-Marie); T.A. Muranen (Taru); K.L. Nathanson (Katherine); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); B.G. Nordestgaard (Børge); R. Nussbaum (Robert); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); A. Osorio (Ana); S.K. Park (Sue K.); P.H.M. Peeters; B. Peissel (Bernard); P. Peterlongo (Paolo); J. Peto (Julian); C. Phelan (Catherine); R. Pilarski (Robert); B. Poppe (Bruce); K. Pykäs (Katri); P. Radice (Paolo); N. Rahman (Nazneen); J. Rantala (Johanna); C. Rappaport (Christine); G. Rennert (Gad); A.L. Richardson (Andrea); M. Robson (Mark); I. Romieu (Isabelle); A. Rudolph (Anja); E.J.T. Rutgers (Emiel); M.-J. Sanchez (Maria-Jose); R. Santella (Regina); E.J. Sawyer (Elinor); D.F. Schmidt (Daniel); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); F.R. Schumacher (Fredrick); R.J. Scott (Rodney); L. Senter (Leigha); P. Sharma (Priyanka); J. Simard (Jacques); C.F. Singer (Christian); O. Sinilnikova (Olga); P. Soucy (Penny); M.C. Southey (Melissa); D. Steinemann (Doris); M. Stenmark-Askmalm (Marie); D. Stoppa-Lyonnet (Dominique); A.J. Swerdlow (Anthony ); C. Szabo (Csilla); R. Tamimi (Rulla); W. Tapper (William); P.J. Teixeira; S.-H. Teo; M.B. Terry (Mary Beth); M. Thomassen (Mads); D. Thompson (Deborah); L. Tihomirova (Laima); A.E. Toland (Amanda); R.A.E.M. Tollenaar (Rob); I.P. Tomlinson (Ian); T. Truong (Thérèse); H. Tsimiklis (Helen); A. Teulé (A.); R. Tumino (Rosario); N. Tung (Nadine); C. Turnbull (Clare); G. Ursin (Giski); C.H.M. van Deurzen (Carolien); E.J. van Rensburg (Elizabeth); R. Varon-Mateeva (Raymonda); Z. Wang (Zhaoming); S. Wang-Gohrke (Shan); E. Weiderpass (Elisabete); J.N. Weitzel (Jeffrey); A.S. Whittemore (Alice S.); H. Wildiers (Hans); R. Winqvist (Robert); X.R. Yang (Xiaohong R.); D. Yannoukakos (Drakoulis); S. Yao (Song); M.P. Zamora (Pilar); W. Zheng (Wei); P. Hall (Per); P. Kraft (Peter); C. Vachon (Celine); S. Slager (Susan); G. Chenevix-Trench (Georgia); P.D.P. Pharoah (Paul); A.A.N. Monteiro (Alvaro A. N.); M. García-Closas (Montserrat); D.F. Easton (Douglas F.); A.C. Antoniou (Antonis C.)

    2016-01-01

    textabstractCommon variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10-8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibili

  20. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions

    Science.gov (United States)

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra; Dunning, Alison M.; Milne, Roger L.; Bojesen, Stig E.; Swerdlow, Anthony; Andrulis, Irene; Brenner, Hermann; Behrens, Sabine; Orr, Nicholas; Jones, Michael; Ashworth, Alan; Li, Jingmei; Cramp, Helen; Connley, Dan; Czene, Kamila; Darabi, Hatef; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Knight, Julia; Glendon, Gord; Mulligan, Anna M.; Dumont, Martine; Severi, Gianluca; Baglietto, Laura; Olson, Janet; Vachon, Celine; Purrington, Kristen; Moisse, Matthieu; Neven, Patrick; Wildiers, Hans; Spurdle, Amanda; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Hamann, Ute; Ko, Yon-Dschun; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Malats, Núria; Arias Perez, JoséI.; Benítez, Javier; Flyger, Henrik; Nordestgaard, Børge G.; Truong, Théresè; Cordina-Duverger, Emilie; Menegaux, Florence; Silva, Isabel dos Santos; Fletcher, Olivia; Johnson, Nichola; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Braaf, Linde; Atsma, Femke; van den Broek, Alexandra J.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Cox, Angela; Simard, Jacques; Giles, Graham G.; Lambrechts, Diether; Mannermaa, Arto; Brauch, Hiltrud; Guénel, Pascal; Peto, Julian; Fasching, Peter A.; Hopper, John; Flesch-Janys, Dieter; Couch, Fergus; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Schmidt, Marjanka K.; Hall, Per; Easton, Douglas F.; Chang-Claude, Jenny

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci. PMID:24248812

  1. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors

    OpenAIRE

    Nickels, Stefan; Truong, Thérèse; Hein, Rebecca; Stevens, Kristen; Buck, Katharina; Behrens, Sabine; Eilber, Ursula; Schmidt, Martina; Häberle, Lothar; Vrieling, Alina; Gaudet, Mia; Figueroa, Jonine; Schoof, Nils; Spurdle, Amanda B.; Rudolph, Anja

    2013-01-01

    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with ...

  2. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

    International Nuclear Information System (INIS)

    Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10−5, we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10−5), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users

  3. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J;

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancest...

  4. Lack of Replication of Seven Pancreatic Cancer Susceptibility Loci Identified in Two Asian Populations

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Bauer, A. S.; Werner, J.; Capurso, G.; Costello, E.; Talar-Wojnarowska, R.; Jamroziak, K.; Pezzilli, R.; Gazouli, M.; Khaw, K. T.; Key, T. J.; Bambi, F.; Mohelníková-Duchoňová, B.; Heller, A.; Landi, S.; Vodičková, Ludmila; Theodoropoulos, G.; Burget, P.; Vodička, Pavel; Hoheisel, J. D.; Delle Fave, G.; Neoptolemos, J. P.; Souček, P.; Buechler, M. W.; Giese, N.; Canzian, F.

    2013-01-01

    Roč. 22, č. 2 (2013), s. 320-323. ISSN 1055-9965 Institutional support: RVO:68378041 Keywords : cancer growth * cancer risk * cancer susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.324, year: 2013

  5. Seven novel prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

    Science.gov (United States)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Severi, Gianluca; Schleutker, Johanna; Weischer, Maren; Canzian, Frederico; Riboli, Elio; Key, Tim; Gronberg, Henrik; Hunter, David J.; Kraft, Peter; Thun, Michael J; Ingles, Sue; Chanock, Stephen; Albanes, Demetrius; Hayes, Richard B; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Pharoah, Paul; Schumacher, Fredrick; Henderson, Brian E.; Stanford, Janet L.; Ostrander, Elaine A.; Sorensen, Karina Dalsgaard; Dörk, Thilo; Andriole, Gerald; Dickinson, Joanne L.; Cybulski, Cezary; Lubinski, Jan; Spurdle, Amanda; Clements, Judith A.; Chambers, Suzanne; Aitken, Joanne; Frank Gardiner, R. A.; Thibodeau, Stephen N.; Schaid, Dan; John, Esther M.; Maier, Christiane; Vogel, Walther; Cooney, Kathleen A.; Park, Jong Y.; Cannon-Albright, Lisa; Brenner, Hermann; Habuchi, Tomonori; Zhang, Hong-Wei; Lu, Yong-Jie; Kaneva, Radka; Muir, Ken; Benlloch, Sara; Leongamornlert, Daniel A.; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; O’Brien, Lynne T.; Wilkinson, Rosemary A.; Hall, Amanda L.; Sawyer, Emma J.; Dadaev, Tokhir; Morrison, Jonathan; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Lophatonanon, Aritaya; Southey, Melissa C.; Hopper, John L.; English, Dallas; Wahlfors, Tiina; Tammela, Teuvo LJ; Klarskov, Peter; Nordestgaard, Børge G.; Røder, M. Andreas; Tybjærg-Hansen, Anne; Bojesen, Stig E.; Travis, Ruth; Campa, Daniele; Kaaks, Rudolf; Wiklund, Fredrik; Aly, Markus; Lindstrom, Sara; Diver, W Ryan; Gapstur, Susan; Stern, Mariana C; Corral, Roman; Virtamo, Jarmo; Cox, Angela; Haiman, Christopher A.; Le Marchand, Loic; FitzGerald, Liesel; Kolb, Suzanne; Kwon, Erika M.; Karyadi, Danielle M.; Orntoft, Torben Falck; Borre, Michael; Meyer, Andreas; Serth, Jürgen; Yeager, Meredith; Berndt, Sonja I.; Marthick, James R; Patterson, Briony; Wokolorczyk, Dominika; Batra, Jyotsna; Lose, Felicity; McDonnell, Shannon K; Joshi, Amit D.; Shahabi, Ahva; Rinckleb, Antje E.; Ray, Ana; Sellers, Thomas A.; Lin, Huo-Yi; Stephenson, Robert A; Farnham, James; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Easton, Douglas F.; Eeles, Rosalind A.

    2012-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. PMID:21743467

  6. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

    DEFF Research Database (Denmark)

    Eeles, Rosalind A; Olama, Ali Amin Al; Benlloch, Sara;

    2013-01-01

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the internationa...

  7. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

    DEFF Research Database (Denmark)

    Schoeps, Anja; Rudolph, Anja; Seibold, Petra;

    2014-01-01

    Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,47...

  8. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    DEFF Research Database (Denmark)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola;

    2015-01-01

    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further...

  9. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2012-12-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  10. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li1, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2014-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  11. Fine-mapping of breast cancer susceptibility loci characterizes genetic risk in African Americans

    OpenAIRE

    Chen, Fang; Chen, Gary K.; Millikan, Robert C.; John, Esther M; Ambrosone, Christine B.; Bernstein, Leslie; Zheng, Wei; Jennifer J Hu; Ziegler, Regina G.; Deming, Sandra L.; Bandera, Elisa V.; Nyante, Sarah; Palmer, Julie R.; Rebbeck, Timothy R.; Sue A Ingles

    2011-01-01

    Genome-wide association studies (GWAS) have revealed 19 common genetic variants that are associated with breast cancer risk. Testing of the index signals found through GWAS and fine-mapping of each locus in diverse populations will be necessary for characterizing the role of these risk regions in contributing to inherited susceptibility. In this large study of breast cancer in African-American women (3016 cases and 2745 controls), we tested the 19 known risk variants identified by GWAS and re...

  12. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    Science.gov (United States)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Gapstur, Susan M; Gaudet, Mia M; Diver, W Ryan; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Berg, Christine D; Chanock, Stephen; Figueroa, Jonine; Hoover, Robert N; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A; van der Luijt, Rob B; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm WR; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; TAN, Gie-Hooi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John WM; Collée, J Margriet; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N; Nord, Silje; Alnaes, Grethe I Grenaker; Giles, Graham G; Milne, Roger L; McLean, Catriona; Canzian, Federico; Trichopoulos, Dmitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Swerdlow, Anthony J; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert AEM; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul PDP; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

    2015-01-01

    Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1. PMID:25751625

  13. A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Daniele Campa

    Full Text Available Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-. Compared with ER-positive (ER+ disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS. We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8 to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3, including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

  14. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

    Science.gov (United States)

    Amin Al Olama, Ali; Benlloch, Sara; Antoniou, Antonis C.; Zeigler-Johnson, Charnita; Stephenson, Robert; Cox, Angela; Southey, Melissa C.; Spurdle, Amanda B.; FitzGerald, Liesel; Leongamornlert, Daniel; Saunders, Edward; Tymrakiewicz, Malgorzata; Guy, Michelle; Dadaev, Tokhir; Little, Sarah J.; Govindasami, Koveela; Sawyer, Emma; Wilkinson, Rosemary; Herkommer, Kathleen; Hopper, John L.; Lophatonanon, Aritaya; Rinckleb, Antje E.; Kote-Jarai, Zsofia; Eeles, Rosalind A.; Easton, Douglas F.

    2015-01-01

    Background Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa. Methods We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history. Results The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2-5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09). Conclusions Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. PMID:25837820

  15. Interactions between breast cancer susceptibility loci and menopausal hormone therapy in relationship to breast cancer in the Breast and Prostate Cancer Cohort Consortium.

    Science.gov (United States)

    Gaudet, Mia M; Barrdahl, Myrto; Lindström, Sara; Travis, Ruth C; Auer, Paul L; Buring, Julie E; Chanock, Stephen J; Eliassen, A Heather; Gapstur, Susan M; Giles, Graham G; Gunter, Marc; Haiman, Christopher; Hunter, David J; Joshi, Amit D; Kaaks, Rudolf; Khaw, Kay-Tee; Lee, I-Min; Le Marchand, Loic; Milne, Roger L; Peeters, Petra H M; Sund, Malin; Tamimi, Rulla; Trichopoulou, Antonia; Weiderpass, Elisabete; Yang, Xiaohong R; Prentice, Ross L; Feigelson, Heather Spencer; Canzian, Federico; Kraft, Peter

    2016-02-01

    Current use of menopausal hormone therapy (MHT) has important implications for postmenopausal breast cancer risk, and observed associations might be modified by known breast cancer susceptibility loci. To provide the most comprehensive assessment of interactions of prospectively collected data on MHT and 17 confirmed susceptibility loci with invasive breast cancer risk, a nested case-control design among eight cohorts within the NCI Breast and Prostate Cancer Cohort Consortium was used. Based on data from 13,304 cases and 15,622 controls, multivariable-adjusted logistic regression analyses were used to estimate odds ratios (OR) and 95 % confidence intervals (CI). Effect modification of current and past use was evaluated on the multiplicative scale. P values <1.5 × 10(-3) were considered statistically significant. The strongest evidence of effect modification was observed for current MHT by 9q31-rs865686. Compared to never users of MHT with the rs865686 GG genotype, the association between current MHT use and breast cancer risk for the TT genotype (OR 1.79, 95 % CI 1.43-2.24; P interaction = 1.2 × 10(-4)) was less than expected on the multiplicative scale. There are no biological implications of the sub-multiplicative interaction between MHT and rs865686. Menopausal hormone therapy is unlikely to have a strong interaction with the common genetic variants associated with invasive breast cancer. PMID:26802016

  16. Genome-wide association study identifies new prostate cancer susceptibility loci

    DEFF Research Database (Denmark)

    Schumacher, Fredrick R.; Berndt, Sonja I.; Siddiq, Afshan;

    2011-01-01

    identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P <0.02) in two...... published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 x 10–8). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 x 10–9). The estimated per-allele odds ratios for these...

  17. Replication of Breast Cancer Susceptibility Loci in Whites and African Americans Using a Bayesian Approach

    OpenAIRE

    O'Brien, Katie M.; Cole, Stephen R.; Poole, Charles; Bensen, Jeannette T.; Herring, Amy H.; Engel, Lawrence S.; Millikan, Robert C.

    2013-01-01

    Genome-wide association studies (GWAS) and candidate gene analyses have led to the discovery of several dozen genetic polymorphisms associated with breast cancer susceptibility, many of which are considered well-established risk factors for the disease. Despite attempts to replicate these same variant-disease associations in African Americans, the evaluable populations are often too small to produce precise or consistent results. We estimated the associations between 83 previously identified ...

  18. Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

    Science.gov (United States)

    Li, Dong; Wei, Lixuan; Xu, Binghe; Yu, Dianke; Chang, Jiang; Yuan, Peng; Du, Zhongli; Tan, Wen; Shen, Hongbing; Wu, Tangchun; Wu, Chen; Lin, Dongxin

    2014-01-01

    Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; P = 0.0187) and 0.73 (95% CI, 0.55–0.96; P = 0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; P = 0.0199) and 1.29 (95% CI, 1.08–1.55; P = 0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC. PMID:25415319

  19. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

    DEFF Research Database (Denmark)

    Garcia-Closas, M.; Hall, P.; Nevanlinna, H.;

    2008-01-01

    A three-stage genome-wide association study recently identified single nucleotide polymorphisms ( SNPs) in five loci ( fibroblast growth receptor 2 ( FGFR2), trinucleotide repeat containing 9 ( TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte- specific protein 1 ( LSP1...

  20. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

    Czech Academy of Sciences Publication Activity Database

    Wolpin, B. M.; Rizzato, C.; Kraft, P.; Kooperberg, Ch.; Petersen, G. M.; Wang, Z.; Arslan, A. A.; Beane-Freeman, L.; Bracci, P. M.; Buring, J.; Canzian, F.; Duell, E. J.; Gallinger, S.; Giles, G.G.; Goodman, G. E.; Goodman, P. J.; Jacobs, E. J.; Kamineni, A.; Klein, A. P.; Kolonel, L. N.; Kulke, M. H.; Li, D.; Malats, N.; Olson, S. H.; Risch, H. A.; Sesso, H. D.; Visvanathan, K.; White, E.; Zheng, W.; Abnet, Ch. C.; Albanes, D.; Andreotti, G.; Austin, M. A.; Barfield, R.; Basso, D.; Berndt, S. I.; Boutron-Ruault, M. Ch.; Brotzman, M.; Büchler, M. W.; Bueno-de-Mesquita, H. B.; Bugert, P.; Burdette, L.; Campa, D.; Caporaso, N. E.; Capurso, G.; Chung, Ch.; Cotterchio, M.; Costello, E.; Elena, J.; Funel, N.; Gaziano, J. M.; Giese, N. A.; Giovannucci, E. L.; Goggins, M.; Gorman, M. J.; Gross, M.; Haiman, Ch. A.; Hassan, M.; Helzlsouer, K. J.; Henderson, B. E.; Holly, E. A.; Hu, N.; Hunter, D. J.; Innocenti, F.; Jenab, M.; Kaaks, R.; Key, T. J.; Khaw, K. T.; Klein, E. A.; Kogevinas, M.; Krogh, V.; Kupcinskas, J.; Kurtz, R. C.; LaCroix, A.; Landi, M. T.; Landi, S.; Le Marchand, L.; Mambrini, A.; Mannisto, S.; Milne, R. L.; Nakamura, Y.; Oberg, A. L.; Owzar, K.; Patel, A. V.; Peeters, P. H. M.; Peters, U.; Pezzilli, R.; Piepoli, A.; Porta, M.; Real, F. X.; Riboli, E.; Rothman, N.; Scarpa, A.; Shu, X. O.; Silverman, D. T.; Souček, P.; Sund, M.; Talar-Wojnarowska, R.; Taylor, P. R.; Theodoropoulos, G. E.; Thornquist, M.; Tjonneland, A.; Tobias, G. S.; Trichopoulos, D.; Vodička, Pavel; Wactawski-Wende, J.; Wentzensen, N.; Wu, Ch.; Yu, H.; Yu, K.; Zeleniuch-Jacquotte, A.; Hoover, R.; Hartge, P.; Fuchs, Ch.; Chanock, S. J.; Stolzenberg-Solomon, R. S.; Amundadottir, L. T.

    2014-01-01

    Roč. 46, č. 9 (2014), s. 994-1000. ISSN 1061-4036 Institutional support: RVO:68378041 Keywords : disease * variants * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 29.352, year: 2014

  1. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

    DEFF Research Database (Denmark)

    Goode, Ellen L; Chenevix-Trench, Georgia; Song, Honglin;

    2010-01-01

    Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with foll...

  2. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

    Science.gov (United States)

    Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya; Hsiung, Chao A; Matsuo, Keitaro; Liu, Jie; Chen, Kexin; Yamji, Taiki; Yang, Yang; Chang, I-Shou; Wu, Chen; Hong, Yun-Chul; Burdett, Laurie; Wyatt, Kathleen; Chung, Charles C; Li, Shengchao A; Yeager, Meredith; Hutchinson, Amy; Hu, Wei; Caporaso, Neil; Landi, Maria T; Chatterjee, Nilanjan; Song, Minsun; Fraumeni, Joseph F; Kohno, Takashi; Yokota, Jun; Kunitoh, Hideo; Ashikawa, Kyota; Momozawa, Yukihide; Daigo, Yataro; Mitsudomi, Tetsuya; Yatabe, Yasushi; Hida, Toyoaki; Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Guan, Peng; Chang, Jiang; Tan, Wen; Chen, Chien-Jen; Chang, Gee-Chen; Tsai, Ying-Huang; Su, Wu-Chou; Chen, Kuan-Yu; Huang, Ming-Shyan; Chen, Yuh-Min; Zheng, Hong; Li, Haixin; Cui, Ping; Guo, Huan; Xu, Ping; Liu, Li; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Park, Jae Yong; Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa; Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu; Kim, Hee Nam; Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young; Kim, Jin Hee; Oh, In-Jae; Kim, Young-Chul; Sung, Sook Whan; Kim, Jun Suk; Yoon, Ho-Il; Kweon, Sun-Seog; Shin, Min-Ho; Seow, Adeline; Chen, Ying; Lim, Wei-Yen; Liu, Jianjun; Wong, Maria Pik; Lee, Victor Ho Fun; Bassig, Bryan A; Tucker, Margaret; Berndt, Sonja I; Chow, Wong-Ho; Ji, Bu-Tian; Wang, Junwen; Xu, Jun; Sihoe, Alan Dart Loon; Ho, James C M; Chan, John K C; Wang, Jiu-Cun; Lu, Daru; Zhao, Xueying; Zhao, Zhenhong; Wu, Junjie; Chen, Hongyan; Jin, Li; Wei, Fusheng; Wu, Guoping; An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long; Gao, Yu-Tang; Xiang, Yong-Bing; He, Xingzhou; Li, Jihua; Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Klein, Robert; Pao, William; Lawrence, Charles; Hosgood, H Dean; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Ying-Hsiang; Chen, Chung-Hsing; Wang, Wen-Chang; Chen, Chih-Yi; Wang, Chih-Liang; Yu, Chong-Jen; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Li, Yao-Jen; Yang, Tsung-Ying; Lin, Chien-Chung; Yang, Pan-Chyr; Wu, Tangchun; Lin, Dongxin; Zhou, Baosen; Yu, Jinming; Shen, Hongbing; Kubo, Michiaki; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-02-01

    Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings. PMID:26732429

  3. Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

    Science.gov (United States)

    Nickels, Stefan; Truong, Thérèse; Hein, Rebecca; Stevens, Kristen; Buck, Katharina; Behrens, Sabine; Eilber, Ursula; Schmidt, Martina; Häberle, Lothar; Vrieling, Alina; Gaudet, Mia; Figueroa, Jonine; Schoof, Nils; Spurdle, Amanda B.; Rudolph, Anja; Fasching, Peter A.; Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.; Southey, Melissa C.; Beckmann, Matthias W.; Ekici, Arif B.; Fletcher, Olivia; Gibson, Lorna; dos Santos Silva, Isabel; Peto, Julian; Humphreys, Manjeet K.; Wang, Jean; Cordina-Duverger, Emilie; Menegaux, Florence; Nordestgaard, Børge G.; Bojesen, Stig E.; Lanng, Charlotte; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Clarke, Christina A.; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Brauch, Hiltrud; Brüning, Thomas; Harth, Volker; The GENICA Network; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; kConFab; Group, AOCS Management; Lambrechts, Diether; Smeets, Dominiek; Neven, Patrick; Paridaens, Robert; Flesch-Janys, Dieter; Obi, Nadia; Wang-Gohrke, Shan; Couch, Fergus J.; Olson, Janet E.; Vachon, Celine M.; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Offit, Kenneth; John, Esther M.; Miron, Alexander; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Chanock, Stephen J.; Lissowska, Jolanta; Liu, Jianjun; Cox, Angela; Cramp, Helen; Connley, Dan; Balasubramanian, Sabapathy; Dunning, Alison M.; Shah, Mitul; Trentham-Dietz, Amy; Newcomb, Polly; Titus, Linda; Egan, Kathleen; Cahoon, Elizabeth K.; Rajaraman, Preetha; Sigurdson, Alice J.; Doody, Michele M.; Guénel, Pascal; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Hall, Per; Easton, Doug F.; Garcia-Closas, Montserrat; Milne, Roger L.; Chang-Claude, Jenny

    2013-01-01

    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors

  4. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.

    Directory of Open Access Journals (Sweden)

    Stefan Nickels

    Full Text Available Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6 and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4. Overall, the per-allele odds ratio (95% confidence interval for LSP1-rs3817198 was 1.08 (1.01-1.16 in nulliparous women and ranged from 1.03 (0.96-1.10 in parous women with one birth to 1.26 (1.16-1.37 in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98 in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85 in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5, with a per-allele OR of 1.14 (1.11-1.17 in parous women and 0.98 (0.92-1.05 in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

  5. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    NARCIS (Netherlands)

    Lan, Q.; Hsiung, C.A.; Matsuo, K.; Hong, Y.C.; Seow, A.; Wang, Z.; Hosgood, H.D.; Chen, K.; Wang, J.C.; Chatterjee, N.; Hu, W.; Wong, M.P.; Zheng, W.; Caporaso, N.; Park, J.Y.; Chen, C.J.; Kim, Y.H.; Kim, Y.T.; Landi, M.T.; Shen, H.; Lawrence, C.; Burdett, L.; Yeager, M.; Yuenger, J.; Jacobs, K.B.; Chang, I.S.; Mitsudomi, T.; Kim, H.N.; Chang, G.C.; Bassig, B.A.; Tucker, M.; Wei, F.; Yin, Y.; Wu, C.; An, S.J.; Qian, B.; Lee, V.H.; Lu, D.; Liu, J.; Jeon, H.S.; Hsiao, C.F.; Sung, J.S.; Kim, J.H.; Gao, Y.T.; Tsai, Y.H.; Jung, Y.J.; Guo, H.; Hu, Z.; Hutchinson, A.; Wang, W.C.; Klein, R.; Chung, C.C.; Oh, I.J.; Chen, K.Y.; Berndt, S.I.; He, X.; Wu, W.; Chang, J.; Zhang, X.C.; Huang, M.S.; Zheng, H.; Wang, J.; Zhao, X.; Li, Y.; Choi, J.E.; Su, W.C.; Park, K.H.; Sung, S.W.; Shu, X.O.; Chen, Y.M.; Liu, L.; Kang, C.H.; Hu, L.; Chen, C.H.; Pao, W.; Kim, Y.C.; Yang, T.Y.; Xu, J.; Guan, P.; Tan, W.; Su, J.; Wang, C.L.; Li, H.; Sihoe, A.D.; Zhao, Z.; Chen, Y.; Choi, Y.Y.; Hung, J.Y.; Kim, J.S.; Yoon, H.I.; Cai, Q.; Lin, C.C.; Park, I.K.; Xu, P.; Dong, J.; Kim, C.; He, Q; Perng, R.P.; Kohno, T.; Kweon, S.S.; Chen, C.Y.; Vermeulen, R.; Wu, J.; Lim, W.Y.; Chen, K.C.; Chow, W.H.; Ji, B.T.; Chan, J.K.; Chu, M.; Li, Y.J.; Yokota, J.; Li, J.; Chen, H.; Xiang, Y.B.; Yu, C.J.; Kunitoh, H.; Wu, G.; Jin, L.; Lo, Y.L.; Shiraishi, K.; Chen, Y.H.; Lin, H.C.; Wu, T.; WU, Y.; Yang, P.C.; Zhou, B.; Shin, M.H.; Fraumeni, J.F.; Lin, D.; Chanock, S.J.; Rothman, N.

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland Ch

  6. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

    OpenAIRE

    Lan, Qing; Hsiung, Chao A.; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; PARK, JAE YONG

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three...

  7. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Benlloch, Sara; Antoniou, Antonis C;

    2015-01-01

    BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 2...

  8. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

    DEFF Research Database (Denmark)

    Rudolph, Anja; Milne, Roger L; Truong, Thérèse;

    2015-01-01

    A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estro...

  9. New basal cell carcinoma susceptibility loci

    Science.gov (United States)

    Stacey, Simon N.; Helgason, Hannes; Gudjonsson, Sigurjon A.; Thorleifsson, Gudmar; Zink, Florian; Sigurdsson, Asgeir; Kehr, Birte; Gudmundsson, Julius; Sulem, Patrick; Sigurgeirsson, Bardur; Benediktsdottir, Kristrun R.; Thorisdottir, Kristin; Ragnarsson, Rafn; Fuentelsaz, Victoria; Corredera, Cristina; Gilaberte, Yolanda; Grasa, Matilde; Planelles, Dolores; Sanmartin, Onofre; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Nexø, Bjørn A.; Tjønneland, Anne; Overvad, Kim; Jonasson, Jon G.; Tryggvadottir, Laufey; Johannsdottir, Hrefna; Kristinsdottir, Anna M.; Stefansson, Hreinn; Masson, Gisli; Magnusson, Olafur T.; Halldorsson, Bjarni V.; Kong, Augustine; Rafnar, Thorunn; Thorsteinsdottir, Unnur; Vogel, Ulla; Kumar, Rajiv; Nagore, Eduardo; Mayordomo, José I.; Gudbjartsson, Daniel F.; Olafsson, Jon H.; Stefansson, Kari

    2015-01-01

    In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10−12), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10−9), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10−12) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10−16). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained. PMID:25855136

  10. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R;

    2013-01-01

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS inc...

  11. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

    Science.gov (United States)

    Petersen, Gloria M.; Amundadottir, Laufey; Fuchs, Charles S.; Kraft, Peter; Stolzenberg-Solomon, Rachael Z.; Jacobs, Kevin B.; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Gallinger, Steven; Gross, Myron; Helzlsouer, Kathy; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P.; LaCroix, Andrea; Li, Donghui; Mandelson, Margaret T.; Olson, Sara H.; Risch, Harvey A.; Zheng, Wei; Albanes, Demetrius; Bamlet, William R.; Berg, Christine D.; Boutron-Ruault, Marie-Christine; Buring, Julie E.; Bracci, Paige M.; Canzian, Federico; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J.; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; Hallmans, Göran; Hankinson, Susan E.; Hassan, Manal; Howard, Barbara; Hunter, David J.; Hutchinson, Amy; Jenab, Mazda; Kaaks, Rudolf; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C.; Lynch, Shannon M.; McWilliams, Robert R.; Mendelsohn, Julie B.; Michaud, Dominique S.; Parikh, Hemang; Patel, Alpa V.; Peeters, Petra H.M.; Rajkovic, Aleksandar; Riboli, Elio; Rodriguez, Laudina; Seminara, Daniela; Shu, Xiao-Ou; Thomas, Gilles; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K.; Virtamo, Jarmo; Wactawski-Wende, Jean; Wang, Zhaoming; Wolpin, Brian M.; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Fraumeni, Joseph F.; Hoover, Robert N.; Hartge, Patricia; Chanock, Stephen J.

    2010-01-01

    We conducted a genome-wide association study (GWAS) of pancreatic cancer in 3,851 cases and 3,934 controls drawn from twelve prospective cohort studies and eight case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P=3.27×10−11; per allele odds ratio, OR 1.26, 95% CI=1.18-1.35) and rs9564966 (P=5.86×10−8; per allele OR 1.21, 95% CI=1.13-1.30) map to a non-genic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2; the strongest signal was rs3790844 (P=2.45×10−10; per allele OR 0.77, 95% CI=0.71-0.84). A single SNP, rs401681 (P=3.66×10−7; per allele OR 1.19, 95% CI=1.11-1.27) maps to the CLPTM1L-TERT locus on 5p15.33, associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies. PMID:20101243

  12. Genome-wide search for strabismus susceptibility loci.

    Directory of Open Access Journals (Sweden)

    Fujiwara H

    2003-06-01

    Full Text Available The purpose of this study was to search for chromosomal susceptibility loci for comitant strabismus. Genomic DNA was isolated from 10mL blood taken from each member of 30 nuclear families in which 2 or more siblings are affected by either esotropia or exotropia. A genome-wide search was performed with amplification by polymerase chain reaction of 400 markers in microsatellite regions with approximately 10 cM resolution. For each locus, non-parametric affected sib-pair analysis and non-parametric linkage analysis for multiple pedigrees (Genehunter software, http://linkage.rockefeller.edu/soft/ were used to calculate multipoint lod scores and non-parametric linkage (NPL scores, respectively. In sib-pair analysis, lod scores showed basically flat lines with several peaks of 0.25 on all chromosomes. In non-parametric linkage analysis for multiple pedigrees, NPL scores showed one peak as high as 1.34 on chromosomes 1, 2, 4, 7, 10, 15, and 16, while 2 such peaks were found on chromosomes 3, 9, 11, 12, 18, and 20. Non-parametric linkage analysis for multiple pedigrees of 30 families with comitant strabismus suggested a number of chromosomal susceptibility loci. Our ongoing study involving a larger number of families will refine the accuracy of statistical analysis to pinpoint susceptibility loci for comitant strabismus.

  13. Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations.

    Science.gov (United States)

    Mancikova, Veronika; Cruz, Raquel; Inglada-Pérez, Lucía; Fernández-Rozadilla, Ceres; Landa, Iñigo; Cameselle-Teijeiro, José; Celeiro, Catuxa; Pastor, Susana; Velázquez, Antonia; Marcos, Ricard; Andía, Victor; Álvarez-Escolá, Cristina; Meoro, Amparo; Schiavi, Francesca; Opocher, Giuseppe; Quintela, Inés; Ansede-Bermejo, Juan; Ruiz-Ponte, Clara; Santisteban, Pilar; Robledo, Mercedes; Carracedo, Angel

    2015-10-15

    Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease. PMID:25855579

  14. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

    Science.gov (United States)

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R.; Wiklund, Fredrik; Berndt, Sonja I.; Benlloch, Sara; Giles, Graham G.; Severi, Gianluca; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Hunter, David J.; Henderson, Brian E.; Thun, Michael J.; Gaziano, Michael; Giovannucci, Edward L.; Siddiq, Afshan; Travis, Ruth C.; Cox, David G.; Canzian, Federico; Riboli, Elio; Key, Timothy J.; Andriole, Gerald; Albanes, Demetrius; Hayes, Richard B.; Schleutker, Johanna; Auvinen, Anssi; Tammela, Teuvo L.J.; Weischer, Maren; Stanford, Janet L.; Ostrander, Elaine A.; Cybulski, Cezary; Lubinski, Jan; Thibodeau, Stephen N.; Schaid, Daniel J.; Sorensen, Karina D.; Batra, Jyotsna; Clements, Judith A.; Chambers, Suzanne; Aitken, Joanne; Gardiner, Robert A.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Brenner, Hermann; Habuchi, Tomonori; Ingles, Sue; John, Esther M.; Dickinson, Joanne L.; Cannon-Albright, Lisa; Teixeira, Manuel R.; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Park, Jong Y.; Cooney, Kathleen A.; Muir, Kenneth R.; Leongamornlert, Daniel A.; Saunders, Edward; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; Govindasami, Koveela; O'Brien, Lynne T.; Wilkinson, Rosemary A.; Hall, Amanda L.; Sawyer, Emma J.; Dadaev, Tokhir; Morrison, Jonathan; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin S.; Lophatonanon, Artitaya; Southey, Melissa C.; Hopper, John L.; English, Dallas; Virtamo, Jarmo; Le Marchand, Loic; Campa, Daniele; Kaaks, Rudolf; Lindstrom, Sara; Diver, W. Ryan; Gapstur, Susan; Yeager, Meredith; Cox, Angela; Stern, Mariana C.; Corral, Roman; Aly, Markus; Isaacs, William; Adolfsson, Jan; Xu, Jianfeng; Zheng, S. Lilly; Wahlfors, Tiina; Taari, Kimmo; Kujala, Paula; Klarskov, Peter; Nordestgaard, Børge G.; Røder, M. Andreas; Frikke-Schmidt, Ruth; Bojesen, Stig E.; FitzGerald, Liesel M.; Kolb, Suzanne; Kwon, Erika M.; Karyadi, Danielle M.; Orntoft, Torben Falck; Borre, Michael; Rinckleb, Antje; Luedeke, Manuel; Herkommer, Kathleen; Meyer, Andreas; Serth, Jürgen; Marthick, James R.; Patterson, Briony; Wokolorczyk, Dominika; Spurdle, Amanda; Lose, Felicity; McDonnell, Shannon K.; Joshi, Amit D.; Shahabi, Ahva; Pinto, Pedro; Santos, Joana; Ray, Ana; Sellers, Thomas A.; Lin, Hui-Yi; Stephenson, Robert A.; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Chanock, Stephen; Gronberg, Henrik; Haiman, Christopher A.; Kraft, Peter; Easton, Douglas F.; Eeles, Rosalind A.

    2013-01-01

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03–1.21), P = 1.4 × 10−8]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis. PMID:23065704

  15. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

    Science.gov (United States)

    Andlauer, Till F M; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A; Loleit, Verena; Luessi, Felix; Meuth, Sven G; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

    2016-06-01

    We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis. PMID:27386562

  16. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci.

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  17. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna;

    2013-01-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10...

  18. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

    Czech Academy of Sciences Publication Activity Database

    Tomlinson, I.P.M.; Webb, E.; Carvajal-Carmona, L.; Broderick, P.; Howarth, K.; Pittman, A.M.; Spain, S.; Lubbe, S.; Walter, A.; Sullivan, K.; Jaeger, E.; Fielding, S.; Rowan, A.; Vijayakrishnan, J.; Domingo, E.; Chandler, I.; Kemp, Z.; Qureshi, M.; Farrington, S.M.; Tenesa, A.; Prendergast, J.G.D.; Barnetson, R.A.; Penegar, S.; Barclay, E.; Wood, W.; Martin, L.; Gorman, M.; Thomas, H.; Peto, J.; Bishop, D.T.; Gray, R.; Maher, E.R.; Lucassen, A.; Kerr, D.; Evans, D.G.R.; Schafmayer, C.; Buch, S.; Völzke, H.; Hampe, J.; Schreber, S.; John, U.; Koessler, T.; Pharoah, P.; van Wezel, T.; Morreau, H.; Wijnen, J.T.; Hopper, J.L.; Southey, M.C.; Giles, G.G.; Severi, G.; Castellví-Bel, S.; Ruiz-Ponte, C.; Carracedo, A.; Castells, A.; Försti, A.; Hemminki, K.; Vodička, Pavel; Naccarati, Alessio; Lipton, L.; Ho, J.W.C.; Cheng, K.K.; Sham, P.C.; Luk, J.; Agúndez, J.A.G.; Ladero, J.M.; de la Hoya, M.; Caldés, T.; Niittymäki, I.; Tuupanene, S.; Karhu, A.; Aaltonen, L.; Cazier, J.B.; Campbell, H.; Dunlop, M.G.; Houlston, R.S.

    2008-01-01

    Roč. 40, č. 5 (2008), s. 623-630. ISSN 1061-4036 R&D Projects: GA ČR GA310/07/1430 Institutional research plan: CEZ:AV0Z50390703 Keywords : Colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 30.259, year: 2008

  19. Replication study for the association of seven genome- GWAS-identified Loci with susceptibility to ovarian cancer in the Polish population.

    Science.gov (United States)

    Mostowska, Adrianna; Sajdak, Stefan; Pawlik, Piotr; Markowska, Janina; Pawałowska, Monika; Lianeri, Margarita; Jagodzinski, Paweł P

    2015-04-01

    We investigated the previously-demonstrated association of seven genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs), including rs2072590 (HOXD-AS1), rs2665390 (TIPARP), rs10088218 and rs10098821 (8q24), rs3814113 (9p22), rs9303542 (SKAP1) and rs2363956 (ANKLE1), as risk factors of epithelial ovarian tumors (EOTs). These SNPs were genotyped in two hundred seventy three patients with EOTs and four hundred sixty four unrelated healthy females from the Polish population. We observed the lowest p values of the trend test for the 9p22 rs3814113 and 8q24 rs10098821 SNPs in patients with all subtypes of ovarian cancer (p(trend) = 0.010 and p(trend) = 0.014, respectively). There were also significant p values for the trend of the 9p22 rs3814113 and the 8q24 rs10098821 SNPs for serous histological subtypes of ovarian cancer (p(trend) = 0.006, p(trend) = 0.033, respectively). Moreover, stratification of the patients based on their histological type of cancer demonstrated, in the dominant hereditary model, a significant association of the 9p22 rs3814113 SNP with serous ovarian carcinoma OR = 0.532 (95% CI = 0.342 - 0.827, p = 0.005, p(corr) = 0.035). Despite the relatively small sample size of cases and controls, our studies confirmed some of the previously-demonstrated GWAS SNPs as genetic risk factors for EOTs. PMID:25173882

  20. Obesity susceptibility loci and dietary intake in the Look AHEAD trial

    Science.gov (United States)

    BACKGROUND: Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear. OBJECTIVE: The objective was to determine the association between obesity susceptibility loci and dietary intake. DESIGN: The association of GWAS-identifi...

  1. 11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer

    DEFF Research Database (Denmark)

    Lambrechts, Diether; Truong, Therese; Justenhoven, Christina;

    2012-01-01

    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we ge...

  2. Ancestral susceptibility to colorectal cancer

    Czech Academy of Sciences Publication Activity Database

    Huhn, S.; Pardini, Barbara; Naccarati, Alessio; Vodička, Pavel (ed.); Hemminki, K.; Försti, A.

    2012-01-01

    Roč. 27, č. 2 (2012), s. 197-204. ISSN 0267-8357 R&D Projects: GA ČR GA310/07/1430; GA ČR GAP304/10/1286 Grant ostatní: EU FP7(XE) HEALTH-F4-2007-200767 Institutional research plan: CEZ:AV0Z50390512 Keywords : cancer susceptibility * molecular epidemiology * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.500, year: 2012

  3. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

    OpenAIRE

    Petersen, Gloria M.; Amundadottir, Laufey; Fuchs, Charles S; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Jacobs, Kevin B.; Arslan, Alan A.; Bueno-de-Mesquita, H Bas; Gallinger, Steven; Gross, Myron; Helzlsouer, Kathy; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P; LaCroix, Andrea

    2010-01-01

    We conducted a genome-wide association study (GWAS) of pancreatic cancer in 3,851 cases and 3,934 controls drawn from twelve prospective cohort studies and eight case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P=3.27×10−11; per allele odds ra...

  4. Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

    OpenAIRE

    Chung, Sharon A.; Brown, Elizabeth E; Williams, Adrienne H; Ramos, Paula S.; Berthier, Celine C.; Bhangale, Tushar; Alarcon-Riquelme, Marta E; Behrens, Timothy W.; Criswell, Lindsey A.; Graham, Deborah Cunninghame; Demirci, F. Yesim; Jeffrey C Edberg; Gaffney, Patrick M.; Harley, John B.; Jacob, Chaim O.

    2014-01-01

    Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis–predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis...

  5. Obesity susceptibility loci and uncontrolled eating, emotional eating and cognitive restraint behaviors in men and women

    OpenAIRE

    Cornelis, Marilyn C.; Rimm, Eric B.; Curhan, Gary C.; Kraft, Peter; Hunter, David J; Hu, Frank B; van Dam, Rob M

    2013-01-01

    Objective: Many confirmed genetic loci for obesity are expressed in regions of the brain that regulate energy intake and reward-seeking behavior. Whether these loci contribute to the development of specific eating behaviors has not been investigated. We examined the relationship between a genetic susceptibility to obesity and cognitive restraint, uncontrolled and emotional eating. Design and Methods Eating behavior and body mass index (BMI) were determined by questionnaires for 1471 men and 2...

  6. Obesity genomics: assessing the transferability of susceptibility loci across diverse populations.

    Science.gov (United States)

    Lu, Yingchang; Loos, Ruth Jf

    2013-01-01

    The prevalence of obesity has nearly doubled worldwide over the past three decades, but substantial differences exist between nations. Although these differences are partly due to the degree of westernization, genetic factors also contribute. To date, little is known about whether the same genes contribute to obesity-susceptibility in populations of different ancestry. We review the transferability of obesity-susceptibility loci (identified by genome-wide association studies) using both single nucleotide polymorphism (SNP) and locus-wide comparisons. SNPs in FTO and near MC4R, obesity-susceptibility loci first identified in Europeans, replicate widely across other ancestries. SNP-to-SNP comparisons suggest that more than half of the 36 body mass index-associated loci are shared across European and East Asian ancestry populations, whereas locus-wide analyses suggest that the transferability might be even more extensive. Furthermore, by taking advantage of differences in haplotype structure, populations of different ancestries can help to narrow down loci, thereby pinpointing causal genes for functional follow-up. Larger-scale genetic association studies in ancestrally diverse populations will be needed for in-depth and locus-wide analyses aimed at determining, with greater confidence, the transferability of loci and allowing fine-mapping. Understanding similarities and differences in genetic susceptibility across populations of diverse ancestries might eventually contribute to a more targeted prevention and customized treatment of obesity. PMID:23806069

  7. Mechanisms of inherited cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    Shirley HODGSON

    2008-01-01

    A small proportion of many cancers are due to inherited mutations in genes, which result in a high risk to the individual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes, oncogenes, genes encoding proteins involved in DNA repair and cell cycle control, and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.

  8. Novel genetic loci associated with prostate cancer in the Japanese population

    Institute of Scientific and Technical Information of China (English)

    Yin Sun; Jiaoti Huang

    2011-01-01

    @@ Takata et al.1 recently reported in Nature Genetics that they have identified five nove associated with prostate cancer in the Japanese population.Using most updated Illumina Quad BeadChip to genotype 3001 prostate cancer patients and 5415 control subjects,they identified263 single-nucleotide polymorphisms(SNPs)showing significant association with prostate cancer in Japan.Further analysis indicated that 80 SNPs reside in the previously known regions,and five of them are novel susceptibility loci associated with the prostate cancer.

  9. Genetic susceptibility to cancer

    International Nuclear Information System (INIS)

    The normal development and function of tissues are under the regulation of programmed expression of genes involved in the proliferation and differentiation. Tumor development can be identified as the abnormal or deregulated expression of such genes. Two distinct classes of genes have been implicated in cancer development; oncogenes and tumor-suppressor genes. Those genes are potential target for radiation carcinogenesis. However, contemporal view of mutations of oncogenes and tumor-suppressor genes in radiogenic and non-radiogenic human cancers do not match to the spectrum of radiation-induced mutation in the selected genes, and raise the question whether radiations are primarily responsible for the initiation of carcinogenesis by mutation of those genes as primary target. There is now a growing evidence for the radiation to stimulate cell growth, which is followed by suppression. Such stimulatory effects of radiation may evoke the growth-promoting and -suppressing genes, or oncogenes and tumor-suppressor genes. This may lead to a testable proposition that constitutively present gain-of-function mutations in oncogenes and/or loss-of-function mutations in tumor-suppressor genes, accumulated spontaneously or environmentally, may play a significant role in the radiation carcinogenesis. (author)

  10. Susceptibility loci revealed for bovine respiratory disease complex in pre-weaned holstein calves

    OpenAIRE

    Neibergs, Holly L.; Seabury, Christopher M.; Wojtowicz, Andrzej J.; Wang, Zeping; Scraggs, Erik; Kiser, Jennifer N; Neupane, Mahesh; Womack, James E.; Van Eenennaam, Alison; Hagevoort, Gerald Robert; Lehenbauer, Terry W.; Aly, Sharif; Davis, Jessica; Taylor, Jeremy F; ,

    2014-01-01

    Background Bovine respiratory disease complex (BRDC) is an infectious disease of cattle that is caused by a combination of viral and/or bacterial pathogens. Selection for cattle with reduced susceptibility to respiratory disease would provide a permanent tool for reducing the prevalence of BRDC. The objective of this study was to identify BRDC susceptibility loci in pre-weaned Holstein calves as a prerequisite to using genetic improvement as a tool for decreasing the prevalence of BRDC. High ...

  11. Sequencing-based approach identified three new susceptibility loci for psoriasis.

    Science.gov (United States)

    Sheng, Yujun; Jin, Xin; Xu, Jinhua; Gao, Jinping; Du, Xiaoqing; Duan, Dawei; Li, Bing; Zhao, Jinhua; Zhan, Wenying; Tang, Huayang; Tang, Xianfa; Li, Yang; Cheng, Hui; Zuo, Xianbo; Mei, Junpu; Zhou, Fusheng; Liang, Bo; Chen, Gang; Shen, Changbing; Cui, Hongzhou; Zhang, Xiaoguang; Zhang, Change; Wang, Wenjun; Zheng, Xiaodong; Fan, Xing; Wang, Zaixing; Xiao, Fengli; Cui, Yong; Li, Yingrui; Wang, Jun; Yang, Sen; Xu, Lei; Sun, Liangdan; Zhang, Xuejun

    2014-01-01

    In a previous large-scale exome sequencing analysis for psoriasis, we discovered seven common and low-frequency missense variants within six genes with genome-wide significance. Here we describe an in-depth analysis of noncoding variants based on sequencing data (10,727 cases and 10,582 controls) with replication in an independent cohort of Han Chinese individuals consisting of 4,480 cases and 6,521 controls to identify additional psoriasis susceptibility loci. We confirmed four known psoriasis susceptibility loci (IL12B, IFIH1, ERAP1 and RNF114; 2.30 × 10(-20)≤P≤2.41 × 10(-7)) and identified three new susceptibility loci: 4q24 (NFKB1) at rs1020760 (P=2.19 × 10(-8)), 12p13.3 (CD27-LAG3) at rs758739 (P=4.08 × 10(-8)) and 17q12 (IKZF3) at rs10852936 (P=1.96 × 10(-8)). Two suggestive loci, 3p21.31 and 17q25, are also identified with P<1.00 × 10(-6). The results of this study increase the number of confirmed psoriasis risk loci and provide novel insight into the pathogenesis of psoriasis. PMID:25006012

  12. Obesity susceptibility loci and dietary intake in the Look AHEAD trial

    Science.gov (United States)

    Genome-wide association studies (GWAS) have identified consistent associations with obesity. However, the mechanisms remain unclear. The objective was to determine the association between obesity susceptibility loci and dietary intake. The association of GWAS-identified obesity risk alleles (FTO, MC...

  13. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

    NARCIS (Netherlands)

    Tsoi, Lam C.; Spain, Sarah L.; Knight, Jo; Ellinghaus, Eva; Stuart, Philip E.; Capon, Francesca; Ding, Jun; Li, Yanming; Tejasvi, Trilokraj; Gudjonsson, Johann E.; Kang, Hyun M.; Allen, Michael H.; McManus, Ross; Novelli, Giuseppe; Samuelsson, Lena; Schalkwijk, Joost; Stahle, Mona; Burden, A. David; Smith, Catherine H.; Cork, Michael J.; Estivill, Xavier; Bowcock, Anne M.; Krueger, Gerald G.; Weger, Wolfgang; Worthington, Jane; Tazi-Ahnini, Rachid; Nestle, Frank O.; Hayday, Adrian; Hoffmann, Per; Winkelmann, Juliane; Wijmenga, Cisca; Langford, Cordelia; Edkins, Sarah; Andrews, Robert; Blackburn, Hannah; Strange, Amy; Band, Gavin; Pearson, Richard D.; Vukcevic, Damjan; Spencer, Chris C. A.; Deloukas, Panos; Mrowietz, Ulrich; Schreiber, Stefan; Weidinger, Stephan; Koks, Sulev; Kingo, Kuelli; Esko, Tonu; Metspalu, Andres; Lim, Henry W.; Voorhees, John J.; Weichenthal, Michael; Wichmann, H. Erich; Chandran, Vinod; Rosen, Cheryl F.; Rahman, Proton; Gladman, Dafna D.; Griffiths, Christopher E. M.; Reis, Andre; Kere, Juha; Nair, Rajan P.; Franke, Andre; Barker, Jonathan N. W. N.; Abecasis, Goncalo R.; Elder, James T.; Trembath, Richard C.; Duffin, Kristina Callis; Helms, Cindy; Goldgar, David; Li, Yun; Paschall, Justin; Malloy, Mary J.; Pullinger, Clive R.; Kane, John P.; Gardner, Jennifer; Perlmutter, Amy; Miner, Andrew; Feng, Bing Jian; Hiremagalore, Ravi; Ike, Robert W.; Christophers, Enno; Henseler, Tilo; Ruether, Andreas; Schrodi, Steven J.; Prahalad, Sampath; Guthery, Stephen L.; Fischer, Judith; Liao, Wilson; Kwok, Pui; Menter, Alan; Lathrop, G. Mark; Wise, C.; Begovich, Ann B.; Onoufriadis, Alexandros; Weale, Michael E.; Hofer, Angelika; Salmhofer, Wolfgang; Wolf, Peter; Kainu, Kati; Saarialho-Kere, Ulpu; Suomela, Sari; Badorf, Petra; Hueffmeier, Ulrike; Kurrat, Werner; Kuester, Wolfgang; Lascorz, Jesus; Moessner, Rotraut; Schuermeier-Horst, Funda; Staender, Markward; Traupe, Heiko; Bergboer, Judith G. M.; den Heijer, Martin; van de Kerkhof, Peter C.; Zeeuwen, Patrick L. J. M.; Barnes, Louise; Campbell, Linda E.; Cusack, Caitriona; Coleman, Ciara; Conroy, Judith; Ennis, Sean; Fitzgerald, Oliver; Gallagher, Phil; Irvine, Alan D.; Kirby, Brian; Markham, Trevor; McLean, W. H. Irwin; McPartlin, Joe; Rogers, Sarah F.; Ryan, Anthony W.; Zawirska, Agnieszka; Giardina, Emiliano; Lepre, Tiziana; Perricone, Carlo; Martin-Ezquerra, Gemma; Pujol, Ramon M.; Riveira-Munoz, Eva; Inerot, Annica; Naluai, Asa T.; Mallbris, Lotus; Wolk, Katarina; Leman, Joyce; Barton, Anne; Warren, Richard B.; Young, Helen S.; Ricaño Ponce, Isis; Trynka, Gosia; Pellett, Fawnda J.; Henschel, Andrew; Aurand, Marin; Bebo, Bruce; Gieger, Christian; Illig, Thomas; Moebus, Susanne; Joeckel, Karl-Heinz; Erbe, Raimund; Donnelly, Peter; Peltonen, Leena; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Craddock, Nicholas; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; McCarthy, Mark I.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Samani, Nilesh; Viswanathan, Ananth C.; Wood, Nicholas W.; Bellenguez, Celine; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Su, Zhan; Hunt, Sarah E.; Gwilliam, Rhian; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Perez, Marc L.; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela

    2012-01-01

    To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36

  14. Investigation of four novel male androgenetic alopecia susceptibility loci: no association with female pattern hair loss.

    Science.gov (United States)

    Nuwaihyd, Rima; Redler, Silke; Heilmann, Stefanie; Drichel, Dmitriy; Wolf, Sabrina; Birch, Pattie; Dobson, Kathy; Lutz, Gerhard; Giehl, Kathrin A; Kruse, Roland; Tazi-Ahnini, Rachid; Hanneken, Sandra; Böhm, Markus; Miesel, Anja; Fischer, Tobias; Wolff, Hans; Becker, Tim; Garcia-Bartels, Natalie; Blume-Peytavi, Ulrike; Nöthen, Markus M; Messenger, Andrew G; Betz, Regina C

    2014-05-01

    Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL. PMID:24352509

  15. Ovarian Cancer in Hereditary Cancer Susceptibility Syndromes.

    Science.gov (United States)

    Nakonechny, Quentin B; Gilks, C Blake

    2016-06-01

    Hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are associated with increased risk of developing ovarian carcinoma. Patients with HBOC have a lifetime risk of up to 50% of developing high-grade serous carcinoma of tube or ovary; patients with LS have a 10% lifetime risk of developing endometrioid or clear cell carcinoma of the ovary. Testing all patients with tubo-ovarian high-grade serous carcinoma for mutations associated with HBOC syndrome, and all patients presenting with endometrioid or clear cell carcinoma of the ovary for mutations associated with LS can identify patients with undiagnosed underlying hereditary cancer susceptibility syndromes. PMID:27241103

  16. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

    OpenAIRE

    Reveille, John D.; Sims, Anne-Marie; Danoy, Patrick; Evans, David M; Leo, Paul; Pointon, Jennifer J.; Jin, Rui; Zhou, Xiaodong; Bradbury, Linda A.; Appleton, Louise H; Davis, John C.; Diekman, Laura; Doan, Tracey; Dowling, Alison; Duan, Ran

    2010-01-01

    To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found associa...

  17. Association analyses identify six new psoriasis susceptibility loci in the Chinese population

    OpenAIRE

    Sun, Liang-Dan; Cheng, Hui; Wang, Zai-Xing; Zhang, An-Ping; Wang, Pei-Guang; Xu, Jin-Hua; Zhu, Qi-Xing; Zhou, Hai-Sheng; Buchert, Eva; Zhang, Fu-Ren; Pu, Xiong-Ming; Yang, Xue-Qin; Zhang, Jian-Zhong; Xu, Ai-E; Wu, Ri-Na

    2010-01-01

    We extended our previous GWAS for psoriasis with a a multistage replication study including 8,312 cases and 12,919 controls from China as well as 3,293 cases, 4,188 controls from Germany and the USA, and 254 nuclear families from the USA. We identified 6 new susceptibility loci associated to psoriasis in Chinese, containing candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A (PCombined

  18. Whole-genome association studies of alcoholism with loci linked to schizophrenia susceptibility

    OpenAIRE

    Kim Youngchul; Namkung Junghyun; Park Taesung

    2005-01-01

    Abstract Background Alcoholism is a complex disease. There have been many reports on significant comorbidity between alcoholism and schizophrenia. For the genetic study of complex diseases, association analysis has been recommended because of its higher power than that of the linkage analysis for detecting genes with modest effects on disease. Results To identify alcoholism susceptibility loci, we performed genome-wide single-nucleotide polymorphisms (SNP) association tests, which yielded 489...

  19. Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases

    NARCIS (Netherlands)

    Li, R.; Brockschmidt, F.F.; Kiefer, A.K.; Stefansson, H.; Nyholt, D.R.; Song, K.; Vermeulen, S.; Kanoni, S.; Glass, D.; Medland, S.E.; Dimitriou, M.; Waterworth, D.; Tung, J.Y.; Geller, F.; Heilmann, S.; Hillmer, A.M.; Bataille, V.; Eigelshoven, S.; Hanneken, S.; Moebus, S.; Herold, C.; Heijer, M. den; Montgomery, G.W.; Deloukas, P.; Eriksson, N.; Heath, A.C.; Becker, T.; Sulem, P.; Mangino, M.; Vollenweider, P.; Spector, T.D.; Dedoussis, G.; Martin, N.G.; Kiemeney, L.A.; Mooser, V.; Stefansson, K.; Hinds, D.A.; Nothen, M.M.; Richards, J.B.

    2012-01-01

    Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven g

  20. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    OpenAIRE

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wid...

  1. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    OpenAIRE

    Garcia-Closas, Montserrat; Couch, Fergus J.; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K.; Brook, Mark N.; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E.; Eccles, Diana; Miron, Penelope; Fasching, Peter A.

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast can...

  2. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B;

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and.......5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry....

  3. SUSCEPTIBILITY LOCI FOR UMBILICAL HERNIA IN SWINE DETECTED BY GENOME-WIDE ASSOCIATION.

    Science.gov (United States)

    Liao, X J; Lia, L; Zhang, Z Y; Long, Y; Yang, B; Ruan, G R; Su, Y; Ai, H S; Zhang, W C; Deng, W Y; Xiao, S J; Ren, J; Ding, N S; Huang, L S

    2015-10-01

    Umbilical hernia (UH) is a complex disorder caused by both genetic and environmental factors. UH brings animal welfare problems and severe economic loss to the pig industry. Until now, the genetic basis of UH is poorly understood. The high-density 60K porcine SNP array enables the rapid application of genome-wide association study (GWAS) to identify genetic loci for phenotypic traits at genome wide scale in pigs. The objective of this research was to identify susceptibility loci for swine umbilical hernia using the GWAS approach. We genotyped 478 piglets from 142 families representing three Western commercial breeds with the Illumina PorcineSNP60 BeadChip. Then significant SNPs were detected by GWAS using ROADTRIPS (Robust Association-Detection Test for Related Individuals with Population Substructure) software base on a Bonferroni corrected threshold (P = 1.67E-06) or suggestive threshold (P = 3.34E-05) and false discovery rate (FDR = 0.05). After quality control, 29,924 qualified SNPs and 472 piglets were used for GWAS. Two suggestive loci predisposing to pig UH were identified at 44.25MB on SSC2 (rs81358018, P = 3.34E-06, FDR = 0.049933) and at 45.90MB on SSC17 (rs81479278, P = 3.30E-06, FDR = 0.049933) in Duroc population, respectively. And no SNP was detected to be associated with pig UH at significant level in neither Landrace nor Large White population. Furthermore, we carried out a meta-analysis in the combined pure-breed population containing all the 472 piglets. rs81479278 (P = 1.16E-06, FDR = 0.022475) was identified to associate with pig UH at genome-wide significant level. SRC was characterized as plausible candidate gene for susceptibility to pig UH according to its genomic position and biological functions. To our knowledge, this study gives the first description of GWAS identifying susceptibility loci for umbilical hernia in pigs. Our findings provide deeper insights to the genetic architecture of umbilical hernia in pigs. PMID:27169231

  4. AN EPIDEMIOLOGY AND MOLECULAR GENETIC STUDY ON BREAST CANCER SUSCEPTIBILITY

    Institute of Scientific and Technical Information of China (English)

    贾卫华; 王继先; 李本孝; 李征

    2000-01-01

    Objectives. To investigate the genetic susceptibility for breast cancer of Chinese, a hospital-based case-control study, pedigree survey and molecular genetic study were conducted. Methods. Logistic regression model and stratification methods were used in the risk factors analysis. Li-Mantel art and Falconer methods were used to analyze the segregation ratio and heritability. Polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis were used to detect AI, G-banding technique was used to detect the chromosome aberration of peripheral blood lymphocyte. Results. Family history of breast cancer is related to enhanced breast cancer risk significartly, OR is 3.905 ( 95 % CI = 1.079 ~ 14.13), and it widely interacts with other risk factors. Accumulative incidence of breast cancer in first degree relatives is 9.99%, which is larger than that in second, third degree and non-blood relatives. Segregation ratio is 0.021, heritability among first degree relatives is 35.6 ± 5.8%. Frequencies of LOH at BRCA1 and BRCA2 loci in sporadic breast cancer are 6.12% and 5.77% respectively. In the sibs, both of them show LOH at D13S173 locus, and high frequencies of chromosome aberrations were observed. Conclusions. Genetic susceptibility contributes to breast cancer occurrence of Chinese, and its racial variation may be one of the important reasons for the large difference of incidence between western and eastern countries.

  5. AN EPIDEMIOLOGY AND MOLECULAR GENETIC STUDY ON BREAST CANCER SUSCEPTIBILITY

    Institute of Scientific and Technical Information of China (English)

    贾卫华; 王继先; 李本孝; 李征

    2000-01-01

    Obieaites. To investigate the genetic susceptibility for breast cancer of Chinese, a hospital-besed case-control study, pedigree survey and molecular genetic study were conducted. Methods. Logistic regression model and stratification methods were used in the risk factors analysis. Li-Mantel-Gart and Falconer methods were used to analyze the segregation ratio and heritability. Polymemse chain reaction (PCR) and polyacrylamide gel electrophoresis were used to detect AI, G-banding technique was used to detect the chromosome aberration of peripheral blood lymphocyte. Results. Family history of breast cancer is related to enhanced breast cancer risk significantly, OR is 3.905(95% CI = 1.079—14.13), and it widely interacts with other risk factors. Accumulative incidence of breast cancer in first degree relatives is 9.99%, which is larger than that in second, third degree and non-blnod relatives. Segregation ratio is 0.021, heritability among first degree relatives is 35.6 ± 5.8%. Frequencies of LDH at BRCA1 and BRCA2 loci in sporadic breast cancer are 6.12% and 5.77% respectively. In the sibs, both of them show LOH at D13S173 locus, and high frequencies of chromosome abermtions were observed.Condusions. Genetic susceptibility contributes to breast cancer occurrence of Chinese, and its racial variation may be one of the important reasons for the large difference of incidence between western and eastern countries.

  6. Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer

    DEFF Research Database (Denmark)

    Song, H.; Koessler, T.; Ahmed, S.; Ramus, S.J.; Kjaer, S.K.; DiCioccio, R.A.; Wozniak, E.; Whittemore, A.S.; McGuire, V.; Ponder, B.A.; Turnbull, C.; Hines, S.; Rahman, N.; Eeles, R.A.; Easton, D.F.; Gayther, S.A.; Dunning, A.M.; Pharoah, P.D.; Høgdall, Estrid Vilma Solyom

    2008-01-01

    Several prostate cancer susceptibility loci have recently been identified by genome-wide association studies. These loci are candidates for susceptibility to other epithelial cancers. The aim of this study was to test these tag single nucleotide polymorphisms (SNP) for association with invasive...... ovarian, colorectal, and breast cancer. Twelve prostate cancer-associated tag SNPs were genotyped in ovarian (2,087 cases/3,491 controls), colorectal (2,148 cases/2,265 controls) and breast (first set, 4,339 cases/4,552 controls; second set, 3,800 cases/3,995 controls) case-control studies. The primary...... cancer [per minor allele OR, 1.19; 95% confidence interval (95% CI), 1.04-1.37; P(trend) = 0.012]. This association was stronger for the serous histologic subtype (OR, 1.29; 95% CI, 1.09-1.53; P = 0.003). SNP rs7931342 (chromosome 11q13) showed some evidence of association with breast cancer (per minor...

  7. Genetic Susceptibility to Pancreatic Cancer

    OpenAIRE

    Klein, Alison P

    2012-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. However, it has the poorest prognosis of any major tumor type, with a 5-yr survival rate of approximately 5%. Cigarette smoking, increased body mass index, heavy alcohol consumption, and a diagnosis of diabetes mellitus have all been demonstrated to increase risk of pancreatic cancer. A family history of pancreatic cancer has also been associated with increased risk suggesting inherited g...

  8. Breast Cancer Susceptibility Gene1 (BRCA1

    Directory of Open Access Journals (Sweden)

    Wasiksiri, S.

    2002-07-01

    Full Text Available Breast Cancer Susceptibility Gene1 (BRCA1 is a tumor suppressor gene for breast and ovarian cancers. The gene locates at chromosome 17q21 and encodes for 1863 amino acids protein. It is believed that BRCA1 protein is involved in many functions such as DNA repair, centrosome replication, cell cycle checkpoint and replication of other genes. More than 800 mutations have been found in the population with an increased risk of cancer incidence in their families. Germ-line mutation of BRCA1 accounts for 5-10 percent of all breast cancer cases. Epigenetic modifications also reduce the function of normal BRCA1 gene. Several methods are used for laboratory diagnosis of cancer-related mutations. The development of breast cancer in carriers at risk with BRCA1 mutations may be prevented by suitable prevention plans such as breast cancer screening, ovarian cancer screening, surgery and cancer chemotherapy.

  9. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

    NARCIS (Netherlands)

    Strange, A.; Capon, F.; Spencer, C.C.; Knight, J.; Weale, M.E.; Allen, M.H.; Barton, A.; Band, G.; Bellenguez, C.; Bergboer, J.G.M.; Blackwell, J.M.; Bramon, E.; Bumpstead, S.J.; Casas, J.P.; Cork, M.J.; Corvin, A.; Deloukas, P.; Dilthey, A.; Duncanson, A.; Edkins, S.; Estivill, X.; Fitzgerald, O.; Freeman, C.; Giardina, E.; Gray, E.; Hofer, A.; Huffmeier, U.; Hunt, S.E.; Irvine, A.D.; Jankowski, J.; Kirby, B.; Langford, C.; Lascorz, J.; Leman, J.; Leslie, S.; Mallbris, L.; Markus, H.S.; Mathew, C.G.; McLean, W.H.I.; McManus, R.; Mossner, R.; Moutsianas, L.; Naluai, A.T.; Nestle, F.O.; Novelli, G.; Onoufriadis, A.; Palmer, C.N.; Perricone, C.; Pirinen, M.; Plomin, R.; Potter, S.C.; Pujol, R.M.; Rautanen, A.; Riveira-Munoz, E.; Ryan, A.W.; Salmhofer, W.; Samuelsson, L.; Sawcer, S.J.; Schalkwijk, J.; Smith, C.H.; Stahle, M.; Su, Z.; Tazi-Ahnini, R.; Traupe, H.; Viswanathan, A.C.; Warren, R.B.; Weger, W.; Wolk, K.; Wood, N.; Worthington, J.; Young, H.S.; Zeeuwen, P.L.J.M.; Hayday, A.; Burden, A.D.; Griffiths, C.E.; Kere, J.; Reis, A.; McVean, G.; Evans, D.M.; Brown, M.A.; Barker, J.N.; Peltonen, L.; Donnelly, P.; Trembath, R.C.

    2010-01-01

    To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (

  10. Characterization of population-based variation and putative functional elements for the multiple-cancer susceptibility loci at 5p15.33 [v1; ref status: indexed, http://f1000r.es/49o

    Directory of Open Access Journals (Sweden)

    Lisa Mirabello

    2014-10-01

    Full Text Available Background: TERT encodes the telomerase reverse transcriptase, which is responsible for maintaining telomere ends by addition of (TTAGGGn nucleotide repeats at the telomere.  Recent genome-wide association studies have found common genetic variants at the TERT-CLPTM1L locus (5p15.33 associated with an increased risk of several cancers.  Results: Data were acquired for 1627 variants in 1092 unrelated individuals from 14 populations within the 1000 Genomes Project.  We assessed the population genetics of the 5p15.33 region, including recombination hotspots, diversity, heterozygosity, differentiation among populations, and potential functional impacts. There were significantly lower polymorphism rates, divergence, and heterozygosity for the coding variants, particularly for non-synonymous sites, compared with non-coding and silent changes. Many of the cancer-associated SNPs had differing genotype frequencies among ancestral groups and were associated with potential regulatory changes.  Conclusions: Surrogate SNPs in linkage disequilibrium with the majority of cancer-associated SNPs were functional variants with a likely role in regulation of TERT and/or CLPTM1L.  Our findings highlight several SNPs that future studies should prioritize for evaluation of functional consequences.

  11. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk

    Science.gov (United States)

    Lindström, Sara; Thompson, Deborah J.; Paterson, Andrew D.; Li, Jingmei; Gierach, Gretchen L.; Scott, Christopher; Stone, Jennifer; Douglas, Julie A.; dos-Santos-Silva, Isabel; Fernandez-Navarro, Pablo; Verghase, Jajini; Smith, Paula; Brown, Judith; Luben, Robert; Wareham, Nicholas J.; Loos, Ruth J.F.; Heit, John A.; Pankratz, V. Shane; Norman, Aaron; Goode, Ellen L.; Cunningham, Julie M.; deAndrade, Mariza; Vierkant, Robert A.; Czene, Kamila; Fasching, Peter A.; Baglietto, Laura; Southey, Melissa C.; Giles, Graham G.; Shah, Kaanan P.; Chan, Heang-Ping; Helvie, Mark A.; Beck, Andrew H.; Knoblauch, Nicholas W.; Hazra, Aditi; Hunter, David J.; Kraft, Peter; Pollan, Marina; Figueroa, Jonine D.; Couch, Fergus J.; Hopper, John L.; Hall, Per; Easton, Douglas F.; Boyd, Norman F.; Vachon, Celine M.; Tamimi, Rulla M.

    2015-01-01

    Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci. PMID:25342443

  12. Replication Study for the Association of 9 East Asian GWAS-Derived Loci with Susceptibility to Type 2 Diabetes in a Japanese Population

    OpenAIRE

    Kensuke Sakai; Minako Imamura; Yasushi Tanaka; Minoru Iwata; Hiroshi Hirose; Kohei Kaku; Hiroshi Maegawa; Hirotaka Watada; Kazuyuki Tobe; Atsunori Kashiwagi; Ryuzo Kawamori; Shiro Maeda

    2013-01-01

    AIMS: East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. METHODS: We genotyped 7,379 Japanese pa...

  13. Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population.

    Directory of Open Access Journals (Sweden)

    Nicola Glorioso

    Full Text Available Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004 and D11S1346 (at 10.6 Mb, P = 0.00000004, suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR, and adrenomedullin (ADM are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]. For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]. Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension.

  14. Polygenic susceptibility to breast cancer: current state-of-the-art

    Science.gov (United States)

    Ghoussaini, Maya; Pharoah, Paul DP

    2016-01-01

    Breast cancer is the most commonly occurring invasive cancer among women and its estimated incidence rate worldwide is approximately 1 million cases annually. Although several breast cancer susceptibility genes have been identified over the past two decades, it is likely that many genes with modest effects are yet to be found. In this review, we discuss the progress that has been recently made with the emergence of empirical genome-wide association studies for breast cancer and the identification of several common, low-penetrance disease alleles at loci that had not been previously implicated as candidates for breast cancer susceptibility. We also discuss the implications of these recent findings for risk prediction, targeted screening and public health interventions, and conclude by discussing the strengths and weaknesses of these studies, and the strategies required to identify additional risk factors for breast cancer. PMID:19519208

  15. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

    Science.gov (United States)

    Beecham, Ashley H; Patsopoulos, Nikolaos A; Xifara, Dionysia K; Davis, Mary F; Kemppinen, Anu; Cotsapas, Chris; Shahi, Tejas S; Spencer, Chris; Booth, David; Goris, An; Oturai, Annette; Saarela, Janna; Fontaine, Bertrand; Hemmer, Bernhard; Martin, Claes; Zipp, Frauke; D’alfonso, Sandra; Martinelli-Boneschi, Filippo; Taylor, Bruce; Harbo, Hanne F; Kockum, Ingrid; Hillert, Jan; Olsson, Tomas; Ban, Maria; Oksenberg, Jorge R; Hintzen, Rogier; Barcellos, Lisa F; Agliardi, Cristina; Alfredsson, Lars; Alizadeh, Mehdi; Anderson, Carl; Andrews, Robert; Søndergaard, Helle Bach; Baker, Amie; Band, Gavin; Baranzini, Sergio E; Barizzone, Nadia; Barrett, Jeffrey; Bellenguez, Céline; Bergamaschi, Laura; Bernardinelli, Luisa; Berthele, Achim; Biberacher, Viola; Binder, Thomas M C; Blackburn, Hannah; Bomfim, Izaura L; Brambilla, Paola; Broadley, Simon; Brochet, Bruno; Brundin, Lou; Buck, Dorothea; Butzkueven, Helmut; Caillier, Stacy J; Camu, William; Carpentier, Wassila; Cavalla, Paola; Celius, Elisabeth G; Coman, Irène; Comi, Giancarlo; Corrado, Lucia; Cosemans, Leentje; Cournu-Rebeix, Isabelle; Cree, Bruce A C; Cusi, Daniele; Damotte, Vincent; Defer, Gilles; Delgado, Silvia R; Deloukas, Panos; di Sapio, Alessia; Dilthey, Alexander T; Donnelly, Peter; Dubois, Bénédicte; Duddy, Martin; Edkins, Sarah; Elovaara, Irina; Esposito, Federica; Evangelou, Nikos; Fiddes, Barnaby; Field, Judith; Franke, Andre; Freeman, Colin; Frohlich, Irene Y; Galimberti, Daniela; Gieger, Christian; Gourraud, Pierre-Antoine; Graetz, Christiane; Graham, Andrew; Grummel, Verena; Guaschino, Clara; Hadjixenofontos, Athena; Hakonarson, Hakon; Halfpenny, Christopher; Hall, Gillian; Hall, Per; Hamsten, Anders; Harley, James; Harrower, Timothy; Hawkins, Clive; Hellenthal, Garrett; Hillier, Charles; Hobart, Jeremy; Hoshi, Muni; Hunt, Sarah E; Jagodic, Maja; Jelčić, Ilijas; Jochim, Angela; Kendall, Brian; Kermode, Allan; Kilpatrick, Trevor; Koivisto, Keijo; Konidari, Ioanna; Korn, Thomas; Kronsbein, Helena; Langford, Cordelia; Larsson, Malin; Lathrop, Mark; Lebrun-Frenay, Christine; Lechner-Scott, Jeannette; Lee, Michelle H; Leone, Maurizio A; Leppä, Virpi; Liberatore, Giuseppe; Lie, Benedicte A; Lill, Christina M; Lindén, Magdalena; Link, Jenny; Luessi, Felix; Lycke, Jan; Macciardi, Fabio; Männistö, Satu; Manrique, Clara P; Martin, Roland; Martinelli, Vittorio; Mason, Deborah; Mazibrada, Gordon; McCabe, Cristin; Mero, Inger-Lise; Mescheriakova, Julia; Moutsianas, Loukas; Myhr, Kjell-Morten; Nagels, Guy; Nicholas, Richard; Nilsson, Petra; Piehl, Fredrik; Pirinen, Matti; Price, Siân E; Quach, Hong; Reunanen, Mauri; Robberecht, Wim; Robertson, Neil P; Rodegher, Mariaemma; Rog, David; Salvetti, Marco; Schnetz-Boutaud, Nathalie C; Sellebjerg, Finn; Selter, Rebecca C; Schaefer, Catherine; Shaunak, Sandip; Shen, Ling; Shields, Simon; Siffrin, Volker; Slee, Mark; Sorensen, Per Soelberg; Sorosina, Melissa; Sospedra, Mireia; Spurkland, Anne; Strange, Amy; Sundqvist, Emilie; Thijs, Vincent; Thorpe, John; Ticca, Anna; Tienari, Pentti; van Duijn, Cornelia; Visser, Elizabeth M; Vucic, Steve; Westerlind, Helga; Wiley, James S; Wilkins, Alastair; Wilson, James F; Winkelmann, Juliane; Zajicek, John; Zindler, Eva; Haines, Jonathan L; Pericak-Vance, Margaret A; Ivinson, Adrian J; Stewart, Graeme; Hafler, David; Hauser, Stephen L; Compston, Alastair; McVean, Gil; De Jager, Philip; Sawcer, Stephen; McCauley, Jacob L

    2013-01-01

    Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals. PMID:24076602

  16. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K;

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying......, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk...... that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2....

  17. Association of breast cancer risk loci with breast cancer survival

    NARCIS (Netherlands)

    Barrdahl, Myrto; Canzian, Federico; Lindström, Sara; Shui, Irene; Black, Amanda; Hoover, Robert N.; Ziegler, Regina G.; Buring, Julie E.; Chanock, Stephen J.; Diver, W. Ryan; Gapstur, Susan M.; Gaudet, Mia M.; Giles, Graham G.; Haiman, Christopher; Henderson, Brian E.; Hankinson, Susan; Hunter, David J.; Joshi, Amit D.; Kraft, Peter; Lee, I. Min; Le Marchand, Loic; Milne, Roger L.; Southey, Melissa C.; Willett, Walter; Gunter, Marc; Panico, Salvatore; Sund, Malin; Weiderpass, Elisabete; Sánchez, María José; Overvad, Kim; Dossus, Laure; Peeters, Petra H.; Khaw, Kay Tee; Trichopoulos, Dimitrios; Kaaks, Rudolf; Campa, Daniele

    2015-01-01

    The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of eviden

  18. Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

    Science.gov (United States)

    Coleman, Ciara; Quinn, Emma M; Ryan, Anthony W; Conroy, Judith; Trimble, Valerie; Mahmud, Nasir; Kennedy, Nicholas; Corvin, Aiden P; Morris, Derek W; Donohoe, Gary; O'Morain, Colm; MacMathuna, Padraic; Byrnes, Valerie; Kiat, Clifford; Trynka, Gosia; Wijmenga, Cisca; Kelleher, Dermot; Ennis, Sean; Anney, Richard J L; McManus, Ross

    2016-02-01

    Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42. PMID:25920553

  19. Association of Breast Cancer Susceptibility Variants with Risk of Pancreatic Cancer

    Science.gov (United States)

    Couch, Fergus J.; Wang, Xianshu; McWilliams, Robert R.; Bamlet, William R.; de Andrade, Mariza; Petersen, Gloria M.

    2011-01-01

    Background A number of susceptibility genes are common to breast and pancreatic cancer. Recently, several breast cancer susceptibility loci have been identified through genome-wide association studies. Here we evaluated possible associations between these single nucleotide polymorphisms (SNPs) and pancreatic cancer risk. Methods Ten SNPs from FGFR2, TOX3, MAP3K1, H19, LSP1, chromosome 8q24, CASP8 and LUM were investigated for associations with pancreatic cancer risk following genotyping in 1143 caucasian individuals with pancreatic adenocarcinoma and 1097 unaffected controls from a clinic-based pancreatic cancer case-control study. Results CASP8 rs1045485 (Odds ratio (OR)= 0.78; 95% confidence interval (95%CI), 0.65-0.9; p=0.005) and MAP3K1 rs889312 (OR= 0.85; 95%CI, 0.74-0.97; p=0.017)) showed evidence of association with risk of pancreatic cancer. The CASP8 rs1045485 association was evident in ever-smokers (p=0.002), but not in non-smokers (p=0.55), and the effect was strongest in heavy smokers (OR, 0.52; 95% CI, 0.29- 0.93; p=0.03). In contrast the MAP3K1 rs889312 association was only evident in non-smokers (OR, 0.78; 95%CI, 0.64-0.95; p=0.01). In addition, evaluation of the influence of the ten SNPs on survival detected significant associations between outcome for locally advanced pancreatic cancer cases and both 8q rs6983561 (p=0.045) and LUM rs2268578 (p=0.02). Conclusion Association studies in a large pancreatic case-control study indicates that SNPs associated with breast cancer may also be associated with pancreatic cancer susceptibility and survival. PMID:19843670

  20. Association of Common Susceptibility Variants of Pancreatic Cancer in Higher-Risk Patients: A PACGENE Study.

    Science.gov (United States)

    Childs, Erica J; Chaffee, Kari G; Gallinger, Steven; Syngal, Sapna; Schwartz, Ann G; Cote, Michele L; Bondy, Melissa L; Hruban, Ralph H; Chanock, Stephen J; Hoover, Robert N; Fuchs, Charles S; Rider, David N; Amundadottir, Laufey T; Stolzenberg-Solomon, Rachael; Wolpin, Brian M; Risch, Harvey A; Goggins, Michael G; Petersen, Gloria M; Klein, Alison P

    2016-07-01

    Individuals from pancreatic cancer families are at increased risk, not only of pancreatic cancer, but also of melanoma, breast, ovarian, and colon cancers. While some of the increased risk may be due to mutations in high-penetrance genes (i.e., BRCA2, PALB2, ATM, p16/CDKN2A or DNA mismatch repair genes), common genetic variants may also be involved. In a high-risk population of cases with either a family history of pancreatic cancer or early-onset pancreatic cancer (diagnosis before the age of 50 years), we examined the role of genetic variants previously associated with risk of pancreatic, breast, ovarian, or prostate cancer. We genotyped 985 cases (79 early-onset cases, 906 cases with a family history of pancreatic cancer) and 877 controls for 215,389 SNPs using the iSelect Collaborative Oncological Gene-Environment Study (iCOGS) array with custom content. Logistic regression was performed using a log-linear additive model. We replicated several previously reported pancreatic cancer susceptibility loci, including recently identified variants on 2p13.3 and 7p13 (2p13.3, rs1486134: OR = 1.36; 95% CI, 1.13-1.63; P = 9.29 × 10(-4); 7p13, rs17688601: OR = 0.76; 95% CI, 0.63-0.93; P = 6.59 × 10(-3)). For the replicated loci, the magnitude of association observed in these high-risk patients was similar to that observed in studies of unselected patients. In addition to the established pancreatic cancer loci, we also found suggestive evidence of association (P pancreatic cancer for SNPs at HDAC9 (7p21.1) and COL6A2 (21q22.3). Even in high-risk populations, common variants influence pancreatic cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 25(7); 1185-91. ©2016 AACR. PMID:27197284

  1. Genetic susceptibility to breast and endometrial cancer

    OpenAIRE

    Wedrén, Sara

    2004-01-01

    Hormones are central in the carcinogenic process in the breast and in the uterine epithelium. Individual genetically determined variation in the response to hormonal influence may alter susceptibility to breast and endometrial cancers. Many small studies of this hypothesis have generated inconclusive results. Since the effect of any genetic variant is expected to be modest, large studies are needed to draw reliable conclusions. Also, there may be interaction between genetic ...

  2. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    DEFF Research Database (Denmark)

    Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji;

    2015-01-01

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct...

  3. Three Ulcerative Colitis Susceptibility Loci Are Associated with Primary Sclerosing Cholangitis and Indicate a Role for IL2, REL, and CARD9

    NARCIS (Netherlands)

    M. Janse; L.E. Lamberts; L. Franke; S. Raychaudhuri; E. Ellinghaus; K.M. Boberg; E. Melum; T. Folseraas; E. Schrumpf; A. Bergquist; E. Bjornsson; J. Fu; H.J. Westra; H.J.M. Groen; R.S.N. Fehrmann; J. Smolonska; L.H. Berg; R.A. Ophoff; R.J. Porte; T.J. Weismueller; J. Wedemeyer; C. Schramm; M. Sterneck; R. Guenther; F. Braun; S. Vermeire; L. Henckaerts; C. Wijmenga; C.Y. Ponsioen; S. Schreiber; T.H. Karlsen; A. Franke; R.K. Weersma

    2011-01-01

    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently ide

  4. Association of New Loci Identified in European Genome-Wide Association Studies with Susceptibility to Type 2 Diabetes in the Japanese

    OpenAIRE

    Toshihiko Ohshige; Minoru Iwata; Shintaro Omori; Yasushi Tanaka; Hiroshi Hirose; Kohei Kaku; Hiroshi Maegawa; Hirotaka Watada; Atsunori Kashiwagi; Ryuzo Kawamori; Kazuyuki Tobe; Takashi Kadowaki; Yusuke Nakamura; Shiro Maeda

    2011-01-01

    BACKGROUND: Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies. METHODOLOGY/PRINCIPAL FINDINGS: We examined t...

  5. Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9

    OpenAIRE

    Janse, Marcel; Lamberts, Laetitia E.; Franke, Lude; Raychaudhuri, Soumya; Ellinghaus, Eva; MuriBoberg, Kirsten; Melum, Espen; Folseraas, Trine; Schrumpf, Erik; Bergquist, Annika; Bjornsson, Einar; Fu, Jingyuan; Westra, Harm Jan; Groen, Harry JM; Fehrmann, Rudolf SN

    2011-01-01

    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1186PSC patients and 1748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854...

  6. Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma.

    Science.gov (United States)

    Shiraishi, Kouya; Okada, Yukinori; Takahashi, Atsushi; Kamatani, Yoichiro; Momozawa, Yukihide; Ashikawa, Kyota; Kunitoh, Hideo; Matsumoto, Shingo; Takano, Atsushi; Shimizu, Kimihiro; Goto, Akiteru; Tsuta, Koji; Watanabe, Shun-Ichi; Ohe, Yuichiro; Watanabe, Yukio; Goto, Yasushi; Nokihara, Hiroshi; Furuta, Koh; Yoshida, Akihiko; Goto, Koichi; Hishida, Tomoyuki; Tsuboi, Masahiro; Tsuchihara, Katsuya; Miyagi, Yohei; Nakayama, Haruhiko; Yokose, Tomoyuki; Tanaka, Kazumi; Nagashima, Toshiteru; Ohtaki, Yoichi; Maeda, Daichi; Imai, Kazuhiro; Minamiya, Yoshihiro; Sakamoto, Hiromi; Saito, Akira; Shimada, Yoko; Sunami, Kuniko; Saito, Motonobu; Inazawa, Johji; Nakamura, Yusuke; Yoshida, Teruhiko; Yokota, Jun; Matsuda, Fumihiko; Matsuo, Keitaro; Daigo, Yataro; Kubo, Michiaki; Kohno, Takashi

    2016-01-01

    Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations. PMID:27501781

  7. Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lipoldová, Marie; Havelková, Helena; Badalová, Jana; Demant, P.

    2005-01-01

    Roč. 114, č. 3 (2005), s. 394-399. ISSN 0020-7136 R&D Projects: GA ČR(CZ) GA310/03/1381 Grant ostatní: European Commission(XE) CIPA-CT940040; Howard Hughes Medical Institute(US) 55000323 Institutional research plan: CEZ:AV0Z5052915 Keywords : lymphocyte activation * interleukin * lung cancer susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.700, year: 2005

  8. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.

    Science.gov (United States)

    Schunkert, Heribert; König, Inke R; Kathiresan, Sekar; Reilly, Muredach P; Assimes, Themistocles L; Holm, Hilma; Preuss, Michael; Stewart, Alexandre F R; Barbalic, Maja; Gieger, Christian; Absher, Devin; Aherrahrou, Zouhair; Allayee, Hooman; Altshuler, David; Anand, Sonia S; Andersen, Karl; Anderson, Jeffrey L; Ardissino, Diego; Ball, Stephen G; Balmforth, Anthony J; Barnes, Timothy A; Becker, Diane M; Becker, Lewis C; Berger, Klaus; Bis, Joshua C; Boekholdt, S Matthijs; Boerwinkle, Eric; Braund, Peter S; Brown, Morris J; Burnett, Mary Susan; Buysschaert, Ian; Carlquist, John F; Chen, Li; Cichon, Sven; Codd, Veryan; Davies, Robert W; Dedoussis, George; Dehghan, Abbas; Demissie, Serkalem; Devaney, Joseph M; Diemert, Patrick; Do, Ron; Doering, Angela; Eifert, Sandra; Mokhtari, Nour Eddine El; Ellis, Stephen G; Elosua, Roberto; Engert, James C; Epstein, Stephen E; de Faire, Ulf; Fischer, Marcus; Folsom, Aaron R; Freyer, Jennifer; Gigante, Bruna; Girelli, Domenico; Gretarsdottir, Solveig; Gudnason, Vilmundur; Gulcher, Jeffrey R; Halperin, Eran; Hammond, Naomi; Hazen, Stanley L; Hofman, Albert; Horne, Benjamin D; Illig, Thomas; Iribarren, Carlos; Jones, Gregory T; Jukema, J Wouter; Kaiser, Michael A; Kaplan, Lee M; Kastelein, John J P; Khaw, Kay-Tee; Knowles, Joshua W; Kolovou, Genovefa; Kong, Augustine; Laaksonen, Reijo; Lambrechts, Diether; Leander, Karin; Lettre, Guillaume; Li, Mingyao; Lieb, Wolfgang; Loley, Christina; Lotery, Andrew J; Mannucci, Pier M; Maouche, Seraya; Martinelli, Nicola; McKeown, Pascal P; Meisinger, Christa; Meitinger, Thomas; Melander, Olle; Merlini, Pier Angelica; Mooser, Vincent; Morgan, Thomas; Mühleisen, Thomas W; Muhlestein, Joseph B; Münzel, Thomas; Musunuru, Kiran; Nahrstaedt, Janja; Nelson, Christopher P; Nöthen, Markus M; Olivieri, Oliviero; Patel, Riyaz S; Patterson, Chris C; Peters, Annette; Peyvandi, Flora; Qu, Liming; Quyyumi, Arshed A; Rader, Daniel J; Rallidis, Loukianos S; Rice, Catherine; Rosendaal, Frits R; Rubin, Diana; Salomaa, Veikko; Sampietro, M Lourdes; Sandhu, Manj S; Schadt, Eric; Schäfer, Arne; Schillert, Arne; Schreiber, Stefan; Schrezenmeir, Jürgen; Schwartz, Stephen M; Siscovick, David S; Sivananthan, Mohan; Sivapalaratnam, Suthesh; Smith, Albert; Smith, Tamara B; Snoep, Jaapjan D; Soranzo, Nicole; Spertus, John A; Stark, Klaus; Stirrups, Kathy; Stoll, Monika; Tang, W H Wilson; Tennstedt, Stephanie; Thorgeirsson, Gudmundur; Thorleifsson, Gudmar; Tomaszewski, Maciej; Uitterlinden, Andre G; van Rij, Andre M; Voight, Benjamin F; Wareham, Nick J; Wells, George A; Wichmann, H-Erich; Wild, Philipp S; Willenborg, Christina; Witteman, Jaqueline C M; Wright, Benjamin J; Ye, Shu; Zeller, Tanja; Ziegler, Andreas; Cambien, Francois; Goodall, Alison H; Cupples, L Adrienne; Quertermous, Thomas; März, Winfried; Hengstenberg, Christian; Blankenberg, Stefan; Ouwehand, Willem H; Hall, Alistair S; Deloukas, Panos; Thompson, John R; Stefansson, Kari; Roberts, Robert; Thorsteinsdottir, Unnur; O'Donnell, Christopher J; McPherson, Ruth; Erdmann, Jeanette; Samani, Nilesh J

    2011-04-01

    We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. PMID:21378990

  9. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease

    OpenAIRE

    Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A; Harold, Denise; Naj, Adam C.; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; Destefano, Anita L.; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.

    2013-01-01

    Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37...

  10. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma

    OpenAIRE

    Khor, CC; Do, T.; Jia, H; Nakano, M; George, R.; Abu-Amero, K; Duvesh, R; Chen, LJ; Z. Li; Nongpiur, ME; Perera, SA; Qiao, C.; Wong, H-T; Sakai, H.; de Melo, MB

    2016-01-01

    Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = ...

  11. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    DEFF Research Database (Denmark)

    Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire;

    2016-01-01

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We...

  12. Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.

    Science.gov (United States)

    Zhang, Yong-Biao; Hu, Jintian; Zhang, Jiao; Zhou, Xu; Li, Xin; Gu, Chaohao; Liu, Tun; Xie, Yangchun; Liu, Jiqiang; Gu, Mingliang; Wang, Panpan; Wu, Tingting; Qian, Jin; Wang, Yue; Dong, Xiaoqun; Yu, Jun; Zhang, Qingguo

    2016-01-01

    Craniofacial microsomia (CFM) is a rare congenital anomaly that involves immature derivatives from the first and second pharyngeal arches. The genetic pathogenesis of CFM is still unclear. Here we interrogate 0.9 million genetic variants in 939 CFM cases and 2,012 controls from China. After genotyping of an additional 443 cases and 1,669 controls, we identify 8 significantly associated loci with the most significant SNP rs13089920 (logistic regression P=2.15 × 10(-120)) and 5 suggestive loci. The above 13 associated loci, harboured by candidates of ROBO1, GATA3, GBX2, FGF3, NRP2, EDNRB, SHROOM3, SEMA7A, PLCD3, KLF12 and EPAS1, are found to be enriched for genes involved in neural crest cell (NCC) development and vasculogenesis. We then perform whole-genome sequencing on 21 samples from the case cohort, and identify several novel loss-of-function mutations within the associated loci. Our results provide new insights into genetic background of craniofacial microsomia. PMID:26853712

  13. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.

    Science.gov (United States)

    Ellinghaus, David; Ellinghaus, Eva; Nair, Rajan P; Stuart, Philip E; Esko, Tõnu; Metspalu, Andres; Debrus, Sophie; Raelson, John V; Tejasvi, Trilokraj; Belouchi, Majid; West, Sarah L; Barker, Jonathan N; Kõks, Sulev; Kingo, Külli; Balschun, Tobias; Palmieri, Orazio; Annese, Vito; Gieger, Christian; Wichmann, H Erich; Kabesch, Michael; Trembath, Richard C; Mathew, Christopher G; Abecasis, Gonçalo R; Weidinger, Stephan; Nikolaus, Susanna; Schreiber, Stefan; Elder, James T; Weichenthal, Michael; Nothnagel, Michael; Franke, Andre

    2012-04-01

    Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p diseases and enlarge the map of shared genetic risk loci. PMID:22482804

  14. A genome-wide association study in chronic obstructive pulmonary disease (COPD: identification of two major susceptibility loci.

    Directory of Open Access Journals (Sweden)

    Sreekumar G Pillai

    2009-03-01

    in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429. The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

  15. Further Evidence of Subphenotype Association with Systemic Lupus Erythematosus Susceptibility Loci: A European Cases Only Study

    Czech Academy of Sciences Publication Activity Database

    Alonso-Perez, E.; Suarez-Gestal, M.; Calaza, M.; Ordi-Ros, J.; Bijl, M.; Papasteriades, Ch.; Carreira, P.; Skopouli, F.N.; Witte, T.; Marchini, M.; Migliaresi, S.; Santos, M.J.; Růžičková, Šárka; Pullmann, R.; Sebastiani, G.D.; Suarez, A.; Blanco, F.J.

    2012-01-01

    Roč. 7, č. 9 (2012), e45356. E-ISSN 1932-6203 Institutional research plan: CEZ:AV0Z50520701 Keywords : GENOME-WIDE ASSOCIATION * GENETIC SUSCEPTIBILITY * DISEASE SUSCEPTIBILITY Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.730, year: 2012

  16. Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.

    LENUS (Irish Health Repository)

    Bowes, John

    2012-08-01

    A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA.

  17. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    DEFF Research Database (Denmark)

    Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig;

    2013-01-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) an...... analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B....

  18. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

    Science.gov (United States)

    Khor, Chiea Chuen; Do, Tan; Jia, Hongyan; Nakano, Masakazu; George, Ronnie; Abu-Amero, Khaled; Duvesh, Roopam; Chen, Li Jia; Li, Zheng; Nongpiur, Monisha E; Perera, Shamira A; Qiao, Chunyan; Wong, Hon-Tym; Sakai, Hiroshi; Barbosa de Melo, Mônica; Lee, Mei-Chin; Chan, Anita S; Azhany, Yaakub; Dao, Thi Lam Huong; Ikeda, Yoko; Perez-Grossmann, Rodolfo A; Zarnowski, Tomasz; Day, Alexander C; Jonas, Jost B; Tam, Pancy O S; Tran, Tuan Anh; Ayub, Humaira; Akhtar, Farah; Micheal, Shazia; Chew, Paul T K; Aljasim, Leyla A; Dada, Tanuj; Luu, Tam Thi; Awadalla, Mona S; Kitnarong, Naris; Wanichwecharungruang, Boonsong; Aung, Yee Yee; Mohamed-Noor, Jelinar; Vijayan, Saravanan; Sarangapani, Sripriya; Husain, Rahat; Jap, Aliza; Baskaran, Mani; Goh, David; Su, Daniel H; Wang, Huaizhou; Yong, Vernon K; Yip, Leonard W; Trinh, Tuyet Bach; Makornwattana, Manchima; Nguyen, Thanh Thu; Leuenberger, Edgar U; Park, Ki-Ho; Wiyogo, Widya Artini; Kumar, Rajesh S; Tello, Celso; Kurimoto, Yasuo; Thapa, Suman S; Pathanapitoon, Kessara; Salmon, John F; Sohn, Yong Ho; Fea, Antonio; Ozaki, Mineo; Lai, Jimmy S M; Tantisevi, Visanee; Khaing, Chaw Chaw; Mizoguchi, Takanori; Nakano, Satoko; Kim, Chan-Yun; Tang, Guangxian; Fan, Sujie; Wu, Renyi; Meng, Hailin; Nguyen, Thi Thuy Giang; Tran, Tien Dat; Ueno, Morio; Martinez, Jose Maria; Ramli, Norlina; Aung, Yin Mon; Reyes, Rigo Daniel; Vernon, Stephen A; Fang, Seng Kheong; Xie, Zhicheng; Chen, Xiao Yin; Foo, Jia Nee; Sim, Kar Seng; Wong, Tina T; Quek, Desmond T; Venkatesh, Rengaraj; Kavitha, Srinivasan; Krishnadas, Subbiah R; Soumittra, Nagaswamy; Shantha, Balekudaru; Lim, Boon-Ang; Ogle, Jeanne; de Vasconcellos, José P C; Costa, Vital P; Abe, Ricardo Y; de Souza, Bruno B; Sng, Chelvin C; Aquino, Maria C; Kosior-Jarecka, Ewa; Fong, Guillermo Barreto; Tamanaja, Vania Castro; Fujita, Ricardo; Jiang, Yuzhen; Waseem, Naushin; Low, Sancy; Pham, Huan Nguyen; Al-Shahwan, Sami; Craven, E Randy; Khan, Muhammad Imran; Dada, Rrima; Mohanty, Kuldeep; Faiq, Muneeb A; Hewitt, Alex W; Burdon, Kathryn P; Gan, Eng Hui; Prutthipongsit, Anuwat; Patthanathamrongkasem, Thipnapa; Catacutan, Mary Ann T; Felarca, Irene R; Liao, Chona S; Rusmayani, Emma; Istiantoro, Vira Wardhana; Consolandi, Giulia; Pignata, Giulia; Lavia, Carlo; Rojanapongpun, Prin; Mangkornkanokpong, Lerprat; Chansangpetch, Sunee; Chan, Jonathan C H; Choy, Bonnie N K; Shum, Jennifer W H; Than, Hlaing May; Oo, Khin Thida; Han, Aye Thi; Yong, Victor H; Ng, Xiao-Yu; Goh, Shuang Ru; Chong, Yaan Fun; Hibberd, Martin L; Seielstad, Mark; Png, Eileen; Dunstan, Sarah J; Chau, Nguyen Van Vinh; Bei, Jinxin; Zeng, Yi Xin; Karkey, Abhilasha; Basnyat, Buddha; Pasutto, Francesca; Paoli, Daniela; Frezzotti, Paolo; Wang, Jie Jin; Mitchell, Paul; Fingert, John H; Allingham, R Rand; Hauser, Michael A; Lim, Soon Thye; Chew, Soo Hong; Ebstein, Richard P; Sakuntabhai, Anavaj; Park, Kyu Hyung; Ahn, Jeeyun; Boland, Greet; Snippe, Harm; Stead, Richard; Quino, Raquel; Zaw, Su Nyunt; Lukasik, Urszula; Shetty, Rohit; Zahari, Mimiwati; Bae, Hyoung Won; Oo, Nay Lin; Kubota, Toshiaki; Manassakorn, Anita; Ho, Wing Lau; Dallorto, Laura; Hwang, Young Hoon; Kiire, Christine A; Kuroda, Masako; Djamal, Zeiras Eka; Peregrino, Jovell Ian M; Ghosh, Arkasubhra; Jeoung, Jin Wook; Hoan, Tung S; Srisamran, Nuttamon; Sandragasu, Thayanithi; Set, Saw Htoo; Doan, Vi Huyen; Bhattacharya, Shomi S; Ho, Ching-Lin; Tan, Donald T; Sihota, Ramanjit; Loon, Seng-Chee; Mori, Kazuhiko; Kinoshita, Shigeru; Hollander, Anneke I den; Qamar, Raheel; Wang, Ya-Xing; Teo, Yik Y; Tai, E-Shyong; Hartleben-Matkin, Curt; Lozano-Giral, David; Saw, Seang Mei; Cheng, Ching-Yu; Zenteno, Juan C; Pang, Chi Pui; Bui, Huong T T; Hee, Owen; Craig, Jamie E; Edward, Deepak P; Yonahara, Michiko; Neto, Jamil Miguel; Guevara-Fujita, Maria L; Xu, Liang; Ritch, Robert; Liza-Sharmini, Ahmad Tajudin; Wong, Tien Y; Al-Obeidan, Saleh; Do, Nhu Hon; Sundaresan, Periasamy; Tham, Clement C; Foster, Paul J; Vijaya, Lingam; Tashiro, Kei; Vithana, Eranga N; Wang, Ningli; Aung, Tin

    2016-05-01

    Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG. PMID:27064256

  19. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

    Science.gov (United States)

    Mitchell, Jonathan S.; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C.; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F.; Kuiper, Rowan; Stephens, Owen W.; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A.; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H.; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y.; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M.; Rafnar, Thorunn; Ross, Fiona M.; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A.; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E.; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J.; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S.

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  20. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

    Science.gov (United States)

    Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Gonçalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Bottinger, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kao, Wen-Hong L; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian'an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Peltonen, Leena; Perry, John R B; Platou, Carl G P; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wiltshire, Steven; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth J F; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöcke, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin N A; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O'Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

    2015-12-01

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

  1. Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    Science.gov (United States)

    Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

    2015-01-01

    We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

  2. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease

    Science.gov (United States)

    Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao-Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Choi, Seung-Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiévet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez-Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton-Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O’Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li-san; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak-Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

    2013-01-01

    Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease. PMID:24162737

  3. Evaluation of two putative susceptibility loci for oral clefts in the Danish population

    DEFF Research Database (Denmark)

    Mitchell, L E; Murray, J C; O'Brien, S; Christensen, Kaare

    2001-01-01

    Previous studies suggest that the risk of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate (CP) is influenced by genetic variation at several loci and that the relation between specific genetic variants and disease risk may be modified by environmental factor...... gene-environment interactions involving MSX1 or TGFB3 and either first trimester exposure to maternal cigarette smoke or alcohol consumption....... environmental exposures, first trimester exposure to maternal cigarette smoke and alcohol intake, were also examined. Analyses of these data provide evidence of an association between the risk of CP and variation at the TGFB3 locus. However, there is no evidence that the risk of CL+/-P or CP is influenced by...

  4. Mapping of murine radiation-induced acute myeloid leukaemia susceptibility loci

    International Nuclear Information System (INIS)

    Studies on radiation-induced AML have shown characteristic phenotypic variation in susceptibility amongst inbred mouse strains, suggesting the involvement of genetic factors in determining the development of AML post-irradiation exposure. The main objective of the present study therefore was to identify and map markers in linkage disequilibrium with gene variants associated with influencing susceptibility to radiation induced AML in mice. Given Chr 2 abnormalities are characteristic of AML in mice, this feature was exploited in an effort to overcome the long latency for AML development. Analysis of Chr 2 aberrations at 24 and 48 h following irradiation established a positive correlation between Chr 2 radiosensitivity and radiation-AML susceptibility thus validating the choice of substitute assay. The analysis also resulted in the identification of a further trait, additional to Chr 2 radiosensitivity, termed overall chromosome radiosensitivity. Genetic mapping of Chr 2 radiosensitivity using public domain microsatellite database information resulted in the definition of cluster regions on 7 different chromosomes. Further genotyping reduced the candidate regions to 3 specific regions of interest. A test of allelic association could not ascertain a conclusive link between markers at these regions and the Chr 2 radiosensitivity/radiation-AML susceptibility phenotype. However, a region on Chr 4 around D4Mit221 appears to be most strongly associated. Similar studies identified three chromosomal regions of interest (on Chrs 4, 8 and 16) associated with overall chromosome radiosensitivity trait. An independent mapping strategy using F3 RCS confirmed the likely involvement of two of the candidate Chr 2 radiosensitivity regions identified by the inbred analysis including that on Chr 4 and also highlighted phenotypic heterogeneity amongst resistant RC strains, suggesting the influence of multiple alleles in specific phenotypes. RFLP analysis of candidate genes, localised on

  5. A comprehensive examination of breast cancer risk loci in African American women

    OpenAIRE

    Feng, Ye; Stram, Daniel O.; Rhie, Suhn Kyong; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F.; Jennifer J Hu; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Sue A Ingles; Michael F. Press

    2014-01-01

    Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American wome...

  6. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    DEFF Research Database (Denmark)

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha;

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions assoc...

  7. Childhood indicators of susceptibility to subsequent cervical cancer

    OpenAIRE

    Montgomery, S M; Ehlin, A G C; Sparén, P.; Björkstén, B; Ekbom, A.

    2002-01-01

    Common warts could indicate cervical cancer susceptibility, as both are caused by human papillomavirus (HPV). Eczema was also investigated, as atopic eczema has been negatively associated with warts, but non-atopic eczema may be associated with compromised host defences, as observed in patients with HIV, suggesting increased susceptibility to HPV infection and cervical cancer. ‘Cervical cancer’ was self-reported during an interview by 87 of 7594 women members of two longitudinal British birth...

  8. Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross.

    Directory of Open Access Journals (Sweden)

    Lisa E Gralinski

    2015-10-01

    Full Text Available New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.

  9. Genetic mapping of quantitative trait loci affecting susceptibility in chicken to develop pulmonary hypertension syndrome.

    Science.gov (United States)

    Rabie, T S K M; Crooijmans, R P M A; Bovenhuis, H; Vereijken, A L J; Veenendaal, T; van der Poel, J J; Van Arendonk, J A M; Pakdel, A; Groenen, M A M

    2005-12-01

    Pulmonary hypertension syndrome (PHS), also referred to as ascites syndrome, is a growth-related disorder of chickens frequently observed in fast-growing broilers with insufficient pulmonary vascular capacity at low temperature and/or at high altitude. A cross between two genetically different broiler dam lines that originated from the White Plymouth Rock breed was used to produce a three-generation population. This population was used for the detection and localization of quantitative trait loci (QTL) affecting PHS-related traits. Ten full-sib families consisting of 456 G2 birds were typed with 420 microsatellite markers covering 24 autosomal chromosomes. Phenotypic observations were collected on 4202 G3 birds and a full-sib across family regression interval mapping approach was used to identify QTL. There was statistical evidence for QTL on chicken chromosome 2 (GGA2), GGA4 and GGA6. Suggestive QTL were found on chromosomes 5, 8, 10, 27 and 28. The most significant QTL were located on GGA2 for right and total ventricular weight as percentage of body weight (%RV and %TV respectively). A related trait, the ratio of right ventricular weight as percentage to total ventricular weight (RATIO), reached the suggestive threshold on this chromosome. All three QTL effects identified on GGA2 had their maximum test statistic in the region flanked by markers MCW0185 and MCW0245 (335-421 cM). PMID:16293119

  10. Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2008-04-01

    Full Text Available Abstract Background Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Familial Adenomatous Polyposis (FAP. In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer. Methods Statistical analysis was performed using multipoint parametric and nonparametric linkage. Results Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL = 2.1. Conclusion The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.

  11. A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population.

    Science.gov (United States)

    Permutt, M A; Wasson, J C; Suarez, B K; Lin, J; Thomas, J; Meyer, J; Lewitzky, S; Rennich, J S; Parker, A; DuPrat, L; Maruti, S; Chayen, S; Glaser, B

    2001-03-01

    A total of 896 individuals of Ashkenazi Jewish descent were ascertained in Israel from 267 multiplex families, including 472 sib-pairs affected with type 2 diabetes. A genome-wide scan with average marker spacing of 9.5 cM revealed five regions on four chromosomes (4q, 8q, 14q, and 20q) that exhibited nominal evidence for linkage (P families were ranked by BMI (in increasing order) did a subset attain nominal significance, and only for chromosome 4. The findings reported here lend credence to the hypothesis, now supported by four studies of Caucasian populations and most recently by a combined analysis of 1,852 pedigrees, that a type 2 diabetes susceptibility locus resides on chromosome 20q. This population, because of its unique genetic attributes, may facilitate identification of this and other genes contributing to type 2 diabetes. PMID:11246891

  12. New susceptibility loci associated with kidney disease in type 1 diabetes.

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    Niina Sandholm

    2012-09-01

    Full Text Available Diabetic kidney disease, or diabetic nephropathy (DN, is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D. Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS of T1D DN comprising ~2.4 million single nucleotide polymorphisms (SNPs imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2 × 10(-8 and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0 × 10(-9. Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1 pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1 × 10(-7, a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

  13. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Couch, Fergus J; Wang, Xianshu; McGuffog, Lesley;

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a fur...

  14. Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9

    Science.gov (United States)

    Janse, Marcel; Lamberts, Laetitia E; Franke, Lude; Raychaudhuri, Soumya; Ellinghaus, Eva; MuriBoberg, Kirsten; Melum, Espen; Folseraas, Trine; Schrumpf, Erik; Bergquist, Annika; Bjornsson, Einar; Fu, Jingyuan; Westra, Harm Jan; Groen, Harry JM; Fehrmann, Rudolf SN; Smolonska, Joanna; van den Berg, Leonard H; Ophoff, Roel A; Porte, Robert J; Weismuller, Tobias J; Wedemeyer, Jochen; Schramm, Christoph; Sterneck, Martina; Gunther, Rainer; Braun, Felix; Vermeire, Severine; Henckaerts, Liesbet; Wijmenga, Cisca; Ponsioen, Cyriel Y.; Schreiber, Stefan; HKarlsen, Tom; Franke, Andre; Weersma, Rinse K

    2011-01-01

    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1186PSC patients and 1748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1491 controls from the Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls) and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes2p16 (p value 4.12×10−4), 4q27 (p value 4.10×10−5) and 9q34 (p value 8.41×10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease(IBD), SNPs at 4q27and9q34 were nominally associated (p<0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify non-random, evidence-based links we used GRAIL analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9 and REL as novel candidates. Conclusion We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2 and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. PMID:21425313

  15. Epidermal characteristics related to skin cancer susceptibility

    International Nuclear Information System (INIS)

    We have compared the basal cell labeling index and cellular architecture in samples of epidermis removed by vacuum blistering from people with or without a personal history of skin cancer. Donors with no family history of skin cancer showed a basal cell labeling index of 5.5% with a standard deviation of 1.3%. Those not personally affected but with a family history gave 4.1% +/- 0.4% but among cancer patients the value was approximately doubled to 11.5% +/- 2.7%. The proportion of cells replicating was reduced after ultraviolet irradiation, with a D0 of 40 J/m2 for UVB but no difference could be demonstrated between individuals with or without a history of skin cancer

  16. CHEK2 1100delC and polygenic susceptibility to breast cancer and colorectal cancer

    NARCIS (Netherlands)

    M. Wasielewski (Marijke)

    2009-01-01

    textabstractApproximately 15-25% of breast cancers are identified in women with a family history of breast cancer. Yet, germline mutations in the currently known breast cancer susceptibility genes account for only one-third of familial breast cancer cases. In 2002, our research group had identified

  17. EXPRESSION OF GENETIC LOCI IN THE PERIPHERAL BLOOD MONONUCLEAR FRACTION FROM PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    M. I. Kogan

    2014-08-01

    Full Text Available The early diagnosis and radical treatment of aggressive prostate cancers (PC is an effective way of improving survival and quality of life in patients. To develop mini-invasive tests is one of the ways of solving the problem. The cells of a peripheral blood mononuclear fraction in the expression patterns of their genetic loci reflect the presence or absence of cancers, including information on therapeutic effectiveness. RT-PRC was used to study the relative expression of 15 genetic loci in a chromosome and one locus of mitochondrial DNA in the cells of the peripheral blood mononuclear fraction in patients with PC or benign prostate hyperplasia and in healthy men. The genetic locus patterns whose change may be of informative value for differential diagnosis in patients with different stages of PC were revealed. The authors studied the relationship and showed the prognostic role and non-relationship of the altered transcriptional activity of loci in the TP53, GSTP1, and IL10 genes in PC to the changes in prostate-specific antigen the level with 90 % specificity and 93 % specificity.

  18. Identification of novel susceptibility Loci for kawasaki disease in a Han chinese population by a genome-wide association study.

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    Fuu-Jen Tsai

    Full Text Available Kawasaki disease (KD is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS in 250 KD patients and 446 controls in a Han Chinese population residing in Taiwan, and further validated our findings in an independent Han Chinese cohort of 208 cases and 366 controls. The most strongly associated single-nucleotide polymorphisms (SNPs detected in the joint analysis corresponded to three novel loci. Among these KD-associated SNPs three were close to the COPB2 (coatomer protein complex beta-2 subunit gene: rs1873668 (p = 9.52×10⁻⁵, rs4243399 (p = 9.93×10⁻⁵, and rs16849083 (p = 9.93×10⁻⁵. We also identified a SNP in the intronic region of the ERAP1 (endoplasmic reticulum amino peptidase 1 gene (rs149481, p(best = 4.61×10⁻⁵. Six SNPs (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667 clustered in an area containing immunoglobulin heavy chain variable regions genes, with p(best-values between 2.08×10⁻⁵ and 8.93×10⁻⁶, were also identified. This is the first KD GWAS performed in a Han Chinese population. The novel KD candidates we identified have been implicated in T cell receptor signaling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses. These findings may lead to a better understanding of the underlying molecular pathogenesis of KD.

  19. Hereditary Breast Cancer: The Era of New Susceptibility Genes

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    Paraskevi Apostolou

    2013-01-01

    Full Text Available Breast cancer is the most common malignancy among females. 5%–10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered reference BRCA1 and BRCA2 genes. As sequencing technologies evolve, more susceptible genes have been discovered and BRCA1 and BRCA2 predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which include TP53 mutations in Li-Fraumeni syndrome, STK11 mutations in Peutz-Jeghers syndrome, and PTEN mutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.

  20. Breast Tissue Composition and Susceptibility to Breast Cancer

    OpenAIRE

    Boyd, Norman F.; Lisa J Martin; Bronskill, Michael; Martin J. Yaffe; Duric, Neb; Minkin, Salomon

    2010-01-01

    Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associat...

  1. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies

    Science.gov (United States)

    Matsuba, Ren; Imamura, Minako; Tanaka, Yasushi; Iwata, Minoru; Hirose, Hiroshi; Kaku, Kohei; Maegawa, Hiroshi; Watada, Hirotaka; Tobe, Kazuyuki; Kashiwagi, Atsunori; Kawamori, Ryuzo; Maeda, Shiro

    2016-01-01

    Aim We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. Methods We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. Results Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. Conclusions Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population. PMID:27115357

  2. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Stolzenberg-Solomon, R.; Pacetti, P.; Vodička, Pavel; Cleary, S.P.; Capurso, G.; Bueno-de-Mesquita, H. B.; Werner, J.; Gazouli, M.; Butterbach, K.; Ivanauskas, A.; Giese, N.; Petersen, G. M.; Fogar, P.; Wang, Z.; Bassi, C.; Ryska, M.; Theodoropoulos, G.E.; Kooperberg, Ch.; Li, D.; Greenhalf, W.; Pasquali, C.; Hackert, T.; Fuchs, Ch.S.; Mohelníková-Duchoňová, B.; Sperti, C.; Funel, N.; Dieffenbach, A.K.; Wareham, N.J.; Buring, J.; Holcátová, I.; Costello, E.; Zambon, C.F.; Kupcinskas, J.; Risch, H.A.; Kraft, P.; Bracci, P.M.; Pezzilli, R.; Olson, S.H.; Sesso, H. D.; Hartge, P.; Strobel, O.; Malecka-Panas, E.; Visvanathan, K.; Arslan, A. A.; Pedrazzoli, S.; Souček, P.; Gioffreda, D.; Key, T.J.; Talar-Wojnarowska, R.; Scarpa, A.; Mambrini, A.; Jacobs, E.J.; Jamroziak, K.; Klein, A.; Tavano, F.; Bambi, F.; Landi, S.; Austin, M. A.; Vodičková, Ludmila; Brenner, H.; Chanock, S. J.; Fave, G.D.; Piepoli, A.; Cantore, M.; Zheng, W.; Wolpin, B.M.; Amundadottir, L. T.; Canzian, F.

    2015-01-01

    Roč. 137, č. 9 (2015), s. 2175-2183. ISSN 0020-7136 R&D Projects: GA ČR GAP301/12/1734 Institutional support: RVO:68378041 Keywords : pancreatic cancer * polymorphisms * telomerase * susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.085, year: 2014

  3. Genome-wide association study for ovarian cancer susceptibility using pooled DNA

    DEFF Research Database (Denmark)

    Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan; Johnatty, Sharon E; Defazio, Anna; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn; Vergotes, Ignace; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Goodman, Marc T; Lurie, Galina; Wilkens, Lynne R; Carney, Michael E; Butzow, Ralf; Nevanlinna, Heli; Heikkinen, Tuomas; Leminen, Arto; Kiemeney, Lambertus A; Massuger, Leon F A G; van Altena, Anne M; Aben, Katja K; Kjaer, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Brooks-Wilson, Angela; Le, Nhu; Cook, Linda; Earp, Madalene; Kelemen, Linda; Easton, Douglas; Pharoah, Paul; Song, Honglin; Tyrer, Jonathan; Ramus, Susan; Menon, Usha; Gentry-Maharaj, Alexandra; Gayther, Simon A; Bandera, Elisa V; Olson, Sara H; Orlow, Irene; Rodriguez-Rodriguez, Lorna; Macgregor, Stuart; Chenevix-Trench, Georgia

    2012-01-01

    Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in...... the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly...... associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for...

  4. Counselling framework for moderate-penetrance cancer-susceptibility mutations.

    Science.gov (United States)

    Tung, Nadine; Domchek, Susan M; Stadler, Zsofia; Nathanson, Katherine L; Couch, Fergus; Garber, Judy E; Offit, Kenneth; Robson, Mark E

    2016-09-01

    The use of multigene panels for the assessment of cancer susceptibility is expanding rapidly in clinical practice, particularly in the USA, despite concerns regarding the uncertain clinical validity for some gene variants and the uncertain clinical utility of most multigene panels. So-called 'moderate-penetrance' gene mutations associated with cancer susceptibility are identified in approximately 2-5% of individuals referred for clinical testing; some of these mutations are potentially actionable. Nevertheless, the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high-penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch syndrome). The extrapolation of guidelines for the management of individuals with high-penetrance variants of cancer-susceptibility genes to the clinical care of patients with moderate-penetrance gene mutations could result in substantial harm. Thus, we provide a framework for clinical decision-making pending the development of a sufficient evidence base to document the clinical utility of the interventions for individuals with inherited moderate-penetrance gene mutations associated with an increased risk of cancer. PMID:27296296

  5. Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.

    Science.gov (United States)

    Xie, Kaipeng; Liang, Cheng; Li, Qin; Yan, Caiwang; Wang, Cheng; Gu, Yayun; Zhu, Meng; Du, Fangzhi; Wang, Hui; Dai, Juncheng; Liu, Xiao'an; Jin, Guangfu; Shen, Hongbing; Ma, Hongxia; Hu, Zhibin

    2016-10-01

    The aim of this article was to evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95% CI = 1.13-1.81; HR = 1.38, 95% CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all p lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. PMID:27225307

  6. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

    OpenAIRE

    CORVIN, AIDEN PETER

    2009-01-01

    PUBLISHED Ulcerative colitis (UC) is a common form of inflammatory bowel disease with a complex aetiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome- wide association scan for UC in 2361 cases and 5417 controls. Loci showing evidence of association at P < 1 ? 10 ?5 were followed up by genotyping in an independent set of 2321 cases and 4818 controls. We find genome-wide significant evidence of association at three new loci, each cont...

  7. Cancer susceptibility and reproductive trade-offs: a model of the evolution of cancer defences.

    Science.gov (United States)

    Boddy, Amy M; Kokko, Hanna; Breden, Felix; Wilkinson, Gerald S; Aktipis, C Athena

    2015-07-19

    The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction. PMID:26056364

  8. Genome-wide association study of osteochondrosis in the tarsocrural joint of Dutch Warmblood horses identifies susceptibility loci on chromosomes 3 and 10.

    Science.gov (United States)

    Orr, N; Hill, E W; Gu, J; Govindarajan, P; Conroy, J; van Grevenhof, E M; Ducro, B J; van Arendonk, J A M; Knaap, J H; van Weeren, P R; Machugh, D E; Ennis, S; Brama, P A J

    2013-08-01

    Equine osteochondrosis is a developmental joint disease that is a significant source of morbidity affecting multiple breeds of horse. The genetic variants underlying osteochondrosis susceptibility have not been established. Here, we describe the results of a genome-wide association study of osteochondrosis using 90 cases and 111 controls from a population of Dutch Warmblood horses. We report putative associations between osteochondrosis and loci on chromosome 3 (BIEC2-808543; P = 5.03 × 10(-7) ) and chromosome 10 (BIEC2-121323; P = 2.62 × 10(-7) ). PMID:23278111

  9. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1

    OpenAIRE

    Kirino, Yohei; Bertsias, George; Ishigatsubo, Yoshiaki; Mizuki, Nobuhisa; Tugal-Tutkun, Ilknur; Seyahi, Emire; Ozyazgan, Yilmaz; Sacli, F. Sevgi; Erer, Burak; Inoko, Hidetoshi; Emrence, Zeliha; Cakar, Atilla; Abaci, Neslihan; Ustek, Duran; Satorius, Colleen

    2013-01-01

    Patients with Behçet's disease (BD) suffer from episodic inflammation often affecting the orogenital mucosa, skin, and eyes. To discover new BD-susceptibility loci, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish BD patients and 1,278 controls. We identified novel associations at CCR1, STAT4, and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln, recessively conferred disease risk. These findings repl...

  10. Prostate Cancer Susceptibility Polymorphism rs2660753 Is Not Associated with Invasive Ovarian Cancer

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Kelemen, Linda E; Wang, Qinggang;

    2011-01-01

    BACKGROUND: We previously reported an association between rs2660753, a prostate cancer susceptibility polymorphism, and invasive epithelial ovarian cancer (EOC; OR = 1.2, 95% CI=1.0-1.4, P(trend) = 0.01) that showed a stronger association with the serous histological subtype (OR = 1.3, 95% CI = 1.......0-1.2, P(trend) = 0.11). There was no evidence for statistical heterogeneity in ORs across the studies. CONCLUSIONS: Although rs2660753 is a strong prostate cancer susceptibility polymorphism, the association with another hormonally related cancer, invasive EOC, is not supported by this replication study.......1-1.5, P(trend) = 0.003). METHODS: We sought to replicate this association in 12 other studies comprising 4,482 cases and 6,894 controls of white non-Hispanic ancestry in the Ovarian Cancer Association Consortium. RESULTS: No evidence for an association with all cancers or serous cancers was observed in a...

  11. High-Resolution Genome-Wide Linkage Mapping Identifies Susceptibility Loci for BMI in the Chinese Population

    DEFF Research Database (Denmark)

    Zhang, Dong Feng; Pang, Zengchang; Li, Shuxia;

    2012-01-01

    performed with Merlin software package for linkage analysis using variance components approach for quantitative trait loci mapping. We identified a strong linkage peak at the end of chromosome 7 (7q36 at 186 cM) with a lod score of 4.06 which overlaps with that reported by a large multicenter study in...

  12. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

    Science.gov (United States)

    Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Dayani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; BK, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

    2016-01-01

    Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations. PMID:26192919

  13. Five endometrial cancer risk loci identified through genome-wide association analysis.

    Science.gov (United States)

    Cheng, Timothy H T; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica M J; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-06-01

    We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. PMID:27135401

  14. SATB1 tethers multiple gene loci to reprogram expression profiledriving breast cancer metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Hye-Jung; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

    2006-07-13

    Global changes in gene expression occur during tumor progression, as indicated by expression profiling of metastatic tumors. How this occurs is poorly understood. SATB1 functions as a genome organizer by folding chromatin via tethering multiple genomic loci and recruiting chromatin remodeling enzymes to regulate chromatin structure and expression of a large number of genes. Here we show that SATB1 is expressed at high levels in aggressive breast cancer cells, and is undetectable in non-malignant breast epithelial cells. Importantly, RNAi-mediated removal of SATB1 from highly-aggressive MDA-MB-231 cells altered the expression levels of over 1200 genes, restored breast-like acinar polarity in three-dimensional cultures, and prevented the metastastic phenotype in vivo. Conversely, overexpression of SATB1 in the less-aggressive breast cancer cell line Hs578T altered the gene expression profile and increased metastasis dramatically in vivo. Thus, SATB1 is a global regulator of gene expression in breast cancer cells, directly regulating crucial metastasis-associated genes, including ERRB2 (HER2/NEU), TGF-{beta}1, matrix metalloproteinase 3, and metastasin. The identification of SATB1 as a protein that re-programs chromatin organization and transcription profiles to promote breast cancer metastasis suggests a new model for metastasis and may provide means of therapeutic intervention.

  15. Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population.

    Directory of Open Access Journals (Sweden)

    Kensuke Sakai

    Full Text Available AIMS: East Asian genome-wide association studies (GWAS for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. METHODS: We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls for each of the 9 single nucleotide polymorphisms (SNPs, rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. RESULTS: With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0 as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4, OR = 1.05, 95% confidence interval: 1.02-1.09. In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. CONCLUSIONS: These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.

  16. Heuristic modeling of carcinogenesis for the population with dichotomous susceptibility to cancer: a pancreatic cancer example.

    Directory of Open Access Journals (Sweden)

    Tengiz Mdzinarishvili

    Full Text Available At present, carcinogenic models imply that all individuals in a population are susceptible to cancer. These models either ignore a fall of the cancer incidence rate at old ages, or use some poorly identifiable parameters for its accounting. In this work, a new heuristic model is proposed. The model assumes that, in a population, only a small fraction (pool of individuals is susceptible to cancer and decomposes the problem of the carcinogenic modeling on two sequentially solvable problems: (i determination of the age-specific hazard rate in individuals susceptible to cancer (individual hazard rate from the observed hazard rate in the population (population hazard rate; and (ii modelling of the individual hazard rate by a chosen "up" of the theoretical hazard function describing cancer occurrence in individuals in time (age. The model considers carcinogenesis as a failure of individuals susceptible to cancer to resist cancer occurrence in aging and uses, as the theoretical hazard function, the three-parameter Weibull hazard function, often utilized in a failure analysis. The parameters of this function, providing the best fit of the modeled and observed individual hazard rates (determined from the population hazard rates, are the outcomes of the modeling. The model was applied to the pancreatic cancer data. It was shown that, in the populations stratified by gender, race and the geographic area of living, the modeled and observed population hazard rates of pancreatic cancer occurrence have similar turnovers at old ages. The sizes of the pools of individuals susceptible to this cancer: (i depend on gender, race and the geographic area of living; (ii proportionally influence the corresponding population hazard rates; and (iii do not influence the individual hazard rates. The model should be further tested using data on other types of cancer and for the populations stratified by different categorical variables.

  17. Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese.

    Directory of Open Access Journals (Sweden)

    Toshihiko Ohshige

    Full Text Available BACKGROUND: Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies. METHODOLOGY/PRINCIPAL FINDINGS: We examined the association of single nucleotide polymorphisms (SNPs within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1 with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls. The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05-1.26 and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05. CONCLUSIONS: These results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.

  18. Functional annotations of diabetes nephropathy susceptibility loci through analysis of genome-wide renal gene expression in rat models of diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Farrall Martin

    2009-07-01

    Full Text Available Abstract Background Hyperglycaemia in diabetes mellitus (DM alters gene expression regulation in various organs and contributes to long term vascular and renal complications. We aimed to generate novel renal genome-wide gene transcription data in rat models of diabetes in order to test the responsiveness to hyperglycaemia and renal structural changes of positional candidate genes at selected diabetic nephropathy (DN susceptibility loci. Methods Both Affymetrix and Illumina technologies were used to identify significant quantitative changes in the abundance of over 15,000 transcripts in kidney of models of spontaneous (genetically determined mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ]. Results Different patterns of transcription regulation in the two rat models of diabetes likely underlie the roles of genetic variants and hyperglycaemia severity. The impact of prolonged hyperglycaemia on gene expression changes was more profound in STZ-WKY rats than in GK rats and involved largely different sets of genes. These included genes already tested in genetic studies of DN and a large number of protein coding sequences of unknown function which can be considered as functional and, when they map to DN loci, positional candidates for DN. Further expression analysis of rat orthologs of human DN positional candidate genes provided functional annotations of known and novel genes that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations. Conclusion Combining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support for testing candidate genes in human genetics.

  19. Contribution of environment and genetics to pancreatic cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Barbara A Hocevar

    Full Text Available Several risk factors have been identified as potential contributors to pancreatic cancer development, including environmental and lifestyle factors, such as smoking, drinking and diet, and medical conditions such as diabetes and pancreatitis, all of which generate oxidative stress and DNA damage. Oxidative stress status can be modified by environmental factors and also by an individual's unique genetic makeup. Here we examined the contribution of environment and genetics to an individual's level of oxidative stress, DNA damage and susceptibility to pancreatic cancer in a pilot study using three groups of subjects: a newly diagnosed pancreatic cancer group, a healthy genetically-unrelated control group living with the case subject, and a healthy genetically-related control group which does not reside with the subject. Oxidative stress and DNA damage was evaluated by measuring total antioxidant capacity, direct and oxidative DNA damage by Comet assay, and malondialdehyde levels. Direct DNA damage was significantly elevated in pancreatic cancer patients (age and sex adjusted mean ± standard error: 1.00 ± 0.05 versus both healthy unrelated and related controls (0.70 ± 0.06, pA and ERCC4 R415Q polymorphisms. These results suggest that measurement of DNA damage, as well as select SNPs, may provide an important screening tool to identify individuals at risk for development of pancreatic cancer.

  20. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

    Directory of Open Access Journals (Sweden)

    Fergus J Couch

    Full Text Available BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer, with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8, HR = 1.14, 95% CI: 1.09-1.20. In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8, HR = 1.27, 95% CI: 1.17-1.38 and 4q32.3 (rs4691139, P = 3.4 × 10(-8, HR = 1.20, 95% CI: 1.17-1.38. The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4. These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  1. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    Science.gov (United States)

    Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Investigators, kConFab; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Ewart Toland, Amanda; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. PMID:23544013

  2. Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia.

    Science.gov (United States)

    Tcheandjieu, Catherine; Lesueur, Fabienne; Sanchez, Marie; Baron-Dubourdieu, Dominique; Guizard, Anne-Valerie; Mulot, Claire; Laurent-Puig, Pierre; Schvartz, Claire; Truong, Therese; Guenel, Pascal

    2016-08-01

    Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p functional studies. PMID:26991144

  3. Identification and characterization of locus specific methylation patterns within novel loci undergoing hypermethylation during breast cancer pathogenesis

    DEFF Research Database (Denmark)

    Wojdacz, Tomasz K; Windeløv, Johanne Agerlin; Thestrup, Britta Boserup;

    2014-01-01

    . Analysis of the screening results showed that all DMRs tested displayed significant gains of methylation in the cancer tissue compared to the levels in control tissue. Interestingly, we observed two types of locus-specific methylation, with loci undergoing either predominantly full or heterogeneous...... regions (DMRs) were validated using methylation-sensitive high-resolution melting (MS-HRM) in a case-control study on a panel of breast carcinomas (n = 275) and non-malignant controls (n = 74). RESULTS: On the basis of microarray results, we selected 19 DMRs for large-scale screening of cases and controls...... methylation during carcinogenesis. Almost all tested DMRs (17 of 19) displayed low-level methylation in nonmalignant breast tissue, independently of locus-specific methylation patterns in cases. CONCLUSIONS: Specific loci can undergo either heterogeneous or full methylation during carcinogenesis, and loci...

  4. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.

    Science.gov (United States)

    Germain, Marine; Chasman, Daniel I; de Haan, Hugoline; Tang, Weihong; Lindström, Sara; Weng, Lu-Chen; de Andrade, Mariza; de Visser, Marieke C H; Wiggins, Kerri L; Suchon, Pierre; Saut, Noémie; Smadja, David M; Le Gal, Grégoire; van Hylckama Vlieg, Astrid; Di Narzo, Antonio; Hao, Ke; Nelson, Christopher P; Rocanin-Arjo, Ares; Folkersen, Lasse; Monajemi, Ramin; Rose, Lynda M; Brody, Jennifer A; Slagboom, Eline; Aïssi, Dylan; Gagnon, France; Deleuze, Jean-Francois; Deloukas, Panos; Tzourio, Christophe; Dartigues, Jean-Francois; Berr, Claudine; Taylor, Kent D; Civelek, Mete; Eriksson, Per; Psaty, Bruce M; Houwing-Duitermaat, Jeanine; Goodall, Alison H; Cambien, François; Kraft, Peter; Amouyel, Philippe; Samani, Nilesh J; Basu, Saonli; Ridker, Paul M; Rosendaal, Frits R; Kabrhel, Christopher; Folsom, Aaron R; Heit, John; Reitsma, Pieter H; Trégouët, David-Alexandre; Smith, Nicholas L; Morange, Pierre-Emmanuel

    2015-04-01

    Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE. Nine loci reached the genome-wide significance level of 5 × 10(-8) including six already known to associate with VTE (ABO, F2, F5, F11, FGG, and PROCR) and three unsuspected loci. SNPs mapping to these latter were selected for replication in three independent case-control studies totaling 3,009 VTE-affected individuals and 2,586 control subjects. This strategy led to the identification and replication of two VTE-associated loci, TSPAN15 and SLC44A2, with lead risk alleles associated with odds ratio for disease of 1.31 (p = 1.67 × 10(-16)) and 1.21 (p = 2.75 × 10(-15)), respectively. The lead SNP at the TSPAN15 locus is the intronic rs78707713 and the lead SLC44A2 SNP is the non-synonymous rs2288904 previously shown to associate with transfusion-related acute lung injury. We further showed that these two variants did not associate with known hemostatic plasma markers. TSPAN15 and SLC44A2 do not belong to conventional pathways for thrombosis and have not been associated to other cardiovascular diseases nor related quantitative biomarkers. Our findings uncovered unexpected actors of VTE etiology and pave the way for novel mechanistic concepts of VTE pathophysiology. PMID:25772935

  5. A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Kendra A Williams

    2014-11-01

    Full Text Available Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP8247Ng/J (TRAMP mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ F2 intercross males (n = 228, which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322 were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2 harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such

  6. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

    DEFF Research Database (Denmark)

    Sørensen, Per Soelberg

    2010-01-01

    same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 x 10(-9)), IL12A (P=3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P=3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele...... seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 x 10(-5)) and in peripheral blood mononuclear cells from subjects with...

  7. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Ramus, S.J.; Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Sinilnikova, O.M.; Healey, S.; Barrowdale, D.; Lee, A.; Thomassen, M.; Gerdes, A.M.; Kruse, T.A.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Swe, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowocka, E.; Gronwald, J.; Huzarski, T.; Byrski, T.; Cybulski, C.; Toloczko-Grabarek, A.; Osorio, A.; Benitez, J.; Duran, M.; Tejada, M.I.; Hamann, U.; Rookus, M.; Leeuwen, F.E. van; Aalfs, C.M.; Meijers-Heijboer, H.E.; Asperen, C.J. van; Roozendaal, K.E. van; Hoogerbrugge-van der Linden, N.; Collee, J.M.; Kriege, M.; Luijt, R.B. van der; Hebon, .; Embrace, .; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Porteous, M.E.; Kennedy, M.J.; Pathak, H.; Godwin, A.K.; Stoppa-Lyonnet, D.; Caux-Moncoutier, V.; Pauw, A. de; Gauthier-Villars, M.; Mazoyer, S.; Leone, M.; Calender, A.; Lasset, C.; Bonadona, V.; Hardouin, A.; Berthet, P.; Bignon, Y.J.; Uhrhammer, N.; Faivre, L.; Loustalot, C.; Gemo, .; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.K.; John, E.M.; Ligtenberg, M.J.

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of

  8. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Antoniou, Antonis C; Kuchenbaecker, Karoline B;

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers ...

  9. Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X.

    Directory of Open Access Journals (Sweden)

    Ching-Yu Cheng

    2009-05-01

    Full Text Available The prevalence of obesity (body mass index (BMI > or =30 kg/m(2 is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20% and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7. In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94; and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62. Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46. Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.

  10. Identification of Novel Susceptibility Loci for Kawasaki Disease in a Han Chinese Population by a Genome-Wide Association Study

    OpenAIRE

    Tsai, Fuu-Jen; Lee, Yi-Ching; Chang, Jeng-Sheng; Huang, Li-Min; Huang, Fu-Yuan; Chiu, Nan-Chang; Chen, Ming-Ren; CHI, Hsin; Lee, Yann-Jinn; Chang, Li-Ching; Liu, Yi-Min; Wang, Hsiang-Hua; Chen, Chien-Hsiun; Chen, Yuan-Tsong; Wu, Jer-Yuarn

    2011-01-01

    Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS) in 250 KD patients and 446 controls in a Han Ch...

  11. Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes

    DEFF Research Database (Denmark)

    Villacis, Rolando A R; Miranda, Priscila M; Gomy, Israel; Santos, Erika M M; Carraro, Dirce M; Achatz, Maria I; Rossi, Benedito M; Rogatto, Silvia R

    2016-01-01

    silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of...... risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary...

  12. Effect of six type II diabetes susceptibility loci and an FTO variant on obesity in Pakistani subjects.

    Science.gov (United States)

    Shabana; Ullah Shahid, Saleem; Wah Li, Ka; Acharya, Jayshree; Cooper, Jackie A; Hasnain, Shahida; Humphries, Stephen E

    2016-06-01

    The aim of the current study was to analyze the effect of six type II diabetes GWAS loci rs3923113 (GRB14), rs16861329 (ST6GAL1), rs1802295 (VPS26A), rs7178572 (HMG20A), rs2028299 (AP3S2) and rs4812829 (HNF4A), and an FTO polymorphism (rs9939609) on obesity. The probable mechanism of action of these SNPs was analyzed by studying their association with various biochemical and anthropometric parameters. A total of 475 subjects (obese=250, controls=225) were genotyped by TaqMan assay and their lipid profile was determined. Allele/genotype frequencies and an unweighted/weighted gene score were calculated. The effect of the gene score on anthropometric and biochemical parameters was analyzed. The minor allele frequencies of all variants were comparable to that reported in the original studies and were associated with obesity in these Pakistani subjects. Subjects with 9 risk alleles differ from those with lipid traits. We are the first to report the association of these T2D SNPs with obesity. In the Pakistani population the reported effect of six SNPs for obesity is similar to that reported for T2D and having a combination of risk alleles on obesity can be considerable. The mechanism of this effect is unclear, but appears not to be mediated by changing serum lipid chemistry. PMID:26395551

  13. 19p13.1 is a triple-negative-specific breast cancer susceptibility locus

    DEFF Research Database (Denmark)

    Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M;

    2012-01-01

    The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone recepto...

  14. The role of genetic breast cancer susceptibility variants as prognostic factors.

    Science.gov (United States)

    Fasching, Peter A; Pharoah, Paul D P; Cox, Angela; Nevanlinna, Heli; Bojesen, Stig E; Karn, Thomas; Broeks, Annegien; van Leeuwen, Flora E; van't Veer, Laura J; Udo, Renate; Dunning, Alison M; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Shah, Mitul; Nordestgaard, Børge G; Flyger, Henrik; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Garcia-Closas, Montserrat; Sherman, Mark; Lissowska, Jolanta; Seynaeve, Caroline; Huijts, Petra E A; Tollenaar, Rob A E M; Ziogas, Argyrios; Ekici, Arif B; Rauh, Claudia; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Andrulis, Irene L; Ozcelik, Hilmi; Mulligan, Anna-Marie; Glendon, Gord; Hall, Per; Czene, Kamila; Liu, Jianjun; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Nickels, Stefan; Dörk, Thilo; Schiekel, Maria; Bremer, Michael; Park-Simon, Tjoung-Won; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Hooning, Maartje J; Martens, John W M; Jager, Agnes; Kriege, Mieke; Lindblom, Annika; Margolin, Sara; Couch, Fergus J; Stevens, Kristen N; Olson, Janet E; Kosel, Matthew; Cross, Simon S; Balasubramanian, Sabapathy P; Reed, Malcolm W R; Miron, Alexander; John, Esther M; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Chenevix-Trench, Georgia; Lambrechts, Diether; Dieudonne, Anne-Sophie; Hatse, Sigrid; van Limbergen, Erik; Benitez, Javier; Milne, Roger L; Zamora, M Pilar; Pérez, José Ignacio Arias; Bonanni, Bernardo; Peissel, Bernard; Loris, Bernard; Peterlongo, Paolo; Rajaraman, Preetha; Schonfeld, Sara J; Anton-Culver, Hoda; Devilee, Peter; Beckmann, Matthias W; Slamon, Dennis J; Phillips, Kelly-Anne; Figueroa, Jonine D; Humphreys, Manjeet K; Easton, Douglas F; Schmidt, Marjanka K

    2012-09-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at PBreast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility. PMID:22532573

  15. Sequence divergence of Mus spretus and Mus musculus across a skin cancer susceptibility locus

    Directory of Open Access Journals (Sweden)

    Balmain Allan

    2008-12-01

    Full Text Available Abstract Background Mus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5 on chromosome 12, shows strong linkage in one cross. Results To identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice. Conclusion Our analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.

  16. Pristane-induced arthritis loci interact with the Slc11a1 gene to determine susceptibility in mice selected for high inflammation.

    Science.gov (United States)

    De Franco, Marcelo; Peters, Luciana C; Correa, Mara A; Galvan, Antonella; Canhamero, Tatiane; Borrego, Andrea; Jensen, José R; Gonçalves, Jussara; Cabrera, Wafa H K; Starobinas, Nancy; Ribeiro, Orlando G; Dragani, Tommaso A; Dragani, Tommaso; Ibañez, Olga M

    2014-01-01

    AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmax (SS) mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmax(SS) mice susceptibility to PIA. PMID:24505471

  17. Experience of parental cancer in childhood is a risk factor for psychological distress during genetic cancer susceptibility testing

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Brocker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; Van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    2006-01-01

    Background: This study explores the effect of age at the time of parental cancer diagnosis or death on psychological distress and cancer risk perception in individuals undergoing genetic testing for a specific cancer susceptibility. Patients and methods: Cancer-related distress, worry and risk perce

  18. Mucin 1 Gene (MUC1 and Gastric-Cancer Susceptibility

    Directory of Open Access Journals (Sweden)

    Norihisa Saeki

    2014-05-01

    Full Text Available Gastric cancer (GC is one of the major malignant diseases worldwide, especially in Asia. It is classified into intestinal and diffuse types. While the intestinal-type GC (IGC is almost certainly caused by Helicobacter pylori (HP infection, its role in the diffuse-type GC (DGC appears limited. Recently, genome-wide association studies (GWAS on Japanese and Chinese populations identified chromosome 1q22 as a GC susceptibility locus which harbors mucin 1 gene (MUC1 encoding a cell membrane-bound mucin protein. MUC1 has been known as an oncogene with an anti-apoptotic function in cancer cells; however, in normal gastric mucosa, it is anticipated that the mucin 1 protein has a role in protecting gastric epithelial cells from a variety of external insults which cause inflammation and carcinogenesis. HP infection is the most definite insult leading to GC, and a protective function of mucin 1 protein has been suggested by studies on Muc1 knocked-out mice.

  19. Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility.

    Science.gov (United States)

    Horn, G T; Bugawan, T L; Long, C M; Erlich, H A

    1988-01-01

    Analysis of sequence variation in the polymorphic second exon of the major histocompatibility complex genes HLA-DQ alpha and -DQ beta has revealed 8 allelic variants at the alpha locus and 13 variants at the beta locus. Correlation of sequence variation with serologic typing suggests that the DQw2, DQw3, and DQ(blank) types are determined by the DQ beta subunit, while the DQw1 specificity is determined by DQ alpha. The nature of the amino acid at position 57 in the DQ beta subunit is correlated with susceptibility to insulin-dependent diabetes mellitus. This region of the DQ beta chain contains shared peptides with Epstein-Barr virus and rubella virus. PMID:2842756

  20. Inherited susceptibility to cancer and other factors influencing occurrence of cancer

    International Nuclear Information System (INIS)

    The types of defects and polymorphisms leading to hereditary susceptibility to cancer include proneness to increased DNA damage, recessive syndromes of faulty DNA repair and differentiation, as well as dominant mutations of cell cycle and control proliferation. The cancer susceptibility syndromes inherited in a dominant fashion are caused by mutations in tumor suppressor genes. These genes are recessive in relation to wild type alleles. In two syndromes of hereditary mutations in tumor suppressor genes (Rb and WT2), their expression 'in vivo' may be influenced by the sex of the transmitting parent, what points to modulation by imprinting. Genetic heterogeneity of the population in susceptibility to genotoxic agents is related to the individual variation in acceptable levels of exposure to agents and factors, such as products of incomplete combustion (PIC), UV ('xeroderma pigmentosum') and ionizing radiation ('ataxia telangiectasia'). DNA damage and adducts are considered to be indicative of genotoxic exposure and its effect as well as modulation of carcinogenic damage by genetic polymorphisms. Gene and protein polymorphisms are considered as markers of increased individual risk. Since environmental factors are considered to be able to control, the individual susceptibility to enhanced DNA damage and environmentally induced cancers could be counteracted by decreasing the levels of contamination or exposure. This explains the wide interest in markers of this individual sensitivity. Most of the postulated markers of sensitivity to PIV do not, however, prove to be generally applicable in that sense. Their prognostic value is limited either by low amplitude of the effect, or by their character specific either to the population or to the cancer type. The polymorphisms most relevant to cancers induced by PIC exposures may be those of inductibility of benzopyrene hydroxylase, and some other DNA polymorphisms concerning the CYP1A1 gene. (author). 24 refs, 1 fig., 3 tabs

  1. Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.

    Science.gov (United States)

    Yadav, Anu; Gupta, Annapurna; Rastogi, Neeraj; Agrawal, Sushma; Kumar, Ashok; Kumar, Vijay; Mittal, Balraj

    2016-02-01

    Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response. PMID:26318430

  2. Susceptibility

    Czech Academy of Sciences Publication Activity Database

    Petrovský, Eduard

    Dordrecht: Springer, 2007 - (Gubbins, D.; Herrero-Bervera, E.), s. 931-933. (Encyclopedia of Earth sciences series). ISBN 978-1-4020-3992-8 Institutional research plan: CEZ:AV0Z30120515 Keywords : magnetic susceptibility * magnetic field * magnetization curve Subject RIV: DE - Earth Magnetism, Geodesy, Geography

  3. Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

    OpenAIRE

    Travis, Lois B.; Rabkin, Charles S.; Brown, Linda Morris; Allan, James M.; Alter, Blanche P.; Ambrosone, Christine B.; Begg, Colin B.; Caporaso, Neil; Chanock, Stephen; DeMichele, Angela; Figg, William Douglas; Mary K Gospodarowicz; Hall, Eric J.; Hisada, Michie; Inskip, Peter

    2006-01-01

    KEYWORDS - CLASSIFICATION: adverse effects;Antineoplastic Agents;biomarkers of individual susceptibility: validation;Biotechnology;cancer epidemiology;chemically induced;Carcinogens;Case-Control Studies;Clinical Trials;Cohort Studies;Congresses;drug therapy;epidemiology;etiology;genetics;Genetic Predisposition to Disease;Humans;methods;mortality;Medical Informatics;Multicenter Studies;Neoplasms;Neoplasms,Radiation-Induced;Neoplasms,Second Primary;radiotherapy;Radiotherapy;Registries;Research;...

  4. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

    Directory of Open Access Journals (Sweden)

    Juliane Winkelmann

    2011-07-01

    Full Text Available Restless legs syndrome (RLS is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA for RLS in 922 cases and 1,526 controls (using 301,406 SNPs followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11, OR = 1.23 and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19, OR = 1.35 in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

  5. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

    Science.gov (United States)

    Winkelmann, Juliane; Czamara, Darina; Schormair, Barbara; Knauf, Franziska; Schulte, Eva C; Trenkwalder, Claudia; Dauvilliers, Yves; Polo, Olli; Högl, Birgit; Berger, Klaus; Fuhs, Andrea; Gross, Nadine; Stiasny-Kolster, Karin; Oertel, Wolfgang; Bachmann, Cornelius G; Paulus, Walter; Xiong, Lan; Montplaisir, Jacques; Rouleau, Guy A; Fietze, Ingo; Vávrová, Jana; Kemlink, David; Sonka, Karel; Nevsimalova, Sona; Lin, Siong-Chi; Wszolek, Zbigniew; Vilariño-Güell, Carles; Farrer, Matthew J; Gschliesser, Viola; Frauscher, Birgit; Falkenstetter, Tina; Poewe, Werner; Allen, Richard P; Earley, Christopher J; Ondo, William G; Le, Wei-Dong; Spieler, Derek; Kaffe, Maria; Zimprich, Alexander; Kettunen, Johannes; Perola, Markus; Silander, Kaisa; Cournu-Rebeix, Isabelle; Francavilla, Marcella; Fontenille, Claire; Fontaine, Bertrand; Vodicka, Pavel; Prokisch, Holger; Lichtner, Peter; Peppard, Paul; Faraco, Juliette; Mignot, Emmanuel; Gieger, Christian; Illig, Thomas; Wichmann, H-Erich; Müller-Myhsok, Bertram; Meitinger, Thomas

    2011-07-01

    Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767. PMID:21779176

  6. Methylenetetrahydrofolate Reductase Genotypes, Dietary Habits and Susceptibility to Stomach Cancer

    Institute of Scientific and Technical Information of China (English)

    ChangmingGao; TakezakiToshiro; JianzhongWu; JianhuoDing; YantingLiu; SupingLi; PingSu; XuHu; TianliongXu; HamajimaNobuyuki; TajimaKazuo

    2004-01-01

    OBJECTIVE To study the relation among methylenetetrahydrofolate reductase (MTHFR) C677T genotypes, dietary habits and the risk of stomach cancer (SC).METHODS A case-control study was conducted with 107 cases of SC and 200 population-based controls in Chuzhou district, Huaian, Jiangsu province, China. The epidemiological data were collected, and DNA of peripheral blood leukocytes was obtained from all of the subjects..MTHFR genotypes were detected by PCR-RFLP. RESULTS (1) The prevalence of the MTHFR C/T or T/T genotypes was found to be significantly different between controls (68.5%) and SC cases (79.4%,P=0.0416), the increased risk had an adjusted OR of 1.79 (95%C1:1.01-3.19). (2) Among subjects who had a low intake of garlic or Chinese onion, MTHFR C/T or T/T genotypes significantly increased the risk of developing SC. Among non-tea drinkers or among subjects who had a frequent intakeof meat, the carriers of the MTHFR C/T or T/T genotypes had a higher risk of SC than individuals with the C/C type MTHFR. CONCLUSION The polymorphism of MTHFR C677T was associated with increased risk of developing SC, and that individuals with differing genotypes may have different susceptibilities to SC, based on their exposure level to environmental factors.

  7. Identification of a breast cancer susceptibility locus at 4q31.22 using a genome-wide association study paradigm.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available More than 40 single nucleotide polymorphisms (SNPs for breast cancer susceptibility were identified by genome-wide association studies (GWASs. However, additional SNPs likely contribute to breast cancer susceptibility and overall genetic risk, prompting this investigation for additional variants. Six putative breast cancer susceptibility SNPs identified in a two-stage GWAS that we reported earlier were replicated in a follow-up stage 3 study using an independent set of breast cancer cases and controls from Canada, with an overall cumulative sample size of 7,219 subjects across all three stages. The study design also encompassed the 11 variants from GWASs previously reported by various consortia between the years 2007-2009 to (i enable comparisons of effect sizes, and (ii identify putative prognostic variants across studies. All SNP associations reported with breast cancer were also adjusted for body mass index (BMI. We report a strong association with 4q31.22-rs1429142 (combined per allele odds ratio and 95% confidence interval = 1.28 [1.17-1.41] and P combined = 1.5×10(-7, when adjusted for BMI. Ten of the 11 breast cancer susceptibility loci reported by consortia also showed associations in our predominantly Caucasian study population, and the associations were independent of BMI; four FGFR2 SNPs and TNRC9-rs3803662 were among the most notable associations. Since the original report by Garcia-Closas et al. 2008, this is the second study to confirm the association of 8q24.21-rs13281615 with breast cancer outcomes.

  8. Lung cancer susceptibility model based on age, family history and genetic variants.

    Directory of Open Access Journals (Sweden)

    Robert P Young

    Full Text Available BACKGROUND: Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: We screened 157 candidate single nucleotide polymorphisms (SNP in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases and identified 30 SNPs associated with either the healthy smokers (protective or lung cancer (susceptibility phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk. CONCLUSIONS/SIGNIFICANCE: Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.

  9. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

    Indian Academy of Sciences (India)

    N. Johns; B. H. Tan; M. Macmillan; T. S. Solheim; J. A. Ross; V. E. Baracos; S. Damaraju; K. C. H. Fearon

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  10. Association of DNA repair gene XRCC1 and lung cancer susceptibility among nonsmoking Chinese women

    DEFF Research Database (Denmark)

    Yin, J.; Vogel, Ulla Birgitte; Ma, Y.;

    2009-01-01

    predisposition to cancer risk. To address this question in more detail, we conducted a hospital-based case-control study consisting of 55 lung cancer cases and 74 cancer-free controls matched on age and ethnicity among nonsmoking Chinese women. We analyzed five coding single-nucleotide polymorphisms in the XRCC1...... the haplotype encompassing the variant alleles may contribute to susceptibility of lung cancer in a Chinese population....

  11. ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry

    OpenAIRE

    Anne-Laure Renault; Fabienne Lesueur; Yan Coulombe; Stéphane Gobeil; Penny Soucy; Yosr Hamdi; Sylvie Desjardins; Florence Le Calvez-Kelm; Maxime Vallée; Catherine Voegele; Hopper, John L.; Andrulis, Irene L.; Southey, Melissa C.; John, Esther M.; Jean-Yves Masson

    2016-01-01

    Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ...

  12. Do variants associated with susceptibility to pancreatic cancer and type 2 diabetes reciprocally affect risk?

    Directory of Open Access Journals (Sweden)

    Lang Wu

    Full Text Available Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility.Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP. Using the PanScan datasets, we tested for association of 38 variants within 37 genomic regions known to be susceptibility factors for type 2 diabetes. We further examined whether type 2 diabetes variants predispose to pancreatic cancer risk stratified by diabetes status. Correspondingly, we examined the association of fourteen pancreatic cancer susceptibility variants within eight genomic regions in the GENEVA Type 2 Diabetes dataset.Four plausible associations of diabetes variants and pancreatic cancer risk were detected at a significance threshold of p = 0.05, and one pancreatic cancer susceptibility variant was associated with diabetes risk at threshold of p = 0.05, but none remained significant after correction for multiple comparisons.Currently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.

  13. Family Matters: Adjustment to genetic cancer susceptibility testing

    NARCIS (Netherlands)

    I.I.H. van Oostrom (Iris)

    2006-01-01

    textabstractCancer is generally feared because it is associated with death and severe physical suffering. It is one of the most common causes of death in the Netherlands. Breast and colon cancer are the most prevalent types of cancer among women. Frequently occurring types in men are cancer of colon

  14. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

    Science.gov (United States)

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bowtell, David; Webb, Penelope M.; deFazio, Anna; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y.; Kruger Kjaer, Susanne; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F. A. G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Sellers, Thomas A.; Shu, Xiao-Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D.; Gayther, Simon A.; Freedman, Matthew L.

    2015-01-01

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC. PMID:26391404

  15. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, RR; Nielsen, CK; Nasser, A; Thomsen, SI; Eghorn, LF; Pham, Y; Schulenburg, C; Syberg, S; Ding, Ming; Stojilkovic, SS; Jorgensen, NR; Heegaard, AM

    2011-01-01

    were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a...

  16. Ovarian Cancer Susceptibility Alleles and Risk of Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    Ramus, Susan J.; Antoniou, Antonis C; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Złowocka, Elżbieta; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Tejada, Maria-Isabel; Hamann, Ute; Rookus, Matti; van Leeuwen, Flora E.; Aalfs, Cora M.; Meijers-Heijboer, Hanne E.J.; van Asperen, Christi J.; van Roozendaal, K.E.P.; Hoogerbrugge, Nicoline; Collée, J. Margriet; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Porteous, Mary E.; Kennedy, M. John; Pathak, Harsh; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Caux-Moncoutier, Virginie; de Pauw, Antoine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Léoné, Mélanie; Calender, Alain; Lasset, Christine; Bonadona, Valérie; Hardouin, Agnès; Berthet, Pascaline; Bignon, Yves-Jean; Uhrhammer, Nancy; Faivre, Laurence; Loustalot, Catherine; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy K.; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Tea, Muy-Kheng; Pfeiler, Georg; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Kirchhoff, Tomas; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion; Phillips, Kelly-Anne; Van Le, Linda; Hoffman, James S; Toland, Amanda Ewart; Montagna, Marco; Tognazzo, Silvia; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Tornero, Eva; Navarro, Matilde; Moysich, Kirsten B.; Karlan, Beth Y.; Gross, Jenny; Olah, Edith; Vaszko, Tibor; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M; van Rensburg, Elizabeth J; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schäfer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Aittomäki, Kristiina; Plante, Marie; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan Chun; Wang, Xianshu; Lindor, Noralane; Fredericksen, Zachary; Pankratz, V. Shane; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Pharoah, Paul D.P.; Gayther, Simon A.; Simard, Jacques; Easton, Douglas F.; Couch, Fergus J.; Chenevix-Trench, Georgia

    2012-01-01

    Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67–0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21–1.83) P-trend = 1.8 × 10−4, rs717852 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.6 × 10−4, rs9303542 HR = 1.16 (95% CI: 1.02–1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81–0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10–1.42) P-trend = 6.1 × 10−4. The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer. PMID:22253144

  17. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

    NARCIS (Netherlands)

    Plon, S.E.; Eccles, D.M.; Easton, D.; Foulkes, W.D.; Genuardi, M.; Greenblatt, M.S.; Hogervorst, F.B.; Hoogerbrugge, N.; Spurdle, A.B.; Tavtigian, S.V.

    2008-01-01

    Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genet

  18. Screening for amplification genomic loci and genes associated prognosis in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Objective:We used a high-resolution array-based comparative genomic hybridization (aCGH) coupled with patient clinical information to identify prognosis-related genomic loci and genes.Methods: aCGH coupled with patient clinical information was applied to identify prognosis-related loci and genes with high-frequency recurrent gains in 129 GC cases. The candidate loci and genes were validated using an independent cohort of 384 cases through branched DNA signal ampliifcation analysis.Results:A copy number gain of three chromosome regions, namely, 8q22, 8q24and 20q11-q13, conferred poor survival for patients. In addition, MYC, TNFRSF11B, ESRP1, CSE1L and MMP9 were found to be well correlated. Further validation verified that only MYC and TNFRSF11B within 8q24 are related to survival. Patients with gains in both MYC and TNFRSF11B presented poorer survival than those with no gains, particularly those with non-cardia GC. Gains in both of these genes were also a signiifcant independent prognostic indicator.Conclusion:Copy number gains in MYC and TNFRSF11B located at 8q24are associated with survival in GC, particularly non-cardia GC.

  19. DNA repair genotypes and phenotypes and cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    Qingyi Wei

    2008-01-01

    @@ The role of DNA repair in the etiology of cancers has been well illustrated in several hereditary syndromes, in which an inherited defect in DNA repair and related biological processes is associated with extraordinarily high incidence of cancer.

  20. Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium

    Czech Academy of Sciences Publication Activity Database

    Campa, D.; Rizzato, C.; Capurso, G.; Giese, N.; Funel, N.; Greenhalf, W.; Souček, P.; Gazouli, M.; Pezzilli, R.; Pasquali, C.; Talar-Wojnarowska, R.; Cantore, M.; Andriulli, A.; Scarpa, A.; Jamroziak, K.; Delle Fave, G.; Costello, E.; Khaw, K. T.; Heller, A.; Key, T. K.; Theodoropoulos, G.; Malecka-Panas, E.; Mambrini, A.; Bambi, F.; Landi, S.; Pedrazzoli, S.; Bassi, C.; Pacetti, P.; Piepoli, A.; Tavano, F.; di Sebastiano, P.; Vodičková, Ludmila; Basso, D.; Plebani, M.; Fogar, P.; Buechler, M. W.; Bugert, P.; Vodička, Pavel; Boggi, U.; Neoptolemos, J. P.; Werner, J.; Canzian, F.

    2013-01-01

    Roč. 45, č. 2 (2013), s. 95-99. ISSN 1590-8658 Institutional support: RVO:68378041 Keywords : cancer susceptibility * genetic polymorphisms * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.889, year: 2013

  1. Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci

    DEFF Research Database (Denmark)

    Kettunen, J; Perola, M; Martin, N G;

    2009-01-01

    odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION: Linkage analysis of the combined data in this large twin...

  2. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency.

    Directory of Open Access Journals (Sweden)

    Ricardo C Ferreira

    2012-01-01

    Full Text Available Selective IgA deficiency (IgAD; serum IgA<0.07 g/l is the most common form of human primary immune deficiency, affecting approximately 1∶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined P = 7.69×10(-57; OR = 2.80 resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined P = 5.86×10(-17; OR = 4.28 and the DRB1*1501 (combined P = 2.24×10(-35; OR = 0.13 alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to

  3. Genetic variants on 3q21 and in the Sp8 transcription factor gene (SP8 as susceptibility loci for psychotic disorders: a genetic association study.

    Directory of Open Access Journals (Sweden)

    Kenji Kondo

    Full Text Available BACKGROUND: Recent genome-wide association studies (GWASs investigating bipolar disorder (BD have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ, two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ in the Japanese population. METHODS: Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993 and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149. We assessed allelic association between BD, SCZ, psychosis (BD+SCZ and the SNPs selected for the analysis. RESULTS: Eight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05. Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively. The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1 was significant on genome-wide association level (P = 5×10(-8 only for BD (P = 9.4×10(-9 and psychosis (P = 2.0×10(-10. Although the association of rs2709722 in Sp8 transcription factor (SP8 was suggestive in the Asian population (P = 2.1×10(-7 for psychosis, this signal weakened when the samples size was increased by including data from a

  4. Women’s perceived susceptibility to and utilisation of cervical cancer screening services in Malawi

    Directory of Open Access Journals (Sweden)

    Melanie Y. Hami

    2014-10-01

    Full Text Available Background: Malawi provides cervical cancer screening services free of charge at some public health facilities. Few women make use of these cancer screening services in Malawi and many women continue to be diagnosed with cervical cancer only during the late inoperable stages of the condition. Objectives: The purpose of this study was to discover whether the perceived susceptibility to cervical cancer, amongst Malawian women aged 42 and older, influenced their intentions to utilise the available free cervical cancer screening services. Method: A quantitative, cross-sectional descriptive study design was adopted. Structured interviews were conducted with 381 women who visited 3 health centres in the Blantyre District of Malawi. Results: A statistically-significant association existed between women’s intentions to be screened for cervical cancer and their knowledge about cervical cancer (X² = 8.9; df = 1; p = 0.003 and with having heard about HPV infection (X² = 4.2; df = 1; p = 0.041 at the 5% significance level. Cervical cancer screening services are provided free of charge in government health institutions in Malawi. Nevertheless, low perceived susceptibility to cervical cancer amongst women, aged 42 and older, might contribute to limited utilisation of cervical screening services, explaining why 80% of cervical cancer patients in Malawi were diagnosed during the late inoperable stages. Conclusion: Malawian women lacked awareness regarding their susceptibility to cervical cancer and required information about the available cervical cancer screening services. Malawi’s women, aged 42 and older, must be informed about the advantages of cervical cancer screening and about the importance of effective treatment if an early diagnosis has been made. Women aged 42 and older rarely attend antenatal, post-natal, well baby or family-planning clinics, where health education about cervical cancer screening is often provided. Consequently, these women

  5. Do Variants Associated with Susceptibility to Pancreatic Cancer and Type 2 Diabetes Reciprocally Affect Risk?

    OpenAIRE

    Wu, Lang; Rabe, Kari G.; Petersen, Gloria M.

    2015-01-01

    Objectives Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility. Methods Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes...

  6. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

    Science.gov (United States)

    Robson, Mark E; Bradbury, Angela R; Arun, Banu; Domchek, Susan M; Ford, James M; Hampel, Heather L; Lipkin, Stephen M; Syngal, Sapna; Wollins, Dana S; Lindor, Noralane M

    2015-11-01

    The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services. PMID:26324357

  7. Functional polymorphisms in the IL-10 gene with susceptibility to esophageal, nasopharyngeal, and oral cancers.

    Science.gov (United States)

    Li, Yu-Fen; Yang, Pei-Zhen; Li, Hua-Feng

    2016-03-18

    Emerging evidence showed that functional polymorphisms in the IL-10 gene may have effects on individuals' susceptibility to nasopharyngeal, oral and esophageal cancers, yet individually published findings are inconsistent. We therefore designed the meta-analysis to investigate the correlations of IL-10 genetic polymorphisms with susceptibility to nasopharyngeal, oral and esophageal cancers. The EMBASE, MEDLINE, CINAHL, Web of Science and the Chinese Biomedical Database (CBM) databases were searched with no language restrictions. We use Comprehensive Meta-analysis 2.0 software to carry out statistical analysis. Ten case-control studies with a number of 1,883 patients and 2,857 healthy subjects were enrolled. Our results revealed that IL-10 rs1800872 T>G and rs1800896 A>G polymorphisms has a significantly association with the increased risk of esophageal cancer under the allele and dominant models; rs1800871 T>G, rs1800872 T>G and rs1800896 A>G under allele and dominant models could increase the risk of nasopharyngeal cancer; rs1800871T>G, rs1800872T>G and rs1800896 A>G SNPs under allele model were closely related to the susceptibility to oral cancer. Our findings support the point that IL-10 genetic polymorphisms may play essential role in identifying esophageal cancer, nasopharyngeal cancer and oral cancer at early stage. PMID:27002767

  8. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

    Science.gov (United States)

    Wang, Zhaoming; Zhu, Bin; Zhang, Mingfeng; Parikh, Hemang; Jia, Jinping; Chung, Charles C.; Sampson, Joshua N.; Hoskins, Jason W.; Hutchinson, Amy; Burdette, Laurie; Ibrahim, Abdisamad; Hautman, Christopher; Raj, Preethi S.; Abnet, Christian C.; Adjei, Andrew A.; Ahlbom, Anders; Albanes, Demetrius; Allen, Naomi E.; Ambrosone, Christine B.; Aldrich, Melinda; Amiano, Pilar; Amos, Christopher; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L.; Arici, Cecilia; Arslan, Alan A.; Austin, Melissa A.; Baris, Dalsu; Barkauskas, Donald A.; Bassig, Bryan A.; Beane Freeman, Laura E.; Berg, Christine D.; Berndt, Sonja I.; Bertazzi, Pier Alberto; Biritwum, Richard B.; Black, Amanda; Blot, William; Boeing, Heiner; Boffetta, Paolo; Bolton, Kelly; Boutron-Ruault, Marie-Christine; Bracci, Paige M.; Brennan, Paul; Brinton, Louise A.; Brotzman, Michelle; Bueno-de-Mesquita, H. Bas; Buring, Julie E.; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Cao, Guangwen; Caporaso, Neil E.; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chang, Gee-Chen; Chang, I-Shou; Chang-Claude, Jenny; Che, Xu; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chung-Hsing; Chen, Constance; Chen, Kuan-Yu; Chen, Yuh-Min; Chokkalingam, Anand P.; Chu, Lisa W.; Clavel-Chapelon, Francoise; Colditz, Graham A.; Colt, Joanne S.; Conti, David; Cook, Michael B.; Cortessis, Victoria K.; Crawford, E. David; Cussenot, Olivier; Davis, Faith G.; De Vivo, Immaculata; Deng, Xiang; Ding, Ti; Dinney, Colin P.; Di Stefano, Anna Luisa; Diver, W. Ryan; Duell, Eric J.; Elena, Joanne W.; Fan, Jin-Hu; Feigelson, Heather Spencer; Feychting, Maria; Figueroa, Jonine D.; Flanagan, Adrienne M.; Fraumeni, Joseph F.; Freedman, Neal D.; Fridley, Brooke L.; Fuchs, Charles S.; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M.; Garcia-Closas, Montserrat; Garcia-Closas, Reina; Gastier-Foster, Julie M.; Gaziano, J. Michael; Gerhard, Daniela S.; Giffen, Carol A.; Giles, Graham G.; Gillanders, Elizabeth M.; Giovannucci, Edward L.; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M.; Gonzalez, Carlos; Gorlick, Richard; Greene, Mark H.; Gross, Myron; Grossman, H. Barton; Grubb, Robert; Gu, Jian; Guan, Peng; Haiman, Christopher A.; Hallmans, Goran; Hankinson, Susan E.; Harris, Curtis C.; Hartge, Patricia; Hattinger, Claudia; Hayes, Richard B.; He, Qincheng; Helman, Lee; Henderson, Brian E.; Henriksson, Roger; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holly, Elizabeth A.; Hong, Yun-Chul; Hoover, Robert N.; Hosgood, H. Dean; Hsiao, Chin-Fu; Hsing, Ann W.; Hsiung, Chao Agnes; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Hunter, David J.; Inskip, Peter D.; Ito, Hidemi; Jacobs, Eric J.; Jacobs, Kevin B.; Jenab, Mazda; Ji, Bu-Tian; Johansen, Christoffer; Johansson, Mattias; Johnson, Alison; Kaaks, Rudolf; Kamat, Ashish M.; Kamineni, Aruna; Karagas, Margaret; Khanna, Chand; Khaw, Kay-Tee; Kim, Christopher; Kim, In-Sam; Kim, Jin Hee; Kim, Yeul Hong; Kim, Young-Chul; Kim, Young Tae; Kang, Chang Hyun; Jung, Yoo Jin; Kitahara, Cari M.; Klein, Alison P.; Klein, Robert; Kogevinas, Manolis; Koh, Woon-Puay; Kohno, Takashi; Kolonel, Laurence N.; Kooperberg, Charles; Kratz, Christian P.; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C.; Kurucu, Nilgun; Lan, Qing; Lathrop, Mark; Lau, Ching C.; Lecanda, Fernando; Lee, Kyoung-Mu; Lee, Maxwell P.; Le Marchand, Loic; Lerner, Seth P.; Li, Donghui; Liao, Linda M.; Lim, Wei-Yen; Lin, Dongxin; Lin, Jie; Lindstrom, Sara; Linet, Martha S.; Lissowska, Jolanta; Liu, Jianjun; Ljungberg, Börje; Lloreta, Josep; Lu, Daru; Ma, Jing; Malats, Nuria; Mannisto, Satu; Marina, Neyssa; Mastrangelo, Giuseppe; Matsuo, Keitaro; McGlynn, Katherine A.; McKean-Cowdin, Roberta; McNeill, Lorna H.; McWilliams, Robert R.; Melin, Beatrice S.; Meltzer, Paul S.; Mensah, James E.; Miao, Xiaoping; Michaud, Dominique S.; Mondul, Alison M.; Moore, Lee E.; Muir, Kenneth; Niwa, Shelley; Olson, Sara H.; Orr, Nick; Panico, Salvatore; Park, Jae Yong; Patel, Alpa V.; Patino-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H. M.; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M.; Picci, Piero; Pike, Malcolm C.; Porru, Stefano; Prescott, Jennifer; Pu, Xia; Purdue, Mark P.; Qiao, You-Lin; Rajaraman, Preetha; Riboli, Elio; Risch, Harvey A.; Rodabough, Rebecca J.; Rothman, Nathaniel; Ruder, Avima M.; Ryu, Jeong-Seon; Sanson, Marc; Schned, Alan; Schumacher, Fredrick R.; Schwartz, Ann G.; Schwartz, Kendra L.; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D.; Severi, Gianluca; Shen, Hongbing; Shen, Min; Shete, Sanjay; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesumaga, Luis; Sierri, Sabina; Loon Sihoe, Alan Dart; Silverman, Debra T.; Simon, Matthias; Southey, Melissa C.; Spector, Logan; Spitz, Margaret; Stampfer, Meir; Stattin, Par; Stern, Mariana C.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael Z.; Stram, Daniel O.; Strom, Sara S.; Su, Wu-Chou; Sund, Malin; Sung, Sook Whan; Swerdlow, Anthony; Tan, Wen; Tanaka, Hideo; Tang, Wei; Tang, Ze-Zhang; Tardon, Adonina; Tay, Evelyn; Taylor, Philip R.; Tettey, Yao; Thomas, David M.; Tirabosco, Roberto; Tjonneland, Anne; Tobias, Geoffrey S.; Toro, Jorge R.; Travis, Ruth C.; Trichopoulos, Dimitrios; Troisi, Rebecca; Truelove, Ann; Tsai, Ying-Huang; Tucker, Margaret A.; Tumino, Rosario; Van Den Berg, David; Van Den Eeden, Stephen K.; Vermeulen, Roel; Vineis, Paolo; Visvanathan, Kala; Vogel, Ulla; Wang, Chaoyu; Wang, Chengfeng; Wang, Junwen; Wang, Sophia S.; Weiderpass, Elisabete; Weinstein, Stephanie J.; Wentzensen, Nicolas; Wheeler, William; White, Emily; Wiencke, John K.; Wolk, Alicja; Wolpin, Brian M.; Wong, Maria Pik; Wrensch, Margaret; Wu, Chen; Wu, Tangchun; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S.; Xiang, Yong-Bing; Xu, Jun; Yang, Hannah P.; Yang, Pan-Chyr; Yatabe, Yasushi; Ye, Yuanqing; Yeboah, Edward D.; Yin, Zhihua; Ying, Chen; Yu, Chong-Jen; Yu, Kai; Yuan, Jian-Min; Zanetti, Krista A.; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Zhou, Baosen; Mirabello, Lisa; Savage, Sharon A.; Kraft, Peter; Chanock, Stephen J.; Yeager, Meredith; Landi, Maria Terese; Shi, Jianxin; Chatterjee, Nilanjan; Amundadottir, Laufey T.

    2014-01-01

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. PMID:25027329

  9. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

    Science.gov (United States)

    Wang, Zhaoming; Zhu, Bin; Zhang, Mingfeng; Parikh, Hemang; Jia, Jinping; Chung, Charles C; Sampson, Joshua N; Hoskins, Jason W; Hutchinson, Amy; Burdette, Laurie; Ibrahim, Abdisamad; Hautman, Christopher; Raj, Preethi S; Abnet, Christian C; Adjei, Andrew A; Ahlbom, Anders; Albanes, Demetrius; Allen, Naomi E; Ambrosone, Christine B; Aldrich, Melinda; Amiano, Pilar; Amos, Christopher; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Arici, Cecilia; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Beane Freeman, Laura E; Berg, Christine D; Berndt, Sonja I; Bertazzi, Pier Alberto; Biritwum, Richard B; Black, Amanda; Blot, William; Boeing, Heiner; Boffetta, Paolo; Bolton, Kelly; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brennan, Paul; Brinton, Louise A; Brotzman, Michelle; Bueno-de-Mesquita, H Bas; Buring, Julie E; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Cao, Guangwen; Caporaso, Neil E; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chang, Gee-Chen; Chang, I-Shou; Chang-Claude, Jenny; Che, Xu; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chung-Hsing; Chen, Constance; Chen, Kuan-Yu; Chen, Yuh-Min; Chokkalingam, Anand P; Chu, Lisa W; Clavel-Chapelon, Francoise; Colditz, Graham A; Colt, Joanne S; Conti, David; Cook, Michael B; Cortessis, Victoria K; Crawford, E David; Cussenot, Olivier; Davis, Faith G; De Vivo, Immaculata; Deng, Xiang; Ding, Ti; Dinney, Colin P; Di Stefano, Anna Luisa; Diver, W Ryan; Duell, Eric J; Elena, Joanne W; Fan, Jin-Hu; Feigelson, Heather Spencer; Feychting, Maria; Figueroa, Jonine D; Flanagan, Adrienne M; Fraumeni, Joseph F; Freedman, Neal D; Fridley, Brooke L; Fuchs, Charles S; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; Garcia-Closas, Reina; Gastier-Foster, Julie M; Gaziano, J Michael; Gerhard, Daniela S; Giffen, Carol A; Giles, Graham G; Gillanders, Elizabeth M; Giovannucci, Edward L; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gonzalez, Carlos; Gorlick, Richard; Greene, Mark H; Gross, Myron; Grossman, H Barton; Grubb, Robert; Gu, Jian; Guan, Peng; Haiman, Christopher A; Hallmans, Goran; Hankinson, Susan E; Harris, Curtis C; Hartge, Patricia; Hattinger, Claudia; Hayes, Richard B; He, Qincheng; Helman, Lee; Henderson, Brian E; Henriksson, Roger; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Hosgood, H Dean; Hsiao, Chin-Fu; Hsing, Ann W; Hsiung, Chao Agnes; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Hunter, David J; Inskip, Peter D; Ito, Hidemi; Jacobs, Eric J; Jacobs, Kevin B; Jenab, Mazda; Ji, Bu-Tian; Johansen, Christoffer; Johansson, Mattias; Johnson, Alison; Kaaks, Rudolf; Kamat, Ashish M; Kamineni, Aruna; Karagas, Margaret; Khanna, Chand; Khaw, Kay-Tee; Kim, Christopher; Kim, In-Sam; Kim, Jin Hee; Kim, Yeul Hong; Kim, Young-Chul; Kim, Young Tae; Kang, Chang Hyun; Jung, Yoo Jin; Kitahara, Cari M; Klein, Alison P; Klein, Robert; Kogevinas, Manolis; Koh, Woon-Puay; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kratz, Christian P; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kurucu, Nilgun; Lan, Qing; Lathrop, Mark; Lau, Ching C; Lecanda, Fernando; Lee, Kyoung-Mu; Lee, Maxwell P; Le Marchand, Loic; Lerner, Seth P; Li, Donghui; Liao, Linda M; Lim, Wei-Yen; Lin, Dongxin; Lin, Jie; Lindstrom, Sara; Linet, Martha S; Lissowska, Jolanta; Liu, Jianjun; Ljungberg, Börje; Lloreta, Josep; Lu, Daru; Ma, Jing; Malats, Nuria; Mannisto, Satu; Marina, Neyssa; Mastrangelo, Giuseppe; Matsuo, Keitaro; McGlynn, Katherine A; McKean-Cowdin, Roberta; McNeill, Lorna H; McWilliams, Robert R; Melin, Beatrice S; Meltzer, Paul S; Mensah, James E; Miao, Xiaoping; Michaud, Dominique S; Mondul, Alison M; Moore, Lee E; Muir, Kenneth; Niwa, Shelley; Olson, Sara H; Orr, Nick; Panico, Salvatore; Park, Jae Yong; Patel, Alpa V; Patino-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Pu, Xia; Purdue, Mark P; Qiao, You-Lin; Rajaraman, Preetha; Riboli, Elio; Risch, Harvey A; Rodabough, Rebecca J; Rothman, Nathaniel; Ruder, Avima M; Ryu, Jeong-Seon; Sanson, Marc; Schned, Alan; Schumacher, Fredrick R; Schwartz, Ann G; Schwartz, Kendra L; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Severi, Gianluca; Shen, Hongbing; Shen, Min; Shete, Sanjay; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesumaga, Luis; Sierri, Sabina; Loon Sihoe, Alan Dart

    2014-12-15

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci. PMID:25027329

  10. Susceptibility to breast cancer Cuban families and intervention strategy proposal

    International Nuclear Information System (INIS)

    In breast cancer, as in most cancers, mutations usually occur in somatic cells, but sometimes occur in germ cells. The carriers of these mutations germ have up to 80% risk of having the disease course of their lives and pass it on to their offspring, they are called hereditary cancers. In this work studied 50 tested history relatives of this neoplasm from consulting advice genetic hereditary breast cancer. The tree was made pedigree of the family of each test and been classified risk using the criteria of Hampel et al. Other malignancies were identified through the analysis of pedigrees and performed syndromic classification of families. It develops an algorithm for the care of breast cancer families hereditary and plotted strategies identified by risk taking that each category implies a different intervention. It recommended to continue studying the value of marking lesions subclinical and train staff to perform this technique for its widespread use in the country. (Author)

  11. The Role of Methylation in Breast Cancer Susceptibility and Treatment.

    Science.gov (United States)

    Pouliot, Marie-Christine; Labrie, Yvan; Diorio, Caroline; Durocher, Francine

    2015-09-01

    DNA methylation is a critical mechanism of epigenetic modification involved in gene expression programming, that can promote the development of several cancers, including breast cancer. The methylation of CpG islands by DNA methyltransferases is reversible and has been shown to modify the transcriptional activity of key proliferation genes or transcription factors involved in suppression or promotion of cell growth. Indeed, aberrant methylation found in gene promoters is a hallmark of cancer that could be used as non-intrusive biomarker in body fluids such as blood and plasma for early detection of breast cancer. Many biomarker genes have been evaluated for breast cancer detection. However, in the absence of a unique biomarker having the sufficient specificity and sensitivity, a panel of multiple genes should be used. Treatments targeting aberrant methylation by DNA methyltransferase inhibitors, which trigger re-expression of silenced genes, are now available and allow for better treatment efficiency. PMID:26254344

  12. SNP-SNP interactions in breast cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Wang Yuanyuan

    2006-05-01

    Full Text Available Abstract Background Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2 are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. Methods In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR principle. Results None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082A], cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val], cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln], and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val] pathways. Conclusion The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their

  13. SNP-SNP interactions in breast cancer susceptibility

    International Nuclear Information System (INIS)

    Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described

  14. Quantitative analysis of methylation of genomic loci in early-stage rectal cancer predicts distant recurrence.

    NARCIS (Netherlands)

    Maat, M.F. de; Velde, C.J. van de; Werff, M.P. van der; Putter, H.; Umetani, N.; Klein-Kranenbarg, E.M.; Turner, R.R.; Krieken, J.H.J.M. van; Bilchik, A.; Tollenaar, R.A.; Hoon, D.S.

    2008-01-01

    PURPOSE: There are no accurate prognostic biomarkers specific for rectal cancer. Epigenetic aberrations, in the form of DNA methylation, accumulate early during rectal tumor formation. In a preliminary study, we investigated absolute quantitative methylation changes associated with tumor progression

  15. Base excision repair mechanisms and relevance to cancer susceptibility

    International Nuclear Information System (INIS)

    The base excision repair (BER) pathway is considered the predominant DNA repair system in mammalian cells for eliminating small DNA lesions generated at DNA bases either exogenously by environmental agents or endogenously by normal cellular metabolic processes (e.g. production of oxyradical species, alkylating agents, etc). The main goal of this project is the understanding of the involvement of BER in genome stability and in particular in sporadic cancer development associated with inflammation such as gastric cancer (GC). A major risk factor of GC is the infection by Helicobacter pylori, which causes oxidative stress. Oxidative DNA damage is mainly repaired by BER

  16. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer

    DEFF Research Database (Denmark)

    Warren, Helen; Dudbridge, Frank; Fletcher, Olivia;

    2012-01-01

    Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).......Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686)....

  17. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

    DEFF Research Database (Denmark)

    Zeggini, Eleftheria; Scott, Laura J; Saxena, Richa;

    2008-01-01

    Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published ...

  18. ABRAXAS (FAM175A and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

    Directory of Open Access Journals (Sweden)

    Anne-Laure Renault

    Full Text Available Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

  19. ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry

    Science.gov (United States)

    Renault, Anne-Laure; Lesueur, Fabienne; Coulombe, Yan; Gobeil, Stéphane; Soucy, Penny; Hamdi, Yosr; Desjardins, Sylvie; Le Calvez-Kelm, Florence; Vallée, Maxime; Voegele, Catherine; Hopper, John L.; Andrulis, Irene L.; Southey, Melissa C.; John, Esther M.; Masson, Jean-Yves; Tavtigian, Sean V.; Simard, Jacques

    2016-01-01

    Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer. PMID:27270457

  20. Fetal radiation exposure induces testicular cancer in genetically susceptible mice.

    Directory of Open Access Journals (Sweden)

    Gunapala Shetty

    Full Text Available The prevalence of testicular germ cell tumors (TGCT, a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES, an antiandrogen (flutamide, or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1 congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.

  1. Analysis of a p53 Mutation Associated with Cancer Susceptibility for Biochemistry and Genetic Laboratory Courses

    Science.gov (United States)

    Soto-Cruz, Isabel; Legorreta-Herrera, Martha

    2009-01-01

    We have devised and implemented a module for an upper division undergraduate laboratory based on the amplification and analysis of a p53 polymorphism associated with cancer susceptibility. First, students collected a drop of peripheral blood cells using a sterile sting and then used FTA cards to extract the genomic DNA. The p53 region is then PCR…

  2. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium

    Science.gov (United States)

    Milne, Roger L.; Herranz, Jesús; Michailidou, Kyriaki; Dennis, Joe; Tyrer, Jonathan P.; Zamora, M. Pilar; Arias-Perez, José Ignacio; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Wang, Qin; Bolla, Manjeet K.; Czene, Kamila; Eriksson, Mikael; Humphreys, Keith; Darabi, Hatef; Li, Jingmei; Anton-Culver, Hoda; Neuhausen, Susan L.; Ziogas, Argyrios; Clarke, Christina A.; Hopper, John L.; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Chenevix-Trench, Georgia; Swerdlow, Anthony; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Wang, Xianshu; Olson, Janet E.; Vachon, Celine; Purrington, Kristen; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Dunning, Alison M.; Shah, Mitul; Guénel, Pascal; Truong, Thérèse; Sanchez, Marie; Mulot, Claire; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J.; Hollestelle, Antoinette; Collée, J. Margriet; Jager, Agnes; Cox, Angela; Brock, Ian W.; Reed, Malcolm W.R.; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Dumont, Martine; Soucy, Penny; Dörk, Thilo; Bogdanova, Natalia V.; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans-Ulrich; Fasching, Peter A.; Häberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; dos Santos Silva, Isabel; Peto, Julian; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Mariani, Paolo; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Marme, Federik; Burwinkel, Barbara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Lambrechts, Diether; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; García-Closas, Montserrat; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Rutgers, Emiel J.; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Couch, Fergus J.; Toland, Amanda E.; Yannoukakos, Drakoulis; Pharoah, Paul D.P.; Hall, Per; Benítez, Javier; Malats, Núria; Easton, Douglas F.

    2014-01-01

    Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome. PMID:24242184

  3. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    International Nuclear Information System (INIS)

    MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH). Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer. It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results

  4. Genetic susceptibility to HPV infection and cervical cancer

    Directory of Open Access Journals (Sweden)

    P.C. Maciag

    1999-07-01

    Full Text Available Squamous cell carcinoma of the cervix (SCCC is one of the leading causes of death in developing countries. Infection with high-risk human papillomavirus (HPV is the major risk factor to develop malignant lesions in the cervix. Polymorphisms of the MHC and p53 genes seem to influence the outcome of HPV infection and progression to SCCC, although controversial data have been reported. MHC are highly polymorphic genes that encode molecules involved in antigen presentation, playing a key role in immune regulation, while p53 is a tumor suppressor gene that regulates cell proliferation. The HPV E6 protein from high-risk types binds p53 and mediates its degradation by the ubiquitin pathway. The role of these polymorphisms in genetic susceptibility to HPV infection and to SCCC remains under investigation.

  5. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Tyrer, Jonathan P; Kar, Siddhartha;

    2015-01-01

    PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for ...

  6. Genome-wide association studies identify four ER negative-specific breast cancer risk loci

    DEFF Research Database (Denmark)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara;

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including diff...

  7. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    International Nuclear Information System (INIS)

    CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations

  8. A genomics approach to identify susceptibilities of breast cancer cells to “fever-range” hyperthermia

    International Nuclear Information System (INIS)

    Preclinical and clinical studies have shown for decades that tumor cells demonstrate significantly enhanced sensitivity to “fever range” hyperthermia (increasing the intratumoral temperature to 42-45°C) than normal cells, although it is unknown why cancer cells exhibit this distinctive susceptibility. To address this issue, mammary epithelial cells and three malignant breast cancer lines were subjected to hyperthermic shock and microarray, bioinformatics, and network analysis of the global transcription changes was subsequently performed. Bioinformatics analysis differentiated the gene expression patterns that distinguish the heat shock response of normal cells from malignant breast cancer cells, revealing that the gene expression profiles of mammary epithelial cells are completely distinct from malignant breast cancer lines following this treatment. Using gene network analysis, we identified altered expression of transcripts involved in mitotic regulators, histones, and non-protein coding RNAs as the significant processes that differed between the hyperthermic response of mammary epithelial cells and breast cancer cells. We confirmed our data via qPCR and flow cytometric analysis to demonstrate that hyperthermia specifically disrupts the expression of key mitotic regulators and G2/M phase progression in the breast cancer cells. These data have identified molecular mechanisms by which breast cancer lines may exhibit enhanced susceptibility to hyperthermic shock

  9. Tagging single nucleotide polymorphisms in the BRIP1 gene and susceptibility to breast and ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Honglin Song

    Full Text Available BACKGROUND: BRIP1 interacts with BRCA1 and functions in regulating DNA double strand break repair pathways. Germline BRIP1 mutations are associated with breast cancer and Fanconi anemia. Thus, common variants in the BRIP1 are candidates for breast and ovarian cancer susceptibility. METHODS: We used a SNP tagging approach to evaluate the association between common variants (minor allele frequency>or=0.05 in BRIP1 and the risks of breast cancer and invasive ovarian cancer. 12 tagging SNPs (tSNPs in the gene were identified and genotyped in up to 2,270 breast cancer cases and 2,280 controls from the UK and up to 1,513 invasive ovarian cancer cases and 2,515 controls from the UK, Denmark and USA. Genotype frequencies in cases and controls were compared using logistic regression. RESULTS: Two tSNPs showed a marginal significant association with ovarian cancer: Carriers of the minor allele of rs2191249 were at reduced risk compared with the common homozygotes (Odds Ratio (OR = 0.90 (95% CI, 0.82-1.0, P-trend = 0.045 and the minor allele of rs4988344 was associated with increased risk (OR = 1.15 (95%CI, 1.02-1.30, P-trend = 0.02. When the analyses were restricted to serous ovarian cancers, these effects became slightly stronger. These results were not significant at the 5% level after adjusting for multiple testing. None of the tSNPs was associated with breast cancer. CONCLUSIONS: It is unlikely that common variants in BRIP1 contribute significantly to breast cancer susceptibility. The possible association of rs2191249 and rs4988344 with ovarian cancer risks warrant confirmation in independent case-control studies.

  10. Integrating Genetic Association, Genetics of Gene Expression, and Single Nucleotide Polymorphism Set Analysis to Identify Susceptibility Loci for Type 2 Diabetes Mellitus

    OpenAIRE

    Greenawalt, Danielle M.; Sieberts, Solveig K.; Cornelis, Marilyn C; Girman, Cynthia J.; Zhong, Hua; Yang, Xia; Guinney, Justin; Qi, Lu; Hu, Frank B.

    2012-01-01

    Large-scale genome-wide association studies (GWAS) have identified over 40 genomic regions significantly associated with type 2 diabetes mellitus. However, GWAS results are not always straightforward to interpret, and linking these loci to meaningful disease etiology is often difficult without extensive follow-up studies. The authors expanded on previously reported type 2 diabetes mellitus GWAS from the nested case-control studies of 2 prospective US cohorts by incorporating expression single...

  11. Low-risk susceptibility alleles in 40 human breast cancer cell lines

    International Nuclear Information System (INIS)

    Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to1.3 fold. Yet, they are common among most populations and therefore are involved in the development of essentially all breast cancers. The mechanism by which the low-risk SNPs confer breast cancer risks is currently unclear. The breast cancer association consortium BCAC has hypothesized that the low-risk SNPs modulate expression levels of nearby located genes. Genotypes of five low-risk SNPs were determined for 40 human breast cancer cell lines, by direct sequencing of PCR-amplified genomic templates. We have analyzed expression of the four genes that are located nearby the low-risk SNPs, by using real-time RT-PCR and Human Exon microarrays. The SNP genotypes and additional phenotypic data on the breast cancer cell lines are presented. We did not detect any effect of the SNP genotypes on expression levels of the nearby-located genes MAP3K1, FGFR2, TNRC9 and LSP1. The SNP genotypes provide a base line for functional studies in a well-characterized cohort of 40 human breast cancer cell lines. Our expression analyses suggest that a putative disease mechanism through gene expression modulation is not operative in breast cancer cell lines

  12. Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

    Science.gov (United States)

    Piccolo, Stephen R; Hoffman, Laura M; Conner, Thomas; Shrestha, Gajendra; Cohen, Adam L; Marks, Jeffrey R; Neumayer, Leigh A; Agarwal, Cori A; Beckerle, Mary C; Andrulis, Irene L; Spira, Avrum E; Moos, Philip J; Buys, Saundra S; Johnson, William Evan; Bild, Andrea H

    2016-03-01

    The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development. PMID:26969729

  13. Endostatin gene variation and protein levels in breast cancer susceptibility and severity

    International Nuclear Information System (INIS)

    Endostatin is a potent endogenous anti-angiogenic agent which inhibits tumour growth. A non-synonymous coding polymorphism in the Endostatin gene is thought to affect Endostatin activity. We aimed to determine the role of this Endostatin polymorphism in breast cancer pathogenesis and any influence on serum Endostatin levels in healthy volunteers. Endostatin protein expression on a breast cancer micro array was also studied to determine any relationship to genotype and to breast cancer prognosis. The 4349G > A (coding non-synonymous) polymorphism in exon 42 of the Endostatin gene was genotyped in approximately 846 breast cancer cases and 707 appropriate controls. In a separate healthy cohort of 57 individuals, in addition to genotyping, serum Endostatin levels were measured using enzyme linked immunosorbant assay (ELISA). A semi-quantitative assessment of Endostatin protein expression on immunostained tissue micro arrays (TMA) constructed from breast cancer samples of patients with genotype data was performed. The rare allele (A) was significantly associated with invasive breast cancers compared to non-invasive tumours (p = 0.03), but there was no association with tumour grade, nodal status, vascular invasion or overall survival. There was no association with breast cancer susceptibility. Serum Endostatin levels and Endostatin protein expression on the tissue micro array were not associated with genotype. The Endostatin 4349A allele is associated with invasive breast cancer. The Endostatin 4349G > A polymorphism however does not appear to be associated with breast cancer susceptibility or severity in invasive disease. By studying circulating levels and tumour Endostatin protein expression, we have shown that any influence of this polymorphism is unlikely to be through an effect on the levels of protein produced

  14. Allelic losses at genomic instability-associated loci in villous adenomas and adjacent colorectal cancers.

    Science.gov (United States)

    Brenner, Bruce M; Stoler, Daniel L; Rodriguez, Luz; Karpenko, Matthew J; Swede, Helen; Petrelli, Nicholas J; Anderson, Garth R

    2007-04-01

    Allelic imbalances in premalignant villous adenomas were compared with those in adjacent microdissected colorectal carcinoma that had arisen directly from the adenomas. Carcinoma-adenoma pairs were examined from 17 patients who underwent resections for colorectal cancer. In all, 28 microsatellite markers were examined, from regions of the genome where individual allelic losses have been associated with overall genomic instability in colorectal carcinomas. Microsatellite instability (MSI) was also evaluated for each marker in each tissue type. Loss of heterozygosity for multiple markers was found in 35% of adenomas and 65% of carcinomas; the average fractional allelic loss rate was 2.5 times higher in carcinomas than in adenomas. Of the 17 patients, 4 had MSI for >30% of markers in both adenoma and carcinoma, with no significant differences between the two tissues. Markers with particularly high imbalance rates in adenomas were seen on chromosomes 11, 14, and 15. These findings provide further evidence that genomic instability is an ongoing process during carcinogenesis, with a markedly increased frequency of allelic losses seen in carcinomas, compared with adjacent adenomas. Markers on chromosomes 11, 14, and 15 may become valuable tools in the identification of patients destined to progress to colorectal carcinomas. PMID:17350461

  15. Association of CYP1A1 and GSTM1 Polymorphisms With Oral Cancer Susceptibility

    OpenAIRE

    Liu, Haitao; Jia, Jinlin; Mao, Xuemei; Lin, Zhiyong

    2015-01-01

    Abstract Our meta-analysis was aimed to evaluate the association of CYP1A1 and glutathione-S-transferase M1 (GSTM1) polymorphisms with oral cancer susceptibility. The related articles were searched in PubMed, Embase, and CNKI databases. Fifty eligible studies were included in our meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the relationship of CYP1A1 (rs4646903 and rs1048943) and GSTM1 polymorphisms with oral cancer risk. A random-effects model or...

  16. CD44 Gene Polymorphisms and Environmental Factors on Oral Cancer Susceptibility in Taiwan

    OpenAIRE

    Chou, Ying-Erh; Hsieh, Ming-Ju; Hsin, Chung-Han; Chiang, Whei-Ling; Lai, Yi-Cheng; Lee, Yu-Hsien; Huang, Shu-Ching; Yang, Shun-Fa; Lin, Chiao-Wen

    2014-01-01

    Background Oral squamous cell carcinoma (OSCC) is the fourth leading cause of male cancer death in Taiwan. Exposure to environmental carcinogens is the primary risk factor for developing OSCC. CD44, a well-known tumor marker, plays a crucial role in tumor cell differentiation, invasion, and metastasis. This study investigated CD44 single-nucleotide polymorphisms (SNPs) with environmental risk factors to determine OSCC susceptibility and clinicopathological characteristics. Methodology/Princip...

  17. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    Directory of Open Access Journals (Sweden)

    Pina Julieta

    2009-09-01

    Full Text Available Abstract Background MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. Methods We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH. Results Using unconditional logistic regression we found that MLH3 (L844P, G>A polymorphism GA (Leu/Pro and AA (Pro/Pro genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95 (p = 0.03 and OR = 0.62 (0.41-0.94 (p = 0.03, respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83, p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49, p = 0.01], GG/AA [OR = 2.11 (1.12-3,98, p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15, p = 0.02] all associated with an increased risk for breast cancer. Conclusion It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.

  18. CHRNA5 polymorphism and susceptibility to lung cancer in a Chinese population

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Bo [Jiangsu Cancer Hospital, Department of Medical Oncology, Nanjing, Jiangsu Province (China); Zhu, Qun [Second Affiliated Hospital, Nanjing Medical University, Department of Endocrinology, Nanjing, Jiangsu Province (China); Zheng, Ma-Qing [College of Pharmacy, Nanjing University of Technology, Nanjing, Jiangsu Province (China); Chen, Jia; Shi, Mei-Qi; Feng, Ji-Feng [Jiangsu Cancer Hospital, Department of Medical Oncology, Nanjing, Jiangsu Province (China)

    2013-01-11

    Polymorphisms in the nicotinic acetylcholine receptor subunit CHRNA5 gene have been associated with lung cancer positive susceptibility in European and American populations. In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals. A single nucleotide polymorphism in CHRNA5 rs503464, c.-166T>A (hereafter T>A), was identified using TaqMan-MGB probes with sequencing via PCR in 600 lung cancer cases and 600 healthy individuals. Genotype frequencies for rs503464 (T>A) were in Hardy-Weinberg equilibrium for the control population. However, genotype frequencies were significantly different between cases and controls (P < 0.05), while allele frequencies were not significantly different between groups. Compared to homozygous genotypes (TT or AA), the risk of lung cancer in those with the heterozygous genotype (TA) was significantly lower (OR = 0.611, 95%CI = 0.486-0.768, P = 0.001). Using genotype AA as a reference, the risk of lung cancer for those with genotype TA was increased 1.5 times (OR = 1.496, 95%CI = 1.120-1.997, P = 0.006). However, no difference in risk was observed between T allele carriers and A allele carriers (OR = 0.914, 95%CI = 0.779-1.073, P = 0.270). Stratification analysis showed that the protective effect of TA was more pronounced in those younger than 60 years, nonsmokers, or those without a family history of cancer, as well as in patients with adenocarcinoma or squamous cell carcinoma in clinical stages III or IV (P < 0.05). Therefore, the heterozygous genotype c.-166T>A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals.

  19. CHRNA5 polymorphism and susceptibility to lung cancer in a Chinese population

    International Nuclear Information System (INIS)

    Polymorphisms in the nicotinic acetylcholine receptor subunit CHRNA5 gene have been associated with lung cancer positive susceptibility in European and American populations. In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals. A single nucleotide polymorphism in CHRNA5 rs503464, c.-166T>A (hereafter T>A), was identified using TaqMan-MGB probes with sequencing via PCR in 600 lung cancer cases and 600 healthy individuals. Genotype frequencies for rs503464 (T>A) were in Hardy-Weinberg equilibrium for the control population. However, genotype frequencies were significantly different between cases and controls (P < 0.05), while allele frequencies were not significantly different between groups. Compared to homozygous genotypes (TT or AA), the risk of lung cancer in those with the heterozygous genotype (TA) was significantly lower (OR = 0.611, 95%CI = 0.486-0.768, P = 0.001). Using genotype AA as a reference, the risk of lung cancer for those with genotype TA was increased 1.5 times (OR = 1.496, 95%CI = 1.120-1.997, P = 0.006). However, no difference in risk was observed between T allele carriers and A allele carriers (OR = 0.914, 95%CI = 0.779-1.073, P = 0.270). Stratification analysis showed that the protective effect of TA was more pronounced in those younger than 60 years, nonsmokers, or those without a family history of cancer, as well as in patients with adenocarcinoma or squamous cell carcinoma in clinical stages III or IV (P < 0.05). Therefore, the heterozygous genotype c.-166T>A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals

  20. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat;

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a...

  1. Relative susceptibilities of male germ cells to genetic defects induced by cancer chemotherapies

    Energy Technology Data Exchange (ETDEWEB)

    Wyrobek, A J; Schmid, T E; Marchetti, F

    2004-06-15

    Some chemotherapy regimens include agents that are mutagenic or clastogenic in model systems. This raises concerns that cancer survivors, who were treated before or during their reproductive years, may be at increased risks for abnormal reproductive outcomes. However, the available data from offspring of cancer survivors are limited, representing diverse cancers, therapies, time-to-pregnancies, and reproductive outcomes. Rodent breeding data after paternal exposures to individual chemotherapeutic agents illustrate the complexity of factors that influence the risk for transmitted genetic damage including agent, dose, endpoint, and the germ-cell susceptibility profiles that vary across agents. Direct measurements of chromosomal abnormalities in sperm of mice and humans by sperm FISH have corroborated the differences in germ-cell susceptibilities. The available evidence suggests that the risk of producing chromosomally defective sperm is highest during the first few weeks after the end of chemotherapy, and decays with time. Thus, sperm samples provided immediately after the initiation of cancer therapies may contain treatment-induced genetic defects that will jeopardize the genetic health of offspring.

  2. Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity

    International Nuclear Information System (INIS)

    Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. Using a case–control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours

  3. Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers to Colon Cancers: Patents and Licensing for Breast, Ovarian and Colon Cancer Testing

    OpenAIRE

    Cook-Deegan, Robert; DeRienzo, Christopher; Carbone, Julia; Chandrasekharan, Subhashini; Heaney, Christopher; Conover, Christopher

    2010-01-01

    Genetic testing for inherited susceptibility to breast and ovarian cancer can be compared to similar testing for colorectal cancer as a “natural experiment.” Inherited susceptibility accounts for a similar fraction of both cancers and genetic testing results guide decisions about options for prophylactic surgery in both sets of conditions. One major difference is that in the United States, Myriad Genetics is the sole provider of genetic testing, because it has sole control of relevant patents...

  4. Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans.

    Science.gov (United States)

    Hansen, Helen M; Xiao, Yuanyuan; Rice, Terri; Bracci, Paige M; Wrensch, Margaret R; Sison, Jennette D; Chang, Jeffery S; Smirnov, Ivan V; Patoka, Joseph; Seldin, Michael F; Quesenberry, Charles P; Kelsey, Karl T; Wiencke, John K

    2010-09-15

    Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P < 10(-20)). In order to narrow the region of association and identify potential causal variations, we performed a fine-mapping study using 77 SNPs in a 194 kb segment of the 15q25.1 region in a sample of 448 African-American lung cancer cases and 611 controls. Four regions, two SNPs and two distinct haplotypes from sliding window analyses, were associated with lung cancer. CHRNA5 rs17486278 G had OR = 1.28, 95% CI 1.07-1.54 and P = 0.008, whereas CHRNB4 rs7178270 G had OR = 0.78, 95% CI 0.66-0.94 and P = 0.008 for lung cancer risk. Lung cancer associations remained significant after pack-year adjustment. Rs7178270 decreased lung cancer risk in women but not in men; gender interaction P = 0.009. For two SNPs (rs7168796 A/G and rs7164594 A/G) upstream of PSMA4, lung cancer risks for people with haplotypes GG and AA were reduced compared with those with AG (OR = 0.56, 95% CI 0.38-0.82; P = 0.003 and OR = 0.73, 95% CI 0.59-0.90, P = 0.004, respectively). A four-SNP haplotype spanning CHRNA5 (rs11637635 C, rs17408276 T, rs16969968 G) and CHRNA3 (rs578776 G) was associated with increased lung cancer risk (P = 0.002). The identified regions contain SNPs predicted to affect gene regulation. There are multiple lung cancer risk loci in the 15q25.1 region in African-Americans. PMID:20587604

  5. Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lipoldová, Marie; Havelková, Helena; Badalová, Jana; Vojtíšková, Jarmila; Quan, L.; Krulová, Magdalena; Sohrabi, Yahya; Stassen, A. P. M.; Demant, P.

    2010-01-01

    Roč. 59, č. 2 (2010), s. 203-213. ISSN 0340-7004 R&D Projects: GA MŠk(CZ) LC06009; GA AV ČR IAA500520606; GA ČR GD310/08/H077 Institutional research plan: CEZ:AV0Z50520514 Keywords : Tumor susceptibility * Genetic control of interferon gamma production * Lymphocyte infiltration of tumors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.293, year: 2010

  6. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium.

    Science.gov (United States)

    Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B; Behrens, Sabine; Goode, Ellen L; Bolla, Manjeet K; Dennis, Joe; Dunning, Alison M; Easton, Douglas F; Wang, Qin; Benitez, Javier; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Fasching, Peter A; Haeberle, Lothar; Peto, Julian; Dos-Santos-Silva, Isabel; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marmé, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Nielsen, Sune F; Nordestgaard, Børge G; González-Neira, Anna; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Fagerholm, Rainer; Dörk, Thilo; Bogdanova, Natalia V; Mannermaa, Arto; Hartikainen, Jaana M; Van Dijck, Laurien; Smeets, Ann; Flesch-Janys, Dieter; Eilber, Ursula; Radice, Paolo; Peterlongo, Paolo; Couch, Fergus J; Hallberg, Emily; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Schumacher, Fredrick; Simard, Jacques; Goldberg, Mark S; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Beeghly-Fadiel, Alicia; Winqvist, Robert; Grip, Mervi; Andrulis, Irene L; Glendon, Gord; García-Closas, Montserrat; Figueroa, Jonine; Czene, Kamila; Brand, Judith S; Darabi, Hatef; Eriksson, Mikael; Hall, Per; Li, Jingmei; Cox, Angela; Cross, Simon S; Pharoah, Paul D P; Shah, Mitul; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Ademuyiwa, Foluso; Ambrosone, Christine B; Swerdlow, Anthony; Jones, Michael; Chang-Claude, Jenny

    2016-01-01

    Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry. PMID:26621531

  7. Genetic Polymorphisms of TGFB1, TGFBR1, SNAI1 and TWIST1 Are Associated with Endometrial Cancer Susceptibility in Chinese Han Women

    Science.gov (United States)

    Yang, Li; Wang, Ya-Jun; Zheng, Li-Yuan; Jia, Yu-Mian; Chen, Yi-Lin; Chen, Lan; Liu, Dong-Ge; Li, Xiang-Hong; Guo, Hong-Yan; Sun, Ying-Li; Tian, Xin-Xia; Fang, Wei-Gang

    2016-01-01

    Endometrial cancer (EC) is a complex disease involving multiple gene-gene and gene–environment interactions. TGF-β signaling plays pivotal roles in EC development. This study aimed to investigate whether the genetic polymorphisms of TGF-β signaling related genes TGFB1, TGFBR1, SNAI1 and TWIST1 contribute to EC susceptibility. Using the TaqMan Genotyping Assay, 19 tagging-SNPs of these four genes were genotyped in 516 EC cases and 707 controls among Chinese Han women. Logistic regression (LR) showed that the genetic variants of TGFB1 rs1800469, TGFBR1 rs6478974 and rs10733710, TWIST1 rs4721745 were associated with decreased EC risk, and these four loci showed a dose-dependent effect (Ptrend pregnancy intervals (˃11 years) and BMI˂24 (aOR = 0.39, 95% CI = 0.17–0.90, P = 0.0275). These results suggest that polymorphisms in TGFB1, TGFBR1, SNAI1 and TWIST1 may modulate EC susceptibility, both separately and corporately. PMID:27171242

  8. Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium

    Science.gov (United States)

    Johnatty, Sharon E.; Tyrer, Jonathan P.; Kar, Siddhartha; Beesley, Jonathan; Lu, Yi; Gao, Bo; Fasching, Peter A.; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Lambrechts, Diether; Nieuwenhuysen, Els Van; Vergote, Ignace; Lambrechts, Sandrina; Rossing, Mary Anne; Doherty, Jennifer A.; Chang-Claude, Jenny; Modugno, Francesmary; Ness, Roberta B.; Moysich, Kirsten B.; Levine, Douglas A.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Brinton, Louise; Lissowska, Jolanta; Wentzensen, Nicolas; Song, Honglin; Rhenius, Valerie; Campbell, Ian; Eccles, Diana; Sieh, Weiva; Whittemore, Alice S.; McGuire, Valerie; Rothstein, Joseph H.; Sutphen, Rebecca; Anton-Culver, Hoda; Ziogas, Argyrios; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J.; Pearce, Celeste L; Pike, Malcolm C; Stram, Daniel O.; Wu, Anna H.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Spiewankiewicz, Beata; Goodman, Marc T.; Wilkens, Lynne R.; Carney, Michael E.; Thompson, Pamela J; Heitz, Florian; du Bois, Andreas; Schwaab, Ira; Harter, Philipp; Pisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Winham, Stacey J; Earp, Madalene; Larson, Melissa C.; Fogarty, Zachary C.; Høgdall, Estrid; Jensen, Allan; Kjaer, Susanne Kruger; Fridley, Brooke L.; Cunningham, Julie M.; Vierkant, Robert A.; Schildkraut, Joellen M.; Iversen, Edwin S.; Terry, Kathryn L.; Cramer, Daniel W.; Bandera, Elisa V.; Orlow, Irene; Pejovic, Tanja; Bean, Yukie; Høgdall, Claus; Lundvall, Lene; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Sellers, Thomas; Kennedy, Catherine; Chiew, Yoke-Eng; Berchuck, Andrew; MacGregor, Stuart; deFazio, Anna; Pharoah, Paul D.P.; Goode, Ellen L.; deFazio, Anna; Webb, Penelope M.; Chenevix-Trench, Georgia

    2015-01-01

    Purpose Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent firstline treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients including patients from The Cancer Genome Atlas. Additionally we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results Five SNPs were significantly associated (p≤1.0x10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11–179A10.1, RP11–314O13.1 and RP11–284F21.8 respectively (p≤7.1x10−6). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11–284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10−3). Conclusion We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. PMID:26152742

  9. Global lung cancer risk from PAH exposure highly depends on emission sources and individual susceptibility

    Science.gov (United States)

    Shen, Huizhong; Tao, Shu; Liu, Junfeng; Huang, Ye; Chen, Han; Li, Wei; Zhang, Yanyan; Chen, Yuanchen; Su, Shu; Lin, Nan; Xu, Yinyin; Li, Bengang; Wang, Xilong; Liu, Wenxin

    2014-10-01

    The health impacts of polycyclic aromatic hydrocarbons (PAHs), the most concerning organic pollutants, depend not only on the locations and strengths of emission sources, but also on individual susceptibility. Moreover, trans-boundary transport makes them a global concern. In this study, a comprehensive analysis of the global health impacts of polycyclic aromatic hydrocarbons (PAHs) in ambient air is presented. Model resolution is critical in exposure modelling. Globally, incremental lifetime lung cancer risk (ILCR) induced by ambient PAH exposure is 3.1 × 10-5. If the individual susceptibility was not taken into consideration, the overall risk would be underestimated by 55% and the proportion of highly vulnerable population would be underestimated by more than 90%. Emphasizing on individual susceptibility, our study provides an instrumental revision of current risk assessment methodology. In terms of lung cancer risk, the most important sources are combustion of biomass fuels (40%) and fossil fuels (14%) in the residential/commercial sector, coke (13%) and aluminium (12%) production, and motor vehicles (9%). PAHs can travel long distance globally especially within the Eurasian continent. Still, the risk is dominantly contributed by local.

  10. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors

    DEFF Research Database (Denmark)

    Nickels, Stefan; Truong, Thérèse; Hein, Rebecca;

    2013-01-01

    menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood...

  11. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

    Science.gov (United States)

    2003-06-15

    As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing: ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility: ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that

  12. The Relationship Between Eight GWAS-Identified Single-Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

    OpenAIRE

    Bayraktar, Soley; Thompson, Patricia A.; Yoo, Suk-Young; Do, Kim-Anh; Sahin, Aysegul A.; Arun, Banu K; Bondy, Melissa L.; Brewster, Abenaa M.

    2013-01-01

    Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies. This study investigated the association of eight risk SNPs with breast cancer disease-free survival and overall survival rates. Results suggest that two previously identified breast cancer risk susceptibility loci may influence breast cancer prognosis or comorbid conditions associated with overall survival.

  13. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype

    DEFF Research Database (Denmark)

    Figueroa, Jonine D; Garcia-Closas, Montserrat; Humphreys, Manjeet;

    2011-01-01

    A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer As...

  14. Functional Analysis of Missense Variants in the Putative Breast Cancer Susceptibility Gene XRCC2.

    Science.gov (United States)

    Hilbers, Florentine S; Luijsterburg, Martijn S; Wiegant, Wouter W; Meijers, Caro M; Völker-Albert, Moritz; Boonen, Rick A; van Asperen, Christi J; Devilee, Peter; van Attikum, Haico

    2016-09-01

    XRCC2 genetic variants have been associated with breast cancer susceptibility. However, association studies have been complicated because XRCC2 variants are extremely rare and consist mainly of amino acid substitutions whose grouping is sensitive to misclassification by the predictive algorithms. We therefore functionally characterized variants in XRCC2 by testing their ability to restore XRCC2-DNA repair deficient phenotypes using a cDNA-based complementation approach. While the protein-truncating variants p.Leu117fs, p.Arg215*, and p.Cys217* were unable to restore XRCC2 deficiency, 19 out of 23 missense variants showed no or just a minor (<25%) reduction in XRCC2 function. The remaining four (p.Cys120Tyr, p.Arg91Trp, p.Leu133Pro, and p.Ile95Leu) had a moderate effect. Overall, measured functional effects correlated poorly with those predicted by in silico analysis. After regrouping variants from published case-control studies based on the functional effect found in this study and reanalysis of the prevalence data, there was no longer evidence for an association with breast cancer. This suggests that if breast cancer susceptibility alleles of XRCC2 exist, they are likely restricted to protein-truncating variants and a minority of missense changes. Our study emphasizes the use of functional analyses of missense variants to support variant classification in association studies. PMID:27233470

  15. Correlations between the COMT gene rs4680 polymorphism and susceptibility to ovarian cancer.

    Science.gov (United States)

    Pan, W; Liao, H

    2015-01-01

    The objective of this study was to perform a systematic review of the correlations between the single nucleotide polymorphism rs4680 in the catechol-O-methyltransferase (COMT) gene and susceptibility to ovarian cancer. A computer search was carried out for relevant case-control studies published between January 2000 to January 2014 in databases such as Ovid, EBSCO, PubMed, CNKI, CBMDISC, VIP, and WanFang Data. The literature was screened based on inclusion and exclusion criteria. A meta-analysis was performed by calculating the combined odds ratios (OR) and 95% confidence intervals (CI) using the RevMan 5.0. A total of 7 case-control studies were selected, which included 1439 cases and 2927 control subjects. Meta-analysis showed that the rs4680 polymorphism was not associated with ovarian cancer [GG vs (GA+AA): OR = 1.02, 95%CI = 0.88-1.19; G vs A allele: OR = 1.0, 95%CI = 0.90-1.11]. We, therefore, conclude that the COMT rs4680 polymorphism is not associated with susceptibility to ovarian cancer. PMID:26681027

  16. Association of rs6983267 Polymorphism and Thyroid Cancer Susceptibility: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Li, Jingdong; Wang, Xiaofei; Dong, Jiahong

    2016-01-01

    BACKGROUND Recent genome-wide association studies have identified rs6983267 polymorphism as a key locus in the 8q24 region associated with multisite cancers. However, the information on its association with thyroid cancer is inconclusive. The aim of this study was to determine whether this locus is a risk factor for susceptibility to thyroid cancer by conducting a meta-analysis. MATERIAL AND METHODS Relevant studies were identified by searching PubMed and Embase databases. The pooled odds ratio (OR) and corresponding 95% confidence interval (95% CI) were calculated. RESULTS A total of 4 studies including 2825 cases and 9684 controls were enrolled to this meta-analysis. The pooled data showed the G allele of the rs6983267 polymorphism is a risk factor for susceptibility to thyroid cancer (OR=1.08, 95%CI: 1.02-1.16, P=0.01). Significant associations were also found in homozygote comparison (GG vs. TT: OR=1.17, 95%CI: 1.03-1.33, P=0.02) and dominant model (GG+GT vs. TT: OR=1.13, 95%CI: 1.01-1.26, P=0.03). Borderline significant associations in similar directions were found in the recessive model (GG vs. GT+TT: OR=1.10, 95%CI: 0.99-1.22, P=0.07) and heterozygote comparison (GT vs. TT: OR=1.10, 95%CI: 0.99-1.24, P=0.09). CONCLUSIONS Our meta-analysis shows that the rs6983267 G>T polymorphism might be associated with higher risk of thyroid cancer. Further research with larger sample sizes and full investigation of confounding risk factors is needed to confirm or revise our conclusions. PMID:27251952

  17. Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Nunes Virginia

    2008-01-01

    Full Text Available Abstract Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

  18. MGMT Leu84Phe polymorphism contributes to cancer susceptibility: evidence from 44 case-control studies.

    Directory of Open Access Journals (Sweden)

    Jun Liu

    Full Text Available BACKGROUND: O(6-methylguanine-DNA methyltransferase is one of the few proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. A large number of case-control studies have been conducted to explore the association between MGMT Leu84Phe polymorphism and cancer risk. However, the results were not consistent. METHODS: We carried out a meta-analysis of 44 case-control studies to clarify the association between the Leu84Phe polymorphism and cancer risk. RESULTS: Overall, significant association of the T allele with cancer susceptibility was verified with meta-analysis under a recessive genetic model (P<0.001, OR=1.30, 95%CI 1.24-1.50 and TT versus CC comparison (P=0.001, OR=1.29, 95% CI 1.12-1.50. In subgroup analysis, a significant increased risk was found for lung cancer (TT versus CC, P=0.027, OR=1.67, 95% CI 1.06-2.63; recessive genetic model, P=0.32, OR=1.64, 95% CI 1.04-2.58, whereas risk of colorectal cancer was significantly low under a dominant genetic model (P=0.019, OR=0.84, 95% CI 0.72-0.97. Additionally, a significant association between TT genetic model and total cancer risk was found in the Caucasian population (TT versus CC, P=0.014, OR=1.29, 95% CI 1.05-1.59; recessive genetic model, P=0.009, OR=1.31, 95% CI 1.07-1.61, but not in the Asian population. An increased risk for lung cancer was also verified in the Caucasian population (TT versus CC, P=0.035, OR=1.62, 95% CI 1.04-2.53; recessive genetic model, P=0.048, OR=1.57, 95% CI 1.01-2.45. CONCLUSIONS: These results suggest that MGMT Leu84Phe polymorphism might contribute to the susceptibility of certain cancers.

  19. MGMT Leu84Phe Polymorphism Contributes to Cancer Susceptibility: Evidence from 44 Case-Control Studies

    Science.gov (United States)

    Yu, Cuicui; Sun, Yan; Jia, Chuanliang; Zhang, Lijing; Salahuddin, Taufiq; Li, Xiaodong; Lang, Juntian; Song, Xicheng

    2013-01-01

    Background O6-methylguanine-DNA methyltransferase is one of the few proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. A large number of case-control studies have been conducted to explore the association between MGMT Leu84Phe polymorphism and cancer risk. However, the results were not consistent. Methods We carried out a meta-analysis of 44 case-control studies to clarify the association between the Leu84Phe polymorphism and cancer risk. Results Overall, significant association of the T allele with cancer susceptibility was verified with meta-analysis under a recessive genetic model (P<0.001, OR=1.30, 95%CI 1.24-1.50) and TT versus CC comparison (P=0.001, OR=1.29, 95% CI 1.12-1.50). In subgroup analysis, a significant increased risk was found for lung cancer (TT versus CC, P=0.027, OR=1.67, 95% CI 1.06-2.63; recessive genetic model, P=0.32, OR=1.64, 95% CI 1.04-2.58), whereas risk of colorectal cancer was significantly low under a dominant genetic model (P=0.019, OR=0.84, 95% CI 0.72-0.97). Additionally, a significant association between TT genetic model and total cancer risk was found in the Caucasian population (TT versus CC, P=0.014, OR=1.29, 95% CI 1.05-1.59; recessive genetic model, P=0.009, OR=1.31, 95% CI 1.07-1.61), but not in the Asian population. An increased risk for lung cancer was also verified in the Caucasian population (TT versus CC, P=0.035, OR=1.62, 95% CI 1.04-2.53; recessive genetic model, P=0.048, OR=1.57, 95% CI 1.01-2.45). Conclusions These results suggest that MGMT Leu84Phe polymorphism might contribute to the susceptibility of certain cancers. PMID:24086516

  20. Replication and Relevance of Multiple Susceptibility Loci Discovered from Genome Wide Association Studies for Type 2 Diabetes in an Indian Population.

    Directory of Open Access Journals (Sweden)

    Nagaraja M Phani

    Full Text Available Several genetic variants for type 2 diabetes (T2D have been identified through genome wide association studies (GWAS from Caucasian population; however replication studies were not consistent across various ethnicities. Objective of the current study is to examine the possible correlation of 9 most significant GWAS single nucleotide polymorphisms (SNPs for T2D susceptibility as well as the interactive effect of these variants on the risk of T2D in an Indian population.Case-control cohorts of 1156 individuals were genotyped for 9 SNPs from an Indian population. Association analyses were performed using logistic regression after adjusting for covariates. Multifactor dimensionality reduction (MDR analysis was adopted to determine gene-gene interactions and discriminatory power of combined SNP effect was assessed by grouping individuals based on the number of risk alleles and by calculating area under the receiver-operator characteristic curve (AUC.We confirm the association of TCF7L2 (rs7903146 and SLC30A8 (rs13266634 with T2D. MDR analysis showed statistically significant interactions among four SNPs of SLC30A8 (rs13266634, IGF2BP2 (rs4402960, HHEX (rs1111875 and CDKN2A (rs10811661 genes. Cumulative analysis showed an increase in odds ratio against the baseline group of individuals carrying 5 to 6 risk alleles and discriminatory power of genetic test based on 9 variants showed higher AUC value when analyzed along with body mass index (BMI.These results provide a strong evidence for independent association between T2D and SNPs for in TCF7L2 and SLC30A8. MDR analysis demonstrates that independently non-significant variants may interact with one another resulting in increased disease susceptibility in the population tested.

  1. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

    OpenAIRE

    Li, Donghui; Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-De-Mesquita, H Bas; Fuchs, Charles S; Gallinger, Steven; Gross, Myron

    2012-01-01

    Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic...

  2. A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population

    International Nuclear Information System (INIS)

    In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case–control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65–0.82; P = 1.6 × 10−7), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19–1.49; P = 5.8 × 10−7), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68–0.94; P = 6.7 × 10−3) and MICA-A5 (OR = 0.60, 95% CI = 0.50–0.72; P = 3.0 × 10−8) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer

  3. Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.

    OpenAIRE

    Ahmed, M.; Dorling, L.; Kerns, S.; Fachal, L; Elliott, R.; Partliament, M.; Rosenstein, B S; Vega, A; Gómez-Caamaño, A.; Barnett, G.; Dearnaley, D. P.; Hall, E.; Sydes, M; Burnet, N.; Pharoah, P. D.

    2016-01-01

    BACKGROUND: Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. METHODS: The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studie...

  4. Interactions between Environmental Factors and Melatonin Receptor Type 1A Polymorphism in Relation to Oral Cancer Susceptibility and Clinicopathologic Development

    OpenAIRE

    Lin, Feng-Yan; Lin, Chiao-Wen; Yang, Shun-Fa; Lee, Wei-Jiunn; Lin, Yung-Wei; Lee, Liang-Ming; Chang, Junn-Liang; Weng, Wei-chun; Lin, Chien-Huang; Chien, Ming-Hsien

    2015-01-01

    Background The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A) gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer. Methodology and Principal Findings Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non-cancer controls were analyzed by real-time polymerase chain reaction (PCR). The CTA haplotype of the studied MTNR1A polymorphi...

  5. HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population

    DEFF Research Database (Denmark)

    Yin, Jiaoyang; Vogel, Ulla Birgitte; Ma, Yegang;

    2009-01-01

    (NER) pathway. To elucidate whether common ERCC2 variants are associated with lung cancer susceptibility, we conducted a case–control study consisting of 339 cases with primary lung cancer and 358 controls matched on age, gender and ethnicity in a Chinese population. Six haplotype tagging single...... polymorphisms. Our results provide evidence to support a role for ERCC2 in lung cancer development in a Chinese population....

  6. Experience with breast cancer, pre-screening perceived susceptibility and the psychological impact of screening

    DEFF Research Database (Denmark)

    Absetz, Pilvikki; Aro, Arja R; Sutton, Stephen R

    2003-01-01

    This prospective study examined whether the psychological impact of organized mammography screening is influenced by women's pre-existing experience with breast cancer and perceived susceptibility (PS) to the disease. From a target population of 16,886, a random sample of women with a normal...... screening finding and all women with a false positive or a benign biopsy finding were included (N=1942). Data were collected with postal questionnaires 1-month before screening invitation and 2 and 12 months after screening. Response rate was 63% at baseline; 86, and 80% of the baseline participants...... responded to the follow-ups. Psychological impact was measured as anxiety (STAI-S), depression (BDI), health-related concerns (IAS), and breast cancer-specific beliefs and concerns. Data was analyzed with repeated measures analyses of variance, with estimates of effect size based on Eta-squared. Women with...

  7. Expression of phosphoenolpyruvate carboxykinase linked to chemoradiation susceptibility of human colon cancer cells

    International Nuclear Information System (INIS)

    Resistance to 5-fluorouracil (5-FU) in patients with colorectal cancer prevents effective treatment and leads to unnecessary and burdensome chemotherapy. Therefore, prediction of 5-FU resistance is imperative. To identify the proteins linked to 5-FU resistance, two-dimensional gel electrophoresis-based proteomics was performed using the human colon cancer cell line SNU-C4R with induced 5-FU resistance. Proteins showing altered expression in SNU-C4R were identified by matrix-associated laser desorption/ionization–time-of-flight analysis, and their roles in susceptibility to 5-FU or radiation were evaluated in various cell lines by transfection of specific siRNA or creation of overexpression constructs. Changes in cellular signaling and expression of mitochondrial apoptotic factors were investigated by Western Blot analysis. A mitochondrial membrane potential probe (JC-1 dye) and a flow cytometry system were employed to determine the mitochondrial membrane potential. Finally, protein levels were determined by Western Blot analysis in tissues from 122 patients with rectal cancer to clarify whether each identified protein is a useful predictor of a chemoradiation response. We identified mitochondrial phosphoenolpyruvate carboxykinase (mPEPCK) as a candidate predictor of 5-FU resistance. PEPCK was downregulated in SNU-C4R compared with its parent cell line SNU-C4. Overexpression of mPEPCK did not significantly alter the susceptibility to either 5-FU or radiation. Suppression of mPEPCK led to a decrease in both the cellular level of phosphoenolpyruvate and the susceptibility to 5-FU and radiation. Furthermore, the cellular levels of phosphoenolpyruvate (an end product of PEPCK and a substrate of pyruvate kinase), phosphorylated AKT, and phosphorylated 4EBP1 were decreased significantly secondary to the mPEPCK suppression in SNU-C4. However, mPEPCK siRNA transfection induced changes in neither the mitochondrial membrane potential nor the expression levels of

  8. Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.

    Directory of Open Access Journals (Sweden)

    Unhee Lim

    Full Text Available BACKGROUND: Risk of non-Hodgkin lymphoma (NHL is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy. OBJECTIVE: We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer. METHODS: As part of the Population Architecture using Genomics and Epidemiology (PAGE consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL, follicular lymphoma (FL, chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies. RESULTS: The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR=1.29, p=0.013; DLBCL OR=1.23, p=0.013; NHL OR=1.22, p=5.9 × E-05. In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele=0.89, p=3.7 × E-03; rs4975616 in TERT: OR per A allele=0.90, p=0.01; rs3131379 in MSH5: OR per T allele=1.16, p=0.03, prostate (rs7679673 in TET2: OR per C allele=0.89, p=5.7 × E-03; rs10993994 in MSMB: OR per T allele=1.09, p=0.04, and breast (rs3817198 in LSP1: OR per C allele=1.12, p=0.01 cancers, but none of these associations remained significant after multiple test correction. CONCLUSION: This study does not support strong pleiotropic effects of non

  9. Construction of label-free electrochemical immunosensor on mesoporous carbon nanospheres for breast cancer susceptibility gene

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Haixia; Zhang, Yong; Wu, Dan; Ma, Hongmin; Li, Xiaojing; Li, Yan; Wang, Huan; Li, He; Du, Bin [Key Laboratory of Chemical Sensing and Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022 (China); Wei, Qin, E-mail: sdjndxwq@163.com [Key Laboratory of Chemical Sensing and Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022 (China)

    2013-04-03

    Highlights: ► The immunosensor is designed to determine breast cancer susceptibility gene. ► Mesoporous carbon nanospheres (MCN) have great adsorption capacity. ► MCN could enhance the electroactivity of toluidine blue. ► Room temperature ionic liquid should increase the electrochemical signal. -- Abstract: In this contribution, mesoporous carbon nanospheres (MCN) were used to fabricate a label-free electrochemical immunosensor for breast cancer susceptibility gene (BRCAl). The detection platform was constructed by conjugation of anti-BRCA1 on glassy carbon electrodes which were modified by mesoporous carbon nanospheres–toluidine blue nanocomposite (MCN–TB)/room temperature ionic-liquid (RTIL) composited film. TB was adsorbed onto MCN and acted as a redox probe. The electroactivity of TB was greatly enhanced in the presence of MCN. The good conductivity of MCN and BMIM·BF{sub 4} could promote the electron transfer and thus enhance the detection sensitivity. Moreover, the large surface area of MCN and the protein-binding properties of BMIM·BF{sub 4} could greatly increase the antibody loading. The specific antibody–antigen immunoreaction on the electrode surface resulted in a decrease of amperometric signal of the electrode. Under optimized conditions, the amperometric signal decreased linearly with BRCAl concentration in the range of 0.01–15 ng mL{sup −1} with a low detection limit of 3.97 pg mL{sup −1}. The immunosensor exhibits high sensitivity, good selectivity and stability.

  10. Bacteriological profile and antibiotic susceptibility patterns of clinical isolates in a tertiary care cancer center

    Directory of Open Access Journals (Sweden)

    Vivek Bhat

    2016-01-01

    Full Text Available Introduction: This increased risk of bacterial infections in the cancer patient is further compounded by the rising trends of antibiotic resistance in commonly implicated organisms. In the Indian setting this is particularly true in case of Gram negative bacilli such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter spp. Increasing resistance among Gram positive organisms is also a matter of concern. The aim of this study was to document the common organisms isolated from bacterial infections in cancer patients and describe their antibiotic susceptibilities. Methods: We conducted a 6 month study of all isolates from blood, urine, skin/soft tissue and respiratory samples of patients received from medical and surgical oncology units in our hospital. All samples were processed as per standard microbiology laboratory operating procedures. Isolates were identified to species level and susceptibility tests were performed as per Clinical Laboratory Standards Institute (CLSI guidelines -2012. Results: A total of 285 specimens from medical oncology (114 and surgical oncology services (171 were cultured. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Acinetobacter spp. were most commonly encountered. More than half of the Acinetobacter strains were resistant to carbapenems. Resistance in Klebsiella pneumoniae to cephalosporins, fluoroquinolones and carbapenems was >50%. Of the Staphylococcus aureus isolates 41.67% were methicillin resistant. Conclusion: There is, in general, a high level of antibiotic resistance among gram negative bacilli, particularly E. coli, Klebsiella pneumoniae and Acinetobacter spp. Resistance among Gram positives is not as acute, although the MRSA incidence is increasing.

  11. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing; Macgregor, Stuart; Duffy, David L; Spurdle, Amanda B; deFazio, Anna; Gava, Natalie; Webb, Penelope M; Rossing, Mary Anne; Doherty, Jennifer Anne; Goodman, Marc T; Lurie, Galina; Thompson, Pamela J; Wilkens, Lynne R; Ness, Roberta B; Moysich, Kirsten B; Chang-Claude, Jenny; Wang-Gohrke, Shan; Cramer, Daniel W; Terry, Kathryn L; Hankinson, Susan E; Tworoger, Shelley S; Garcia-Closas, Montserrat; Yang, Hannah; Lissowska, Jolanta; Chanock, Stephen J; Pharoah, Paul D; Song, Honglin; Whitemore, Alice S; Pearce, Celeste L; Stram, Daniel O; Wu, Anna H; Pike, Malcolm C; Gayther, Simon A; Ramus, Susan J; Menon, Usha; Gentry-Maharaj, Aleksandra; Anton-Culver, Hoda; Ziogas, Argyrios; Hogdall, Estrid; Kjaer, Susanne K; Hogdall, Claus; Berchuck, Andrew; Schildkraut, Joellen M; Iversen, Edwin S; Moorman, Patricia G; Phelan, Catherine M; Sellers, Thomas A; Cunningham, Julie M; Vierkant, Robert A; Rider, David N; Goode, Ellen L; Haviv, Izhak; Chenevix-Trench, Georgia

    2010-01-01

    We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes in...

  12. Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers : Implications for Risk Prediction

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall'Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernstroem, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Duran, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; van Asperen, Christi J.; Devilee, Peter; Meijers-Heijboer, E. J.; Blok, Marinus J.; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valerie; Lasset, Christine; Dreyfus, Helene; Leroux, Dominique; Hardouin, Agnes; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frenay, Marc; Venat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alexander; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jnson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schoenbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomaeki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 i

  13. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley;

    2010-01-01

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs650495...

  14. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction

    NARCIS (Netherlands)

    A.C. Antoniou (Antonis); J. Beesley (Jonathan); L. McGuffog (Lesley); O. Sinilnikova (Olga); S. Healey (Sue); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); R. Rebbeck (Timothy); J.N. Weitzel (Jeffrey); H. Lynch (Henry); C. Isaacs (Claudine); P.A. Ganz (Patricia); G. Tomlinson (Gail); O.I. Olopade (Olofunmilayo); F.J. Couch (Fergus); X. Wang (Xing); N.M. Lindor (Noralane); V.S. Pankratz (Shane); P. Radice (Paolo); S. Manoukian (Siranoush); B. Peissel (Bernard); D. Zaffaroni (D.); M. Barile (Monica); A. Viel (Alessandra); A. Allavena (Anna); V. Dall'Olio (Valentina); P. Peterlongo (Paolo); C. Szabo (Csilla); M. Zikan (Michal); K. Claes (Kathleen); B. Poppe (Bruce); L. Foretova (Lenka); P.L. Mai (Phuong); M.H. Greene (Mark); G. Rennert (Gad); F. Lejbkowicz (Flavio); G. Glendon (Gord); H. Ozcelik (Hilmi); I.L. Andrulis (Irene); M. Thomassen (Mads); A-M. Gerdes (Anne-Marie); L. Sunde (Lone); D. Cruger (Dorthe); U.B. Jensen; M.A. Caligo (Maria); E. Friedman (Eitan); B. Kaufman (Bella); Y. Laitman (Yael); R. Milgrom (Roni); M. Dubrovsky (Maya); S. Cohen (Shimrit); Å. Borg (Åke); H. Jernström (H.); A. Lindblom (Annika); J. Rantala (Johanna); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); K.L. Nathanson (Katherine); S.M. Domchek (Susan); A. Jakubowska (Anna); J. Lubinski (Jan); T. Huzarski (Tomasz); A. Osorio (Ana); A. Lasa (Adriana); M. Durán (Mercedes); M.I. Tejada; J. Godino (Javier); J. Benitez (Javier); U. Hamann (Ute); M. Kriege (Mieke); N. Hoogerbrugge (Nicoline); R.B. van der Luijt (Rob); C.J. van Asperen (Christi); P. Devilee (Peter); E.J. Meijers-Heijboer (Hanne); M.J. Blok (Marinus); C.M. Aalfs (Cora); F.B.L. Hogervorst (Frans); M.A. Rookus (Matti); M. Cook (Margaret); C.T. Oliver (Clare); D. Frost (Debra); D. Conroy (Don); D.G. Evans (Gareth); F. Lalloo (Fiona); G. Pichert (Gabriella); R. Davidson (Rosemarie); T.J. Cole (Trevor); J. Paterson (Joan); S.V. Hodgson (Shirley); P.J. Morrison (Patrick); M.E. Porteous (Mary); L.J. Walker (Lisa); M.J. Kennedy (John); H. Dorkins (Huw); S. Peock (Susan); A.K. Godwin (Andrew); D. Stoppa-Lyonnet (Dominique); A. de Pauw (Antoine); S. Mazoyer (Sylvie); V. Bonadona (Valérie); C. Lasset (Christine); H. Dreyfus (Hélène); D. Leroux (Dominique); A. hardouin (Agnès); P. Berthet (Pascaline); L. Faivre (Laurence); C. Loustalot (Catherine); T. Noguchi (Tetsuro); H. Sobol (Hagay); E. Rouleau (Etienne); C. Nogues (Catherine); M. Frenay (Marc); L. Vénat-Bouvet (Laurence); J. Hopper (John); M.J. Daly (Mark); M-B. Terry (Mary-beth); E.M. John (Esther); S.S. Buys (Saundra); Y. Yassin (Yosuf); A. Miron (Alexander); D. Goldgar (David); C.F. Singer (Christian); C. Dressler (Catherina); D. Gschwantler-Kaulich (Daphne); G. Pfeiler (Georg); T.V.O. Hansen (Thomas); L. Jnson (Lars); B.A. Agnarsson (Bjarni); T. Kircchoff (Tomas); K. Offit (Kenneth); V. Devlin (Vincent); A. Dutra-Clarke (Ana); M. Piedmonte (Marion); G.C. Rodriguez (Gustavo); K. Wakeley (Katie); J.F. Boggess (John); J. Basil (Jack); P.E. Schwartz (Peter); S.V. Blank (Stephanie); A.E. Toland (Amanda); M. Montagna (Marco); C. Casella (Cinzia); E.N. Imyanitov (Evgeny); L. Tihomirova (Laima); I. Blanco (Ignacio); C. Lazaro (Conxi); S.J. Ramus (Susan); L. Sucheston (Lara); B.Y. Karlan (Beth); J. Gross (Jenny); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); C. Engel (Christoph); A. Meindl (Alfons); M. Lochmann (Magdalena); N. Arnold (Norbert); S. Heidemann (Simone); R. Varon-Mateeva (Raymonda); D. Niederacher (Dieter); C. Sutter (Christian); H. Deissler (Helmut); D. Gadzicki (Dorothea); S. Preisler-Adams (Sabine); K. Kast (Karin); I. Schönbuchner (Ines); T. Caldes (Trinidad); M. de La Hoya (Miguel); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J. Simard (Jacques); A.B. Spurdle (Amanda); H. Holland (Helene); G. Chenevix-Trench (Georgia); R. Platte (Radka); D.F. Easton (Douglas)

    2010-01-01

    textabstractThe known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10,

  15. Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females

    Directory of Open Access Journals (Sweden)

    Alaa Mohammed Ali

    2016-01-01

    Full Text Available We investigated three common polymorphisms (SNPs in the XRCC3 gene (rs861539, rs1799794, and rs1799796 in 143 Saudi females suffering from breast cancer (median age = 51.4 years and 145 age matched normal healthy controls. DNA was extracted from whole blood and genotyping was conducted using PCR-RFLP. rs1799794 showed significant association, where AA and AA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR: 28.1; 95% CI: 3.76–21.12; χ2: 22.82; pT and rs1799796 A>G did not show a significant difference when the results in the patients and controls were compared. However, the frequency of rs1799796 differed significantly in patients with different age of diagnosis, tumor grade, and ER and HER2 status. The wild type A allele occurred at a higher frequency in the ER− and HER2− group. Our results among Saudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility. In conclusion, the results obtained during this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females.

  16. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  17. Variants of MUC5B minisatellites and the susceptibility of bladder cancer.

    Science.gov (United States)

    Ahn, Eun-Kyung; Kim, Wun-Jae; Kwon, Jeong-Ah; Choi, Phil-Jo; Kim, Woo Jin; Sunwoo, Yangil; Heo, Jeonghoon; Leem, Sun-Hee

    2009-04-01

    The human MUC5B gene, which is primarily expressed in the tracheobronchial tract, is clustered to chromosome 11p15.5 with three other secreted gel-forming mucins, MUC6, MUC2, and MUC5AC. In this study, we identified seven variable number of tandem repeats (VNTRs; minisatellites) from the entire MUC5B region. Six (MUC5B-MS1, -MS2, -MS3, -MS4, -MS5, and -MS7) of the seven minisatellites evaluated in this study were novel minisatellites, but the MUC5B-MS6 minisatellite was described in a previous study. These minisatellites of MUC5B were analyzed in genomic DNA extracted from controls, cancer patients, and multigenerational families. Three (MUC5B-MS3, -MS6, and -MS7) of the seven minisatellites were found to be polymorphic and transmitted through meiosis following Mendelian inheritance in seven families; therefore, these minisatellite polymorphisms could be useful as markers for paternity mapping and DNA fingerprinting. In addition, we evaluated allelic variation in these minisatellites to determine if such variation affected the susceptibility to various carcinomas. To accomplish this, we conducted a case-control study in which the genomic DNA of 789 cancer-free controls and cancer patients with five types of cancer were compared. A statistically significant association between the long rare MUC5B-MS6 alleles and the occurrence of bladder cancer was identified in the younger group (<60; odds ratio, 4.54; 95% confidence interval, 1.0-20.7; p=0.03). This observation suggests that the long rare MUC5B-MS6 alleles evaluated in this study could be used to identify the risk of bladder cancer. PMID:19191526

  18. Susceptibility of Adult Cat Fleas (Siphonaptera: Pulicidae) to Insecticides and Status of Insecticide Resistance Mutations at the Rdl and Knockdown Resistance Loci.

    Science.gov (United States)

    Rust, Michael K; Vetter, Richard; Denholm, Ian; Blagburn, Byron; Williamson, Martin S; Kopp, Steven; Coleman, Glen; Hostetler, Joe; Davis, Wendell; Mencke, Norbert; Rees, Robert; Foit, Sabrina; Böhm, Claudia; Tetzner, Kathrin

    2015-08-01

    The susceptibility of 12 field-collected isolates and 4 laboratory strains of cat fleas, Ctenocephalides felis was determined by topical application of some of the insecticides used as on-animal therapies to control them. In the tested field-collected flea isolates the LD50 values for fipronil and imidacloprid ranged from 0.09 to 0.35 ng/flea and 0.02 to 0.19 ng/flea, respectively, and were consistent with baseline figures published previously. The extent of variation in response to four pyrethroid insecticides differed between compounds with the LD50 values for deltamethrin ranging from 2.3 to 28.2 ng/flea, etofenprox ranging from 26.7 to 86.7 ng/flea, permethrin ranging from 17.5 to 85.6 ng/flea, and d-phenothrin ranging from 14.5 to 130 ng/flea. A comparison with earlier data for permethrin and deltamethrin implied a level of pyrethroid resistance in all isolates and strains. LD50 values for tetrachlorvinphos ranged from 20.0 to 420.0 ng/flea. The rdl mutation (conferring target-site resistance to cyclodiene insecticides) was present in most field-collected and laboratory strains, but had no discernible effect on responses to fipronil, which acts on the same receptor protein as cyclodienes. The kdr and skdr mutations conferring target-site resistance to pyrethroids but segregated in opposition to one another, precluding the formation of genotypes homozygous for both mutations. PMID:26152407

  19. Polymorphisms of the Hypoxia Inducible Factor 1 and microRNA Related Genes and the Susceptibility and Survival of Lung Cancer and Upper Aero-Digestive Tract Cancers

    OpenAIRE

    Yang, Ying

    2014-01-01

    Background: Hypoxia inducible factor 1(HIF-1) and microRNAs (miRNAs) regulate transcriptional activities and contribute in several biological processes such as oxygen homeostasis, cell growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer etiology and outcomes. Nonetheless, there are few published studies of the relationship between HIF-1 and miRNA gene polymorphisms and susceptibility and survival of lung cancer or UADT cancers. Methods: 1,...

  20. Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    WANG Fang; HAN Xue-yao; REN Qian; ZHANG Xiu-ying; HAN Ling-chuan; LUO Ying-ying; ZHOU Xiang-hai; JI Li-nong

    2009-01-01

    Background KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes.Methods We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG and HNF4A by genotyping them using ABI SnaPshot(R) Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. Results rs5219(E23K) in KCNJ11 was associated with genetic susceptibility to type 2 diabetes (OR=1.400 with 95% Cl 1.117 1.755, P=0.004 under an additive model, OR=-1.652 with 95% Cl 1.086 2.513, P=0.019 under a recessive model,and OR=1.521 with 95% Cl 1.089 2.123, P=0.014 under a dominant model) after adjusting for sex and body mass index (BMI). We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 (Pro12Ala) and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion (P=0.005) after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P=-0.004 under an additive model for rs2144908;and P=0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala.Conclusions Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.

  1. NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis.

    Science.gov (United States)

    Zhang, Jian; Qiu, Li-Xin; Wang, Zhong-Hua; Wang, Jia-Lei; He, Shuang-Shuang; Hu, Xi-Chun

    2010-10-01

    To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968-1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938-1.068) or Asians (OR = 1.155, 95% CI = 0.886-1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037-1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886-1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844-1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099-1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility. PMID:20180012

  2. Clinical application of micronucleus test: a case-control study on the prediction of breast cancer risk/susceptibility.

    Directory of Open Access Journals (Sweden)

    Claudia Bolognesi

    Full Text Available The micronucleus test is a well-established DNA damage assay in human monitoring. The test was proposed as a promising marker of cancer risk/susceptibility mainly on the basis of studies on breast cancer. Our recent meta-analysis showed that the association between micronuclei frequency, either at baseline or after irradiation, and breast cancer risk or susceptibility, has been evaluated in few studies of small size, with inconsistent results. The aim of the present study is to investigate the role of micronucleus assay in evaluating individual breast cancer susceptibility. Two-hundred and twenty untreated breast cancer patients and 295 female controls were enrolled in the study. All women were characterized for cancer family history and 155 subjects were evaluated for the presence of BRCA mutations. Micronuclei frequency was evaluated at baseline and after irradiation with 1-Gy gamma rays from a 137Cs source. The results show a non significant increase of frequency of micronucleated binucleated lymphocytes in cancer patients compared with the controls at baseline (Mean (S.E.: 16.8 (0.7 vs 15.7 (0.5, but not after irradiation (Mean (S.E.: 145.8 (3.0 vs 154.0 (2.6. Neither a family history of breast cancer nor the presence of a pathogenic mutation in BRCA1/2 genes were associated with an increased micronuclei frequency. Our results do not support a significant role of micronucleus frequency as a biomarker of breast cancer risk/susceptibility.

  3. Interactions between environmental factors and melatonin receptor type 1A polymorphism in relation to oral cancer susceptibility and clinicopathologic development.

    Directory of Open Access Journals (Sweden)

    Feng-Yan Lin

    Full Text Available The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer.Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non-cancer controls were analyzed by real-time polymerase chain reaction (PCR. The CTA haplotype of the studied MTNR1A polymorphisms (rs2119882, rs13140012, rs6553010 was related to a higher risk of oral cancer. Moreover, MTNR1A gene polymorphisms exhibited synergistic effects of environmental factors (betel quid and tobacco use on the susceptibility of oral cancer. Finally, oral-cancer patients with betel quid-chewing habit who had T/T allele of MTNR1A rs13140012 were at higher risk for developing an advanced clinical stage and lymph node metastasis.These results support gene-environment interactions of MTNR1A polymorphisms with smoking and betel quid-chewing habits possibly altering oral-cancer susceptibility and metastasis.

  4. Bioinformatics Analysis for Coding SNPs of the HLADQA1 Gene Involved in Susceptibility to Cervical Cancer

    Institute of Scientific and Technical Information of China (English)

    Yanyun Li; Jun Xing; Linsheng Zhao; Yanni Li; Yuchuan Wang; Weiming Zhang

    2006-01-01

    OBJECTIVE To analyze coding SNPs of the HLA-DQA1 gene involved in susceptibility for cervical cancer by a bioinformatics approach, and to choose some SNPs that may have an association with cervical cancer.METHODS By a SNPper tool we extracted SNPs from a public database (dbSNP), exporting them in FASTA formats suitable for subsequent use.Then we used PARSESNP as a tool for the analysis of the cSNPs.RESULTS In the cSNPs of the HLA-DQA1 gene, we find that rs9272693and rs9272703, are made up of missense mutations which convert a codon for one amino acid into a codon for a different amino acid. We chose a PSSM Difference >10 as a lower level for the scores of changes predicted to be deldterious.CONCLUSION We used a bioinformatics approach for cSNPs analysis of the HLA-DQA1 gene. This method can select the variants in a conserved region, and give a PSSM Difference score. But the results need to be verified in cervical cancer patients and a control population.

  5. Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

    Directory of Open Access Journals (Sweden)

    Tuomo Mantere

    2016-01-01

    Full Text Available Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3 was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3 and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3. A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007. Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007, suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.

  6. Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility

    Science.gov (United States)

    Mantere, Tuomo; Winqvist, Robert; Kauppila, Saila; Grip, Mervi; Jukkola-Vuorinen, Arja; Tervasmäki, Anna; Rapakko, Katrin; Pylkäs, Katri

    2016-01-01

    Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations. PMID:26820313

  7. Teen smoking, field cancerization, and a "critical period" hypothesis for lung cancer susceptibility.

    OpenAIRE

    Wiencke, John K.; Kelsey, Karl T.

    2002-01-01

    Cigarette smoking by children and adolescents continues to be prevalent, and this fact represents a major public health problem and challenge. Epidemiologic work has previously suggested that exposure of the lung to tobacco carcinogens at an early age may be an independent risk factor for lung cancer. Recent studies at the molecular and cellular levels are consistent with this, now suggesting that early exposure enhances DNA damage and is associated with the induction of DNA alterations in sp...

  8. IL-1α -889 C/T polymorphism and cancer susceptibility: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Cheng D

    2014-11-01

    Full Text Available Daye Cheng, Yiwen Hao, Wenling Zhou Department of Transfusion, First Hospital of China Medical University, Shenyang, People's Republic of China Abstract: The -889 C/T polymorphism in the interleukin-1α (IL-1α gene has been implicated in the risk of cancer, but the results are inconclusive. The present meta-analysis aimed to investigate the association between the -889 C/T polymorphism and cancer risk. A literature search in PubMed, Embase™, Web of Science™, Science Direct®, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure (CNKI databases was carried out to identify studies investigating the association between IL-1α -889 C/T polymorphism and cancer risk. The odds ratio (OR with 95% confidence interval (CI were used to assess the strength of association. A total of 20 publications, involving 6,782 cases and 7,767 controls, were included in this meta-analysis. Combined analysis revealed a significant association between -889 C/T polymorphism and cancer risk under an allele model (OR =1.12, 95% CI =1.02–1.24, P=0.02, recessive model (OR =1.34, 95% CI =1.06–1.68, P=0.01, and homozygous comparison (OR =1.38, 95% CI =1.10–1.74, P<0.01. Subgroup analysis by ethnicity showed there was significant association between cancer risk and IL-1a -889C/T polymorphism in Asian populations under a recessive model (OR =2.57, 95% CI =1.11–5.98, P=0.03 and homozygous comparison (OR =2.60, 95% CI =1.12–6.04, P=0.03. Moreover, a subgroup analysis was conducted by source of control, and a statistically increased cancer risk was found in the hospital-based group, under a recessive model (OR =1.62, 95% CI =1.03–2.56, P=0.04 and homozygous comparison (OR =1.67, 95% CI =1.04–2.68, P=0.03. This meta-analysis suggests that IL-1α -889 C/T polymorphism contributes to cancer susceptibility. Further large and well-designed studies are needed to confirm this association. Keywords: neoplasma, biomarker, cytokine, systematic review

  9. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Science.gov (United States)

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  10. Antibacterial susceptibility of bacteria isolated from burns and wounds of cancer patients

    Directory of Open Access Journals (Sweden)

    Sulaiman A. Alharbi

    2014-01-01

    Full Text Available In this study 540 burns and wound swabs were collected from cancer patients of some Egyptian hospitals. The single infection was detected from 210, and 70 cases among wounded and burned patients, while mixed infection was 30 and 45, respectively. We recovered where 60 isolates of Pseudomonas aeruginosa, 60 isolates of Staphylococcus aureus, 7 isolates of Staphylococcus epidermidis, 4 isolates of Streptococcus pyogenes, 25 isolates of Escherichia coli, 23 isolates of Klebsiella pneumoniae and 27 isolates of Proteus vulgaris from 355 burn and surgical wound infections . All bacterial isolates showed high resistance to the commonly used β-lactams (amoxycillin, cefaclor, ampicillin, vancomycin, amoxicillin/clavulonic, and low resistance to imepenim and ciprofloxacin. Plasmid analysis of six multidrug resistant and two susceptible bacterial isolates revealed the same plasmid pattern. This indicated that R-factor is not responsible for the resistance phenomenon among the isolated opportunistic bacteria. The effect of ultraviolet radiation on the isolated bacteria was studied.

  11. Impacts of CA9 gene polymorphisms and environmental factors on oral-cancer susceptibility and clinicopathologic characteristics in Taiwan.

    Directory of Open Access Journals (Sweden)

    Ming-Hsien Chien

    Full Text Available BACKGROUND: In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9 is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC and the clinicopathological characteristics of the tumors. METHODOLOGY AND PRINCIPAL FINDINGS: Four single-nucleotide polymorphisms (SNPs of the CA9 gene from 462 patients with oral cancer and 519 non-cancer controls were analyzed by a real-time polymerase chain reaction (PCR. While the studied SNPs (CA9 rs2071676, rs3829078, rs1048638 and +376 Del were not associated with susceptibility to oral cancer, the GAA haplotype of 3 CA9 SNPs (rs2071676, rs3829078, and rs1048638 was related to a higher risk of oral cancer. Moreover, the four CA9 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. Finally, patients with oral cancer who had at least one G allele of CA9 rs2071676 were at higher risk for developing lymph-node metastasis (p = 0.022, compared to those patients homozygous for AA. CONCLUSIONS: Our results suggest that the haplotype of rs2071676, rs3829078, and rs1048638 combined has potential predictive significance in oral carcinogenesis. Gene-environment interactions of CA9 polymorphisms, smoking, and betel-quid chewing might alter oral cancer susceptibility and metastasis.

  12. Possible association of β2- and β3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer

    OpenAIRE

    Xin-en HUANG; Hamajima, Nobuyuki; Saito, Toshiko; Matsuo, Keitaro; Mizutani, Mitsuhiro; Iwata, Hiroji; Iwase, Takuji; Miura, Shigeto; Mizuno, Tsutomu; Tokudome, Shinkan; Tajima, Kazuo

    2001-01-01

    Background The involvement of β2-adrenergic receptor (ADRB2) and β3-adrenergic receptor (ADRB3) in both adipocyte lipolysis and thermogenic activity suggests that polymorphisms in the encoding genes might be linked with interindividual variation in obesity, an important risk factor for postmenopausal breast cancer. In order to examine the hypothesis that genetic variations in ADRB2 and ADRB3 represent interindividual susceptibility factors for obesity and breast cancer, we conducted a hospita...

  13. Clustering of sebaceous gland carcinoma, papillary thyroid carcinoma and breast cancer in a woman as a new cancer susceptibility disorder: a case report

    Directory of Open Access Journals (Sweden)

    Newman Brian D

    2009-07-01

    Full Text Available Abstract Introduction Multiple distinct tumors arising in a single individual or within members of a family raise the suspicion of a genetic susceptibility disorder. Case presentation We present the case of a 52-year-old Caucasian woman diagnosed with sebaceous gland carcinoma of the eyelid, followed several years later with subsequent diagnoses of breast cancer and papillary carcinoma of the thyroid. Although the patient was also exposed to radiation from a pipe used in the oil field industry, the constellation of neoplasms in this patient suggests the manifestation of a known hereditary susceptibility cancer syndrome. However, testing for the most likely candidates such as Muir-Torre and Cowden syndrome proved negative. Conclusion We propose that our patient's clustering of neoplasms either represents a novel cancer susceptibility disorder, of which sebaceous gland carcinoma is a characteristic feature, or is a variant of the Muir-Torre syndrome.

  14. Gene by Environment Interaction Linking the Chromosome 15q25 Locus With Cigarette Consumption and Lung Cancer Susceptibility — Are African American Affected Differently?

    OpenAIRE

    Hopkins, R.J.; R. P. Young

    2016-01-01

    The majority of lung cancer cases result from complex interactions between smoking exposure, genetic susceptibility and a person's immune response to chronic inflammation or lung remodelling. Epidemiological studies confirm that susceptibility to developing chronic obstructive pulmonary disease (COPD), especially emphysema, is also closely linked to lung cancer susceptibility. Genetic epidemiology studies have consistently reported associations between the chromosome 15q25 locus with lung can...

  15. Sporadic colorectal cancer and individual susceptibility: A review of the association studies investigating the role of DNA repair genetic polymorphisms

    Czech Academy of Sciences Publication Activity Database

    Naccarati, Alessio; Pardini, B.; Hemminki, K.; Vodička, Pavel

    2007-01-01

    Roč. 635, 2-3(2007), s.118-145. ISSN 1383-5742 R&D Projects: GA MZd NR8563; GA ČR GA310/05/2626 Institutional research plan: CEZ:AV0Z50390512 Keywords : Sporadic colorectal cancer * Individual susceptibility * DNA repair Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.353, year: 2007

  16. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

    DEFF Research Database (Denmark)

    Permuth-Wey, Jennifer; Lawrenson, Kate; Shen, Howard C;

    2013-01-01

    Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent...

  17. Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer.

    Science.gov (United States)

    Su, Chun-Wen; Huang, Yi-Wen; Chen, Mu-Kuan; Su, Shih-Chi; Yang, Shun-Fa; Lin, Chiao-Wen

    2015-11-01

    Oral cancer, the fourth most common cancer among men in Taiwan, is associated with environmental carcinogens. Tissue inhibitor of metalloproteinase-3 (TIMP3), a member of the TIMP family, is the only protein that binds to the extracellular matrix for suppressing cancer cell growth, angiogenesis, migration, and invasion. The association of TIMP3 polymorphism with oral cancer susceptibility, however, has not yet been reported. In this study, 1947 participants-1200 healthy male controls and 747 male patients with oral cancer-were recruited. Allelic discrimination of TIMP3 -1296 T > C (rs9619311), TIMP3 C > T (rs9862), and TIMP3 C > T (rs11547635) polymorphisms were assessed through real-time polymerase chain reaction. The authors discovered that individuals carrying the polymorphic rs9862 allele are more susceptible to oral cancer [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.2-1.9; adjusted OR (AOR), 1.6; 95% CI, 1.2-2.1] after adjustment for betel quid chewing, alcohol, and tobacco consumption. Among 601 betel quid chewers, the TIMP3 polymorphism rs9862 T/T carriers had a 32.2-fold (95% CI, 20.2-51.3) increased oral cancer risk compared with those carrying C/C and not chewing betel quid. In addition, the authors observed a significant association between rs9862 variants and large tumors (OR, 1.5; 95% CI, 1.0-2.3) development. Moreover, TIMP3 plasma levels significantly increased in oral cancer patients who have large tumor or carry T allele rs9862 polymorphism. In conclusion, these results suggest that gene-environment interactions between the TIMP3 rs9862 polymorphisms and betel quid may alter oral cancer susceptibility and tumor growth in Taiwanese men. PMID:26579821

  18. Genetic variants at 1q22 and 10q23 reproducibly associated with gastric cancer susceptibility in a Chinese population

    OpenAIRE

    Zhang, Hanze; Jin, Guangfu; Li, Huizhang; Ren, Chuanli; Ding, Yanbing; Zhang, Qin; Deng, Bin; Wang, Jianming; Hu, Zhibin; Xu, Yaochu; Shen, Hongbing

    2011-01-01

    Two recent genome-wide association studies reported significant associations of genetic variants at 1q22, 10q23 and 20p13 with gastric cancer (GC) risk in Chinese populations. However, these findings have not been confirmed in other independent studies. Here, we performed an independent case–control study in a Chinese population by genotyping three loci (rs4072037A>G at 1q22, rs2274223A>G at 10q23 and rs13042395C>T at 20p13) in 1681 GC cases and 1858 controls. We found that rs4072037 at 1q22 ...

  19. Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia

    Science.gov (United States)

    Wang, Yang; Cao, Yanfei; Huang, Xiaoye; Yu, Tao; Wei, Zhiyun; McGrath, John; Xu, Fei; Bi, Yan; Li, Xingwang; Yang, Fengping; Li, Weidong; Zou, Xia; Peng, Zhihai; Xiao, Yanzeng; Zhang, Yan; He, Lin; He, Guang

    2016-01-01

    Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression. PMID:27226254

  20. Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness

    International Nuclear Information System (INIS)

    Interleukin-8 (IL-8/CXCL-8) is a prototype of the ELR+CXC chemokines that play an important role in the promotion and progression of many human cancers including breast cancer. We have recently showed the implication of polymorphism (-251) T/A of IL-8 gene in the susceptibility and prognosis of breast carcinoma. IL-8 acts through its CXCR1 and CXCR2 receptors. CXCR2, expressed on the endothelial cells, is the receptor involved in mediating the angiogenic effects of ELR+CXC chemokines and in particular IL-8. In the current study, we investigated the susceptibility and prognostic implications of the genetic variation in CXCR2 in breast carcinoma. We also confirmed the implication of IL-8 (-251) T/A polymorphism in a larger cohort. Finally, we combined the IL-8 and CXCR2 variant alleles and analyzed their effects in breast cancer risk and prognosis. We used the allele-specific polymerase chain reaction to characterize the variation of IL-8 and CXCR2 for 409 unrelated Tunisian patients with breast carcinoma and 301 healthy control subjects. To estimate the relative risks, Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression after adjusting for the known risk factors for breast cancer. Associations of the genetic marker with the rates of breast carcinoma-specific overall survival and disease-free survival were assessed using univariate and multivariate analyses. A highly significant association was found between the homozygous CXCR2 (+ 1208) TT genotype (adjusted OR = 2.89; P = 0.008) and breast carcinoma. A significantly increased risk of breast carcinoma was associated with IL-8 (-251) A allele (adjusted OR = 1.86; P = 0.001). The presence of two higher risk genotypes (the TA and TT in IL-8, and the TT in CXCR2) significantly increased the risk of developing breast carcinoma (adjusted OR = 4.15; P = 0.0004). The CXCR2 (+ 1208) T allele manifested a significant association with an aggressive phenotype of breast carcinoma as

  1. Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

    DEFF Research Database (Denmark)

    Milne, Roger L; Goode, Ellen L; García-Closas, Montserrat;

    2011-01-01

    Consortium. METHODS: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness......, and 3/4, respectively; P(trend) = 5 × 10(-7)]. CONCLUSION: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol...

  2. Gly71Arg UGT1A1 polymorphism is associated with breast cancer susceptibility in Han Chinese women.

    Science.gov (United States)

    Shi, J; Li, L H; Duan, X Y; Liu, Q; Sun, L L; Tian, Y T

    2016-01-01

    Breast cancer is among the most common causes of cancer-related death in women worldwide. Previous studies have demonstrated an association between prolonged estrogen exposure and increased risk of breast cancer. Uridine 5'-diphospho-glucuronosyltransferase 1-1 (UGT1A1) plays a significant role in the detoxification of estrogens. Two major genetic polymorphisms have been identified in the UGT1A1 locus. UGT1A1*28 has been previously linked to increased risk of breast cancer. The aim of this study was to elucidate the possible correlation between UGT1A1*6, a single nucleotide polymorphism causing a Gly71Arg substitution, and breast cancer susceptibility. Forty-six women diagnosed with breast cancer, 15 patients with gastrointestinal cancer, and 13 healthy women were recruited to this study. The genotype in the polymorphic UGT1A1 locus was determined by DNA sequencing. The frequency of each genotype was compared among the three groups. The frequency of the UGT1A1*6 allele was significantly higher in breast cancer and gastrointestinal cancer patients than that in healthy females (both P 0.05). Therefore, the UGT1A1*6 polymorphism was deduced to be a risk factor for breast cancer in women of Han Chinese ethnicity. UGT1A1 may serve as a therapeutic target for the prevention and treatment of breast cancer and other estrogen-related diseases. PMID:27525948

  3. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

    DEFF Research Database (Denmark)

    Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I;

    2010-01-01

    in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators...

  4. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

    DEFF Research Database (Denmark)

    Kote-Jarai, Zsofia; Saunders, Edward J; Leongamornlert, Daniel A;

    2013-01-01

    Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that...

  5. Smoking behaviour, knowledge and perceived susceptibility to lung cancer among secondary-school students in Amman, Jordan.

    Science.gov (United States)

    Shadid, H M; Hossain, S Z

    2015-03-01

    Smoking in Jordan is a serious problem as it affects almost all segments of society including children. This study aimed to evaluate the smoking behaviour of Jordanian secondary-school students (aged 16-18 years), their awareness of the dangers of smoking and their perceived susceptibility to lung cancer. Of the stratified random sample of students from Amman schools (n = 648), 43% were ever smokers (had smoked for 1 year) and 27.6% were current smokers, while 81% reported having a smoker in the family. Students in western Amman (higher socioeconomic status) and those who started smoking at a younger age demonstrated better knowledge about smoking-related consequences. Perceived susceptibility to lung cancer was significantly associated with sex, perceived seriousness of lung cancer and school location. Students' sex, socioeconomic status and the family environment were important factors that influenced students' smoking behaviour and risk perceptions and these findings have significant policy implications. PMID:26074218

  6. The role of the breast cancer susceptibility gene 1 (BRCA1 in sporadic epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Mueller Christopher R

    2003-10-01

    Full Text Available Abstract Mutations within the BRCA1 tumor suppressor gene occur frequently in familial epithelial ovarian carcinomas but they are a rare event in the much more prevalent sporadic form of the disease. However, decreased BRCA1 expression occurs frequently in sporadic tumors, and the magnitude of this decrease has been correlated with increased disease progression. The near absence of somatic mutations consequently suggests that there are alternative mechanisms that may contribute to the observed loss of BRCA1 in sporadic tumors. Indeed, both allelic loss at the BRCA1 locus and epigenetic hypermethylation of the BRCA1 promoter play an important role in BRCA1 down-regulation; yet these mechanisms alone or in combination do not always account for the reduced BRCA1 expression. Alternatively, misregulation of specific upstream factors that control BRCA1 transcription may be a crucial means by which BRCA1 is lost. Therefore, determining how regulators of BRCA1 expression may be co-opted during sporadic ovarian tumorigenesis will lead to a better understanding of ovarian cancer etiology and it may help foster the future development of novel therapeutic strategies aimed at halting ovarian tumor progression.

  7. Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk

    DEFF Research Database (Denmark)

    Guo, Xingyi; Long, Jirong; Zeng, Chenjie;

    2015-01-01

    BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. METHODS: We conducted a fine-mapping analysis in 55,540 breast...... cancer cases and 51,168 controls from the Breast Cancer Association Consortium. RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs......62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2...

  8. Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival.

    Science.gov (United States)

    Yadav, Anu; Gupta, Annapurna; Yadav, Saurabh; Rastogi, Neeraj; Agrawal, Sushma; Kumar, Ashok; Kumar, Vijay; Misra, Sanjeev; Mittal, Balraj

    2016-06-01

    Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients. PMID:26715268

  9. Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.

    Science.gov (United States)

    Vuorela, Mikko; Pylkäs, Katri; Hartikainen, Jaana M; Sundfeldt, Karin; Lindblom, Annika; von Wachenfeldt Wäppling, Anna; Haanpää, Maria; Puistola, Ulla; Rosengren, Annika; Anttila, Maarit; Kosma, Veli-Matti; Mannermaa, Arto; Winqvist, Robert

    2011-12-01

    RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families. PMID:21750962

  10. Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population

    DEFF Research Database (Denmark)

    Duell, Eric J; Bonet, Catalina; Muñoz, Xavier;

    2015-01-01

    to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group...... A (AO+AA, odds ratio=1.84, 95%CI=1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes...... the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis. What's New? Blood type A indicates a higher risk of gastric cancer, but why? This study examined the relationship between blood group genes and cancer. The authors investigated 32 variants among not only...

  11. Susceptibility to oral cancers with CD95 and CD95L promoter SNPs may vary with the site and gender.

    Science.gov (United States)

    Daripally, Sarika; Nallapalle, Sateesh Reddy; Katta, Saritha; Prasad, Vidudala V T S

    2015-09-01

    We investigated risk association of oral cancers (tongue and buccal mucosa cancers) with FAS (-1377G > A and FAS -670 A > G) and FASL (-844 T > C) SNPs, in males and females. A case-control study of 535 oral cancer and 525 control subjects was performed. SNPs were detected in the genomic DNA isolated from peripheral blood using PCR-RFLP. We report FASL -844 T > C SNPs increased risk for buccal mucosa cancer in females but not in males. On the other hand, FAS genotypes did not alter the risk of the cancers in both females and males. However, co-occurrence of FAS -1377 GA and -670 GG, FAS -1377 AA and -670 GG genotypes, and combined genotypes of FAS and FASL (FAS -1377 AA + FAS -670 GG + FASL -844 CC) alter male susceptibility towards tongue cancer. In females, combined genotypes of FAS (-1377GA and -670 AA) were found to be a risk factor of buccal mucosa cancer (OR = 3.27, CI = 1.28-8.36; P ≤ 0.01). FASL variants (GA and AA) increased tongue cancer risk in females who were tobacco users compared to non-tobacco users. In conclusion, SNPs of the FAS and FASL might alter risk of tongue and buccal mucosa cancers differentially, in a gender-dependent manner. PMID:25944167

  12. Detecting Susceptibility to Breast Cancer with SNP-SNP Interaction Using BPSOHS and Emotional Neural Networks

    Science.gov (United States)

    Wang, Xiao; Fan, Yue

    2016-01-01

    Studies for the association between diseases and informative single nucleotide polymorphisms (SNPs) have received great attention. However, most of them just use the whole set of useful SNPs and fail to consider the SNP-SNP interactions, while these interactions have already been proven in biology experiments. In this paper, we use a binary particle swarm optimization with hierarchical structure (BPSOHS) algorithm to improve the effective of PSO for the identification of the SNP-SNP interactions. Furthermore, in order to use these SNP interactions in the susceptibility analysis, we propose an emotional neural network (ENN) to treat SNP interactions as emotional tendency. Different from the normal architecture, just as the emotional brain, this architecture provides a specific path to treat the emotional value, by which the SNP interactions can be considered more quickly and directly. The ENN helps us use the prior knowledge about the SNP interactions and other influence factors together. Finally, the experimental results prove that the proposed BPSOHS_ENN algorithm can detect the informative SNP-SNP interaction and predict the breast cancer risk with a much higher accuracy than existing methods. PMID:27294121

  13. Detecting Susceptibility to Breast Cancer with SNP-SNP Interaction Using BPSOHS and Emotional Neural Networks.

    Science.gov (United States)

    Wang, Xiao; Peng, Qinke; Fan, Yue

    2016-01-01

    Studies for the association between diseases and informative single nucleotide polymorphisms (SNPs) have received great attention. However, most of them just use the whole set of useful SNPs and fail to consider the SNP-SNP interactions, while these interactions have already been proven in biology experiments. In this paper, we use a binary particle swarm optimization with hierarchical structure (BPSOHS) algorithm to improve the effective of PSO for the identification of the SNP-SNP interactions. Furthermore, in order to use these SNP interactions in the susceptibility analysis, we propose an emotional neural network (ENN) to treat SNP interactions as emotional tendency. Different from the normal architecture, just as the emotional brain, this architecture provides a specific path to treat the emotional value, by which the SNP interactions can be considered more quickly and directly. The ENN helps us use the prior knowledge about the SNP interactions and other influence factors together. Finally, the experimental results prove that the proposed BPSOHS_ENN algorithm can detect the informative SNP-SNP interaction and predict the breast cancer risk with a much higher accuracy than existing methods. PMID:27294121

  14. Haplotypes of nine single nucleotide polymorphisms on chromosome 19q13.2-3 associated with susceptibility of lung cancer in a Chinese population

    DEFF Research Database (Denmark)

    Yin, Jiaoyang; Vogel, Ulla Birgitte; Ma, Yegang;

    2008-01-01

    To evaluate the joint effect of nine single nucleotide polymorphisms for three DNA repair genes in the region of chromosome 19q13.2-3 on susceptibility of lung cancer in a Chinese population, we conducted a hospital-based case-control study consisting of 247 lung cancer cases and 253 cancer...

  15. Meta-Analysis of a Multi-Ethnic, Breast Cancer Case-Control Targeted Sequencing Study

    OpenAIRE

    Ablorh, Akweley

    2015-01-01

    Breast cancer, the most commonly diagnosed cancer in American women, is a heritable disease with nearly one hundred known genetic risk factors. Using next generation sequencing, we explored the contribution of genetics at 12 GWAS-identified loci to breast cancer susceptibility in a multi-ethnic breast cancer case-control study. Methods: The study population consists of 4,611 breast cancer cases and controls (2,316 cases and 2,295 controls) from four mutually exclusive ethnicities: Africa...

  16. Fine-scale mapping of the 4q24 locus identifies & pr two Independent loci associated with breast cancer risk

    NARCIS (Netherlands)

    X. Guo (Xingyi); J. Long (Jirong); C. Zeng (Chenjie); K. Michailidou (Kyriaki); M. Ghoussaini (Maya); M.K. Bolla (Manjeet); Q. Wang (Qing); R.L. Milne (Roger L.); X.-O. Shu (Xiao-Ou); Q. Cai (Qiuyin); J. Beesley (Jonathan); S. Kar (Siddhartha); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); V. Arndt (Volker); M.W. Beckmann (Matthias W.); A. Beeghly-Fadiel (Alicia); J. Benítez (Javier); W.J. Blot (William); N.V. Bogdanova (Natalia); S.E. Bojesen (Stig); H. Brauch (Hiltrud); H. Brenner (Hermann); L.A. Brinton (Louise); A. Broekss (Annegien); T. Brüning (Thomas); B. Burwinkel (Barbara); H. Cai (Hui); S. Canisius (Sander); J. Chang-Claude (Jenny); J.-Y. Choi (J.); F.J. Couch (Fergus); A. Cox (Angela); S.S. Cross (Simon); K. Czene (Kamila); H. Darabi (Hatef); P. Devilee (Peter); A. Droit (Arnaud); T. Dörk (Thilo); P.A. Fasching (Peter); O. Fletcher (Olivia); H. Flyger (Henrik); F. Fostira (Florentia); V. Gaborieau (Valerie); M. García-Closas (Montserrat); G.G. Giles (Graham G.); M. Grip (Mervi); P. Guénel (Pascal); C.A. Haiman (Christopher A.); U. Hamann (Ute); J.M. Hartman (Joost); A. Hollestelle (Antoinette); J.L. Hopper (John L.); C.-N. Hsiung (Chia-Ni); H. Ito (Hidemi); A. Jakubowska (Anna); N. Johnson (Nichola); M. Kabisch (Maria); D. Kang (Daehee); S. Khan (Sofia); J.A. Knight (Julia); V-M. Kosma (Veli-Matti); D. Lambrechts (Diether); L. Le Marchand (Loic); J. Li (Jingmei); A. Lindblom (Annika); A. Lophatananon (Artitaya); J. Lubinski (Jan); A. Mannermaa (Arto); S. Manoukian (Siranoush); S. Margolin (Sara); F. Marme (Federick); K. Matsuo (Keitaro); C.A. McLean (Catriona Ann); A. Meindl (Alfons); K. Muir (Kenneth); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); S. Nord (Silje); J.E. Olson (Janet); N. Orr (Nick); P. Peterlongo (Paolo); T.C. Putti (Thomas Choudary); A. Rudolph (Anja); S. Sangrajrang (Suleeporn); E.J. Sawyer (Elinor); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); C-Y. Shen (Chen-Yang); J. Shi (Jiajun); M. Shrubsole (Martha); M.C. Southey (Melissa); A.J. Swerdlow (Anthony ); S.H. Teo (Soo Hwang); B. Thienpont (Bernard); A.E. Toland (Amanda); R.A.E.M. Tollenaar (Rob); I. Tomlinson (Ian); T. Truong (Thérèse); C.-C. Tseng (Chiu-chen); A.M.W. van den Ouweland (Ans); W. Wen (Wanqing); R. Winqvist (Robert); A. Wu (Anna); C.H. Yip (Cheng Har); M.P. Zamora (Pilar); Y. Zheng (Ying); P. Hall (Per); P.D.P. Pharoah (Paul); J. Simard (Jacques); G. Chenevix-Trench (Georgia); A.M. Dunning (Alison); D.F. Easton (Douglas F.); W. Zheng (Wei); R. Eeles (Rosalind); A.A. Al Olama (Ali Amin); Z. Kote-Jarai; S. Benlloch (Sara); A.C. Antoniou (Antonis C.); L. McGuffog (Lesley); K. Offit (Kenneth); A. Lee (Andrew); E. Dicks (Ed); C. Luccarini (Craig); D.C. Tessier (Daniel C.); F. Bacot (Francois); D. Vincent (Daniel); S. La Boissière (Sylvie); F. Robidoux (Frederic); S.F. Nielsen (Sune); J.M. Cunningham (Julie); S.A. Windebank (Sharon A.); C.A. Hilker (Christopher A.); J. Meyer (Jeffrey); M. Angelakos (Maggie); J. Maskiell (Judi); E.J. Rutgers (Emiel J.); S. Verhoef; F.B.L. Hogervorst (Frans); P. Boonyawongviroj (Prat); P. Siriwanarungsan (Pornthep); A. Schrauder (André); M. Rübner (Matthias); S. Oeser (Sonja); S. Landrith (Silke); E. Williams (Eileen); E. Ryder-Mills (Elaine); K. Sargus (Kara); N. McInerney (Niall); G. Colleran (Gabrielle); A. Rowan (Andrew); A. Jones (Angela); C. Sohn (Christof); A. Schneeweiß (Andeas); P. Bugert (Peter); N. Álvarez (Nuria); L. Bernstein (Leslie); J. Lacey (James); S. Wang (Sophia); H. Ma (Huiyan); Y. Lu (Yani); J. Clague De Hart (Jessica); D. Deapen (Dennis); R. Pinder (Rich); E. Lee (Eunjung); F.R. Schumacher (Fredrick); P. Horn-Ross (Pam); P. Reynolds (Peggy); D. Nelson (David); H. Park (Hannah); H. Ziegler (Hartwig); S. Wolf (Sonja); V. Hermann (Volker); W.-Y. Lo (Wing-Yee); C. Justenhoven (Christina); Y.-D. Ko (Yon-Dschun); C. Baisch (Christian); H.-P. Fischer (Hans-Peter); B. Pesch (Beate); S. Rabstein (Sylvia); A. Lotz (Anne); V. Harth (Volker); T. Heikkinen (Tuomas); I. Erkkilä (Irja); K. Aaltonen (Kirsimari); K. von Smitten (Karl); N.N. Antonenkova (Natalia); P. Hillemanns (Peter); H. Christiansen (Hans); E. Myöhänen (Eija); H. Kemiläinen (Helena); H. Thorne (Heather); E. Niedermayr (Eveline); D. Bowtell; G. Chenevix-Trench (Georgia); A. De Fazio (Anna); D. Gertig; A. Green; P. Webb (Penny); A. Green; P. Parsons; N. Hayward; P.M. Webb (P.); D. Whiteman; A. Fung (Annie); J. Yashiki (June); G. Peuteman (Gilian); D. Smeets (Dominiek); T. Van Brussel (Thomas); K. Corthouts (Kathleen); N. Obi (Nadia); J. Heinz (Judith); T.W. Behrens (Timothy); U. Eilber (Ursula); M. Celik (Muhabbet); T. Olchers (Til); B. Peissel (Bernard); G. Scuvera (Giulietta); D. Zaffaroni (Daniela); B. Bonnani (Bernardo); I. Feroce (Irene); A. Maniscalco (Angela); A. Rossi (Alessandra); L. Bernard (Loris); M. Tranchant (Martine); M.-F. Valois (Marie-France); A. Turgeon (Annie); L. Heguy (Lea); P.S. Yee (Phuah Sze); P. Kang (Peter); K.I. Nee (Kang In); S. Mariapun (Shivaani); Y. Sook-Yee (Yoon); D.S.C. Lee (Daphne S.C.); T.Y. Ching (Teh Yew); N.A.M. Taib (Nur Aishah Mohd); M. Otsukka (Meeri); K. Mononen (Kari); T. Selander (Teresa); N. Weerasooriya (Nayana); E.M.M. Krol-Warmerdam (Elly); J. Molenaar; J. Blom; N. Szeszenia-Dabrowska (Neonilia); B. Peplonska (Beata); W. Zatonski (Witold); P. Chao (Pei); M. Stagner (Michael); P. Bos (Petra); J. Blom (Jannet); E. Crepin (Ellen); A. Nieuwlaat (Anja); A. Heemskerk (Annette); S. Higham (Sue); H.E. Cramp (Helen); D. Connley (Daniel); S. Balasubramanian (Sabapathy); I.W. Brock (Ian); M. Kerin (Michael); N. Miller (Nicola); P. Kerbrat (Pierre); P. Arveux (Patrick); R. Le Scodan (Romuald); Y. Raoul (Yves); P. Laurent-Puig (Pierre); C. Mulot (Claire); C. Stegmaier (Christa); K. Butterbach (Katja); J.H. Karstens (Johann); D. Flesch-Janys (Dieter); P. Seibold (Petra); A. Vrieling (Alina); S. Nickels (Stefan); P. Radice (Paolo); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); S. Kauppila (Saila); D. Conroy (Don); C. Baynes (Caroline); K. Chua (Kimberley); R. Pilarski (Robert)

    2015-01-01

    textabstractBackground: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540

  17. Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study

    OpenAIRE

    Benusiglio, Patrick R; Giraud, Sophie; Deveaux, Sophie; Méjean, Arnaud; Correas, Jean-Michel; Joly, Dominique; Timsit, Marc-Olivier; Ferlicot, Sophie; Verkarre, Virginie; Abadie, Caroline; Chauveau, Dominique; Leroux, Dominique; Avril, Marie-Françoise; Cordier, Jean-François; Richard, Stéphane

    2014-01-01

    Background The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome. Methods We studied French Birt-Hogg-Dubé patients with a history of renal tumour. Results We included 33 patients with 21 distinct germline FLCN mutations...

  18. Impacts of CA9 Gene Polymorphisms and Environmental Factors on Oral-Cancer Susceptibility and Clinicopathologic Characteristics in Taiwan

    OpenAIRE

    Chien, Ming-Hsien; Yang, Jia-Sin; Chu, Yin-Hung; Lin, Chien-huang; Wei, Lin-Hung; Yang, Shun-Fa; Lin, Chiao-Wen

    2012-01-01

    Background In Taiwan, oral cancer has causally been associated with environmental carcinogens. Carbonic anhydrase 9 (CA9) is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the combined effect of CA9 gene polymorphisms and exposure to environmental carcinogens on the susceptibility of developing oral squamous cell carcinoma (OSCC) and the clinicopathological characteristics of the tumors. Methodology and Pr...

  19. Speciation and antifungal susceptibility of esophageal candidiasis in cancer patients in a tertiary care hospital in South India

    Directory of Open Access Journals (Sweden)

    J. Abirami Lakshmy

    2016-01-01

    Full Text Available Esophageal candidiasis is the most common opportunistic infection in patients with altered immunity such as Human Immunodeficiency Virus (HIV infection, cancer patients on chemotherapy and radiotherapy. Neutropenia, irradiation and chemotherapy will facilitate deeper mucosal invasion leading to esophageal candidiasis. Empirical treatment of esophageal candidiasis without antifungal susceptibility testing will lead to the emergence of drug resistant species increasing the morbidity and mortality associated with cancer. The present study aimed to study the frequency of esophageal candida in individuals with cancer, species level identification and antifungal susceptibility pattern. Scrapings of whitish appearing lesions were obtained from a total of thirty five cases of endoscopically identified esophageal candidiasis were obtained from cancer patients. Identification of the Candida isolates were done by cultivation in Sabouraud dextrose agar (SDA, Gram staining, germ tube test, colony morphology in Chrom agar and corn meal agar, sugar assimilation and fermentation tests. Antifungal susceptibility was done by Microbroth dilution method for Fluconazole, Itraconazole and Amphotericin B. We found that Candida albicans was the predominant species isolated followed by Candida tropicalis and Candida glabrata. Sensitivity rates were 94%, 96% and 100% for Fluconazole, Itraconazole and Amphotericin B. Species level identification of Candida isolated from esophageal candidiasis and their antifungal sensitivity testing should be performed for early identification of resistant strains and for promptly treating the cases there by preventing the dissemination of infection in case of immune-compromised individuals. Further the susceptibility pattern will facilitate therapeutic guidance especially in individuals prone to relapse. [J Med Allied Sci 2016; 6(1: 29-34

  20. Relevance of GSTM1, GSTT1 and GSTP1 Gene Polymorphism to Breast Cancer Susceptibility in Mizoram Population, Northeast India.

    Science.gov (United States)

    Kimi, Lalro; Ghatak, Souvik; Yadav, Ravi Prakash; Chhuani, Lalhma; Lallawmzuali, Doris; Pautu, Jeremy L; Senthil Kumar, Nachimuthu

    2016-02-01

    The enzymes encoded by glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genes are involved in the metabolism of wide range of carcinogens that are ubiquitous in the environment. Homozygous deletions of the GSTM1 and GSTT1 genes are commonly found and result in lack of enzyme activity. This study was undertaken to evaluate the association between GSTM1, GSTT1 and GSTP1 gene polymorphism and breast cancer risk in Mizoram population. Odd ratio (OR) and 95% confidence interval (CI) from conditional logistic regression model were used to estimate the association between genetic polymorphism and breast cancer risk. The GSTM1 and GSTT1 null genotypes were associated with an increased risk of breast cancer [OR = 10.80 (95% CI 1.16-100.43)]. The risk of breast cancer associated with the GSTT1 null genotype was observed to be low among postmenopausal women. When considered together, GSTM1 and GSTT1 genotypes were found to be associated with an increased risk of breast cancer. The relationship between GSTM1 and GSTT1 gene deletions and breast cancer risk was substantially altered by consumption of Smoked Meat/Vegetable. In the present study, GSTP1Ile105Val (rs1695) polymorphism was related to breast cancer susceptibility or phenotype. Our data provides evidence for substantially increased risk of breast cancer associated with GSTM1 and/or GSTT1 homozygous gene deletions in Mizoram population. PMID:26407578

  1. Effects of NFKB1 and NFKBIA gene polymorphisms on susceptibility to environmental factors and the clinicopathologic development of oral cancer.

    Directory of Open Access Journals (Sweden)

    Chiao-Wen Lin

    Full Text Available BACKGROUND: Oral cancer, which is the fourth most common cancer in Taiwanese men, is associated with environmental carcinogens. The possibility that genetic predisposition in nuclear factor-kappa B (NF-κB-signaling pathways activation is linked to the development of oral squamous cell carcinoma (OSCC requires investigation. The current study examines associations between polymorphisms within promoter regions of NFKB1 encoding NF-κB1 and NFKBIA encoding IkappaBalpha (IκBα with both the susceptibility to develop OSCC and the clinicopathological characteristics of the tumors. METHODOLOGY/PRINCIPAL FINDINGS: Genetic polymorphisms of NFKB1 and NFKBIA were analyzed by a real-time polymerase chain reaction (real-time PCR for 462 patients with oral cancer and 520 non-cancer controls. We found that NFKB1 -94 ATGG1/ATGG2, -94 ATGG2/ATGG2, and the combination of -94 ATGG1/ATGG2 and ATGG2/ATGG2 genotypes NFKBIA -826 T (CT+TT and -881 G (AG+GG allelic carriages, were more prevalent in OSCC patients than in non-cancer participants. Moreover, we found that NFKB1 or NFKBIA gene polymorphisms seem to be related to susceptibility to develop oral cancer linked to betel nut and tobacco consumption. Finally, patients with oral cancer who had at least one -519 T allele of the NFKBIA gene were at higher risk for developing distant metastasis (P<.05, compared with those patients CC homozygotes. CONCLUSIONS: Our results suggest that NFKB1 -94 ATTG2, NFKBIA -826 T, and -881 G alleles are associated with oral carcinogenesis. The combination of NFKB1 or NFKBIA gene polymorphisms and environmental carcinogens appears related to an increased risk of oral cancer. More importantly, the genetic polymorphism of NFKBIA -519 might be a predictive factor for the distal metastasis of OSCC in Taiwanese.

  2. Diagnosis of oral fungal infection in patients undergoing head and neck cancer radiation. Antifungal susceptibility of isolates

    International Nuclear Information System (INIS)

    Radiotherapy adverse effects are very common, they contribute to development of opportunistic infections. Genus Candida is often associated with oral diseases in susceptible patients. The aim of this study was to study the presence of yeast in oral lesions, in patients receiving radiotherapy for head and neck cancer, and to evaluate antifungal susceptibility of isolates. Swabs of oral mucosal lesions of 76 patients were studied. Antifungal susceptibility of the isolates was evaluated, with ATB Fungus-3 method, which tests 5-fluorcitosine (5-FC), amphotericin B (AMB), fluconazole (FCA), itraconazole (ITR) and voriconazole (VRC); and allows the estimation of the minimum inhibitory concentration (MIC). Yeasts were isolated in 74% of samples, being Candida albicans, most frequent specie (53%), followed by C.tropicalis (24%), C.parapsilosis (14%), C.krusei (5%), C.dubliniensis (2%) and Saccharomyces cerevisiae (2%). All strains were susceptible to VRC. For other antifungals, there were resistant or dose-dependent-susceptible strains. Only C.krusei was resistant to the FCA. About AMB, 2 isolates of C. tropicalis presented a value of 2 mg/l MIC, dose with high incidence of adverse effects. These studies are important to establish early and suitable therapy, wich contribute to achieve lowers rates of disseminated forms of candidiasis, and to reduce the difficulties in food intake that carries the presence of oral lesions. (authors)

  3. NOVEL EFFECTS OF DIOXIN ON BREAST DEVELOPMENT, FUNCTION, AND SUSCEPTIBILITY TO CANCER

    Science.gov (United States)

    Breast cancer is the most common type of non-dermal cancer among women in this country. Breast cancer risk in women is known to be significantly influenced by genetics, but over 70% of the women that are diagnosed with breast cancer have non-inherited or sporadic cancer. The ris...

  4. The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes

    Directory of Open Access Journals (Sweden)

    Johnson Julie K

    2012-06-01

    Full Text Available Abstract Background Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product 1. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI, has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. Methods We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. Results The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein

  5. The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes

    International Nuclear Information System (INIS)

    Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product [1]. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein truncating mutations. Haplotype analysis using short

  6. The Polymorphism of DNA Repair Gene ERCC2/XPD Arg156Arg and Susceptibility to Breast Cancer in a Chinese Population

    DEFF Research Database (Denmark)

    Yin, J. Y.; Liang, D. H.; Vogel, Ulla Birgitte;

    2009-01-01

    association between ERCC2/XPD Arg156Arg and susceptibility to breast cancer in a Chinese population, we conducted a hospital-based case-control study consisting of 129 patients with breast cancer and 205 controls matched by age, gender, and ethnicity. PCR-RFLP was used for genotyping. No associations were...... (mean age 45 years) than cases with the wild CC genotype (mean age 50 years) (P = 0.05). There were no differences in risk estimates in relation to menopause and occurrence of breast cancer. Our findings do not suggest that ERCC2/XPD Arg156Arg contributes to breast cancer susceptibility in a Chinese...

  7. The breast cancer susceptibility gene BRCA1: DNA repair and other functions

    International Nuclear Information System (INIS)

    BRCA1 is a tumour suppressor gene. Germline mutations in BRCA1 confer susceptibility to breast and ovarian cancer and levels of BRCA1 mRNA and/or protein are reduced in a significant proportion of sporadic breast tumours. The product of this gene is a large multifunctional nuclear phosphoprotein that has been implicated in the regulation of cell cycle progression, apoptosis, transcription and DNA repair. Thus BRCA1 is thought to function as a genomic caretaker, responding to DNA damage by halting cell-cycle progression and activating DNA repair or cell death pathways. Evidence of a role for BRCA1 in DNA repair includes the identification of a novel C-terminal amino acid sequence motif (BRCT) common to a broad range of DNA repair proteins, the observation that the BRCA1 protein interacts with a number of DNA repair proteins, including Rad50, and the demonstration of defective double-strand break repair by homologous recombination and genetic instability in BRCA1-deficient cells. Loss of BRCA1 contributes to breast tumourigenesis by inducing genomic instability. The consistent histological phenotype of BRCA1 tumours, including their high-grade, pushing margins and syncytial appearance, together with the results of differential-expression analyses, indicate that the mutations that accumulate in these tumours are far from random. At present however the pathway between BRCA1 loss and BRCA1-mediated tumour development is poorly understood. In an attempt to address this we have studied the cellular and molecular effects of disrupting BRCA1 function. Results from this analysis and our studies on the regulation of BRCA1 expression will be presented

  8. Matrix metalloproteinase 3 polymorphisms as a potential marker of enhanced susceptibility to lung cancer in chronic obstructive pulmonary disease subjects

    Directory of Open Access Journals (Sweden)

    Kamil Brzóska

    2014-09-01

    Full Text Available [b]Introduction and objective[/b]. Chronic obstructive pulmonary disease (COPD is often accompanied by lung cancer. Among the genes that may play a role in the occurrence of COPD and lung cancer are those encoding the proteolytic enzymes, such as matrix metalloproteinases (MMPs and their tissue inhibitors. The objective of this study was to find MMPs-associated markers useful in the identification of COPD subjects with increased susceptibility to developing lung cancer. [b]Materials and methods[/b]. We compared the frequency of single nucleotide polymorphisms in genes coding for matrix proteinases ([i]MMP1, MMP2, MMP3, MMP9, MMP12[/i] as well as tissue inhibitor of metalloproteinases ([i]TIMP1[/i] in two groups of subjects: COPD patients (54 subjects and COPD patients diagnosed for lung cancer occurrence (53 subjects.The levels of the respective proteins in blood serum were also analyzed. [b]Results[/b]. The frequencies of 2 genotypes, [i]MMP3[/i] rs3025058 and MMP3 rs678815, were significantly different between the studied groups. In both cases, more heterozygotes and less homozygotes (both types were observed in the COPD group than in the COPD + cancer group. A significantly higher TIMP1 level in blood serum was observed in the COPD + cancer group than in the COPD group. There were no statistically significant differences in[i] MMPs[/i] blood levels between the studied groups. In addition, no genotype-associated differences in [i]TIMP1[/i] or[i] MMPs[/i] blood levels were observed. [b]Conclusions[/b]. Homozygocity for [i]MMP3[/i] rs3025058 and rs678815 polymorphisms is a potential marker of enhanced susceptibility to lung cancer development among COPD subjects.

  9. Importance of TP53 codon 72 and intron 3 duplication 16bp polymorphisms in prediction of susceptibility on breast cancer

    International Nuclear Information System (INIS)

    TP53 is one of major tumour suppressor genes being essential in preservation of genome integrity. Two very common polymorphisms have been demonstrated to contribute to cancer susceptibility and tumour behaviour. The purpose of this study was to evaluate the role of Arg72Pro and PIN3 Ins16bp polymorphisms in TP53 gene as genetic susceptibility and predictive markers to breast cancer. We analysed DNA samples from 264 breast cancer patients and 440 controls, for TP53 Arg72Pro and PIN3 Ins16bp polymorphisms using PCR-RFLP. We observed that women with A2A2 genotype have increased risk for developing breast cancer, either in women with or without familial history (FH) of the disease (OR = 4.40, 95% CI 1.60–12.0; p = 0.004; OR = 3.88, 95% CI 1.18–12.8; p = 0.026, respectively). In haplotype analysis, statistically significant differences were found between TP53 Arg-A2 haplotype frequencies and familial breast cancer cases and the respective control group (OR = 2.10, 95% CI 1.08–4.06; p = 0.028). Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases. Our findings suggest TP53 PIN3 Ins16bp polymorphism as a real risk modifier in breast cancer disease, either in sporadic and familial breast cancer. Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases

  10. Genetic variants in insulin-like growth factor binding protein-3 are associated with prostate cancer susceptibility in Eastern Chinese Han men

    Directory of Open Access Journals (Sweden)

    Zhang G

    2015-12-01

    Full Text Available Guiming Zhang,1–3 Yao Zhu,1,2 Fang Liu,4,5 Chengyuan Gu,1,2 Haitao Chen,4,5 Jianfeng Xu,4–6 Dingwei Ye1,2 1Department of Urology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 3Department of Urology, The Affiliated Hospital of Qingdao University, Shandong, 4Fudan Institute of Urology, Huashan Hospital, Fudan University, 5State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, People’s Republic of China; 6Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA Background: Growing evidence has indicated that insulin-like growth factor binding protein-3 (IGFBP-3 polymorphisms are associated with altered risk of prostate cancer (PCa. However, few studies have been conducted in Chinese population to validate this association. Materials and methods: Herein, we examined the association between genetic variants in the IGFBP-3 gene and PCa risk in the Chinese Han population based on a genome-wide association study (1,417 cases and 1,008 controls, and replicated three genetic variants loci in an independent case-control study (1,755 cases and 1,523 controls using Sequenom platform. Logistic regression analyses were performed to estimate odds ratios (ORs and 95% confidence intervals (95% CIs. Results: We found that in the discovery stage, rs9691259 (OR =0.691, 95% CI: 0.587–0.814, P<0.001 and rs6950179 (OR =1.420, 95% CI: 1.201–1.677, P<0.001 were significantly associated with PCa risk, whereas rs2854744 showed a marginal association with PCa risk. In the replication stage, the association between rs9691259 and rs6950179 and PCa risk was not replicated, whereas rs2854744 conferred a significant association with PCa risk (OR =1.399, 95% CI: 1.010–1.937, P=0.043. After combining the two stages, we found that rs9691259, rs6950179, and rs2854744 were all significantly associated with PCa risk. Conclusion

  11. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    Science.gov (United States)

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  12. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny;

    2012-01-01

    Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 ...

  13. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Lee, A.; Barrowdale, D.; Healey, S.; Sinilnikova, O.M.; Caligo, M.A.; Loman, N.; Harbst, K.; Lindblom, A.; Arver, B.; Rosenquist, R.; Karlsson, P.; Nathanson, K.; Domchek, S.; Rebbeck, T.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowowcka-Perlowska, E.; Osorio, A.; Duran, M.; Andres, R.; Benitez, J.; Hamann, U.; Hogervorst, F.B.; Os, T.A. van; Verhoef, S.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Ligtenberg, M.J.L.; Kriege, M.; Collee, J.M.; Ausems, M.G.; Oosterwijk, J.C.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Rogers, M.T.; Donaldson, A.; Dorkins, H.; Godwin, A.K.; Bove, B.; Stoppa-Lyonnet, D.; Houdayer, C.; Buecher, B.; Pauw, A. de; Mazoyer, S.; Calender, A.; Leone, M.; Bressac-de Paillerets, B.; Caron, O.; Sobol, H.; Frenay, M.; Prieur, F.; Ferrer, S.U.; Mortemousque, I.; Buys, S.; Daly, M.; Miron, A.; Terry, M.U.; Hopper, J.L.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Fink-Retter, A.; Tea, M.K.; Kaulich, D.U.; Hansen, T.V.; Nielsen, F.C.; Barkardottir, R.B.; Gaudet, M.; Kirchhoff, T.; Joseph, V.; Dutra-Clarke, A.; Offit, K.; Piedmonte, M., et al.

    2012-01-01

    INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  14. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Lee, Andrew; Barrowdale, Daniel; Healey, Sue; Sinilnikova, Olga M.; Caligo, Maria A.; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Rosenquist, Richard; Karlsson, Per; Nathanson, Kate; Domchek, Susan; Rebbeck, Tim; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Zlowowcka-Perlowska, Elzbieta; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; van Os, Theo A.; Verhoef, Senno; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Ligtenberg, Marjolijn J.; Kriege, Mieke; Collee, Margriet; Ausems, Margreet G. E. M.; Oosterwijk, Jan C.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Rogers, Mark T.; Donaldson, Alan; Dorkins, Huw; Godwin, Andrew K.; Bove, Betsy; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Buecher, Bruno; de Pauw, Antoine; Mazoyer, Sylvie; Calender, Alain; Leone, Melanie; Bressac-de Paillerets, Brigitte; Caron, Olivier; Sobol, Hagay; Frenay, Marc; Prieur, Fabienne; Ferrer, Sandra Fert; Mortemousque, Isabelle; Buys, Saundra; Daly, Mary; Miron, Alexander; Terry, Mary Beth; Hopper, John L.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Fink-Retter, Anneliese; Tea, Muy-Kheng; Kaulich, Daphne Geschwantler; Hansen, Thomas V. O.; Nielsen, Finn C.; Barkardottir, Rosa B.; Gaudet, Mia; Kirchhoff, Tomas; Joseph, Vijai; Dutra-Clarke, Ana; Offit, Kenneth; Piedmonte, Marion; Kirk, Judy; Cohn, David; Hurteau, Jean; Byron, John; Fiorica, James; Toland, Amanda E.; Montagna, Marco; Oliani, Cristina; Imyanitov, Evgeny; Isaacs, Claudine; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Teule, Alex; Del Valle, J.; Gayther, Simon A.; Odunsi, Kunle; Gross, Jenny; Karlan, Beth Y.; Olah, Edith; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth Jansen; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schaefer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Muranen, Taru A.; Lesperance, Bernard; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Loud, Jennifer T.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Glendon, Gord; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe B.; Skytte, Anne-Bine; Kruse, Torben A.; Chenevix-Trench, Georgia; Couch, Fergus J.; Simard, Jacques; Easton, Douglas F.

    2012-01-01

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  15. Polymorphism of CYPIA1 and GSTM1 genes associated with susceptibility of gastric cancer in Shandong Province of China

    Institute of Scientific and Technical Information of China (English)

    Hao Li; Xue-Liang Chen; Hui-Qing Li

    2005-01-01

    AIM: To explore whether polymorphisms of the CYPIA1 and GSTM1 genes are associated with susceptibility of stomach cancer.METHODS: A total of 102 stomach cancer cases and 62 healthy persons were diagnosed by pathology in 1998-2000 in the Qilu Hospital of Shandong University. Gene polymorphisms were detected by the PCR using sequence-specific primers. Data analysis of the case-control study was carried out using the unconditional logistic method.RESULTS: After adjustment for age, sex, educational levels, and occupation, the risk factors for stomach cancer were shown to be smoking, Helicobacter pylori(H pylori),and presence of the CYPIM G/G and GSTM1 O/O genotypes.Interaction was observed between the combined genotypes of either CYPIA1 G/G and GSTM1 O/O or H pylori infection,or GSTM1 O/O and H pylori infection or smoking.CONCLUSION: Polymorphisms of the CYPIA1 and GSTM1 genes, H pylori infection and smoking are related to susceptibility to stomach cancer.

  16. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression.

    Science.gov (United States)

    Kote-Jarai, Zsofia; Saunders, Edward J; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Jugurnauth-Little, Sarah; Ross-Adams, Helen; Al Olama, Ali Amin; Benlloch, Sara; Halim, Silvia; Russell, Roslin; Russel, Roslin; Dunning, Alison M; Luccarini, Craig; Dennis, Joe; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Muir, Ken; Giles, Graham G; Severi, Gianluca; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Lindstrom, Sara; Kraft, Peter; Hunter, David J; Gapstur, Susan; Chanock, Stephen; Berndt, Sonja I; Albanes, Demetrius; Andriole, Gerald; Schleutker, Johanna; Weischer, Maren; Canzian, Federico; Riboli, Elio; Key, Tim J; Travis, Ruth C; Campa, Daniele; Ingles, Sue A; John, Esther M; Hayes, Richard B; Pharoah, Paul; Khaw, Kay-Tee; Stanford, Janet L; Ostrander, Elaine A; Signorello, Lisa B; Thibodeau, Stephen N; Schaid, Dan; Maier, Christiane; Vogel, Walther; Kibel, Adam S; Cybulski, Cezary; Lubinski, Jan; Cannon-Albright, Lisa; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A; Sawyer, Emma J; Morgan, Angela; Dicks, Ed; Baynes, Caroline; Conroy, Don; Bojesen, Stig E; Kaaks, Rudolf; Vincent, Daniel; Bacot, François; Tessier, Daniel C; Easton, Douglas F; Eeles, Rosalind A

    2013-06-15

    Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease. PMID:23535824

  17. High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study

    International Nuclear Information System (INIS)

    The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4–5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd

  18. Genetic polymorphisms of GSTM1,GSTP1 and GSTT1 genes and lung cancer susceptibility in the Bangladeshi population

    Institute of Scientific and Technical Information of China (English)

    Mir; Muhammad; Nasir; Uddin; Maizbha; Uddin; Ahmed; Mohammad; Safiqul; Islam; Mohammad; Siddiqul; Islam; Muhammad; Shahdaat; Bin; Sayeed; Yearul; Kabir; Abul; Hasnat

    2014-01-01

    Objective:To verify possible associations between polymorphisms of glutathione S-transferase Mu(GSTM1),glutathione S-transferase θ(GSTT1) and glutathione S-transferase Pi(GSTP1)genes and susceptibility to lung cancer.Methods:A total of 106 lung cancer patients and 116 controls were enrolled in a case-control study.The GSTM1 and GSTT1 were analyzed using PCR while GSTP1 was analyzed using PCR-restriction fragment length polymorphism.Risk of lung cancer was estimated as odds ratio at 95%confidence interval using unconditional logistic regression models adjusting for age,sex,and tobacco use.Results:GSTM1 null and GSTT1 null genotypes did not show a significant risk for developing lung cancer.A significandy elevated lung cancer risk was associated with GSTP1 heterozygous,mutant and combined heterozygous+mutant variants of rs1695.When classified by tobacco consumption status,no association with risk of lung cancer was found in case of tobacco smokers and nonsmokers carrying null and present genotypes of GSTM1 and GSTTL There is a three-fold(approximately) increase in the risk of lung cancer in case of both heterozygous(AG) and heterozygous+mutant homozygous(AG+GG) genotypes whereas there is an eightfold increase in risk of lung cancer in cases of GG with respect to AA genotype in smokers.Conclusions:Carrying the GSTM1 and GSTT1 null genotype is not a risk factor for lung cancer and GSTP1Ile105 Val is associated with elevated risk of lung cancer.

  19. Genetic polymorphisms of GSTM1, GSTP1 and GSTT1 genes and lung cancer susceptibility in the Bangladeshi population

    Institute of Scientific and Technical Information of China (English)

    Mir Muhammad Nasir Uddin; Maizbha Uddin Ahmed; Mohammad Safiqul Islam; Mohammad Siddiqul Islam; Muhammad Shahdaat Bin Sayeed; Yearul Kabir; Abul Hasnat

    2014-01-01

    To verify possible associations between polymorphisms of glutathione S-transferase Mu (GSTM1), glutathione S-transferase θ (GSTT1) and glutathione S-transferase Pi (GSTP1) genes and susceptibility to lung cancer. Methods: A total of 106 lung cancer patients and 116 controls were enrolled in a case-control study. The GSTM1 and GSTT1 were analyzed using PCR while GSTP1 was analyzed using PCR-restriction fragment length polymorphism. Risk of lung cancer was estimated as odds ratio at 95% confidence interval using unconditional logistic regression models adjusting for age, sex, and tobacco use. Results: GSTM1 null and GSTT1 null genotypes did not show a significant risk for developing lung cancer. A significantly elevated lung cancer risk was associated with GSTP1 heterozygous, mutant and combined heterozygous+mutant variants of rs1695. When classified by tobacco consumption status, no association with risk of lung cancer was found in case of tobacco smokers and nonsmokers carrying null and present genotypes of GSTM1 and GSTT1. There is a three-fold (approximately) increase in the risk of lung cancer in case of both heterozygous (AG) and heterozygous+mutant homozygous (AG+GG) genotypes whereas there is an eight-fold increase in risk of lung cancer in cases of GG with respect to AA genotype in smokers. Conclusions: Carrying the GSTM1 and GSTT1 null genotype is not a risk factor for lung cancer and GSTP1Ile105Val is associated with elevated risk of lung cancer.

  20. HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

    Directory of Open Access Journals (Sweden)

    Angeline S Andrew

    Full Text Available Bladder cancer is the 4(th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62. This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63. The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25 than females (OR 1.56 95%CI 0.83-2.95, (SNP-gender interaction P = 0.048. We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003. The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

  1. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Kjaer, Susanne Krüger;

    2009-01-01

    Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive.......01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast...... ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially...

  2. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

    DEFF Research Database (Denmark)

    Milne, Roger L; Gaudet, Mia M; Spurdle, Amanda B;

    2010-01-01

    Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the...... Breast Cancer Association Consortium....

  3. Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability

    International Nuclear Information System (INIS)

    Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer. To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR) cells. Heat-shock protein 27 (HSP27) expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex. Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability

  4. Basal-subtype and MEK-Pl3K feedback signaling determine susceptibility of breast cancer cells to MEK inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Mirzoeva, Olga K.; Das, Debopriya; Heiser, Laura M.; Bhattacharya, Sanchita; Siwak, Doris; Gendelman, Rina; Bayani, Nora; Wang, Nicholas J.; Neve, Richard M.; Knight, Zachary; Feiler, Heidi S.; Gascard, Philippe; Parvin, Bahram; Spellman, Paul T.; Shokat, Kevan M.; Wyrobek, Andrew J.; Bissell, Mina J.; McCormick, Frank; Kuo, Wen-Lin; Mills, Gordon B.; Gray, Joe W.; Korn, W. Michael

    2009-01-23

    Specific inhibitors of MEK have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We employed a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth-inhibition by small-molecule MEK inhibitors. Activation of the PI3 kinase pathway in response to MEK inhibition through a negative MEK-EGFR-PI3 kinase feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3 kinase produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.

  5. Family system characteristics and psychological adjustment to cancer susceptibility genetic testing : a prospective study

    NARCIS (Netherlands)

    van Oostrom, I.; Meijers-Heijboer, H.; Duivenvoorden, H. J.; Brocker-Vriends, A. H. J. T.; van Asperen, C. J.; Sijmons, R. H.; Seynaeve, C.; Van Gool, A. R.; Klijn, J. G. M.; Tibben, A.

    2007-01-01

    This study examined prospectively the contribution of family functioning, differentiation to parents, family communication and support from relatives to psychological distress in individuals undergoing genetic susceptibility testing for a known familial pathogenic BRCA1/2 or Hereditary nonpolyposis

  6. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    International Nuclear Information System (INIS)

    Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1

  7. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

    Directory of Open Access Journals (Sweden)

    Moreno Victor

    2011-08-01

    Full Text Available Abstract Background Colorectal cancer (CRC is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. Methods CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. Results None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive, rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive, rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant, and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive. In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1

  8. Correlation between XRCC1 Arg399Gln genetic polymorphisms and susceptibility to bladder cancer: a meta-analysis

    Science.gov (United States)

    Liu, Nannan; Fei, Xiawei; Shen, Yi; Shi, Weifeng; Ma, Jinhong

    2016-01-01

    The relationship between XRCC1 polymorphisms and bladder cancer has been widely studied. Here, our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in XRCC1 and susceptibility to bladder cancer. In order to derive a more precise estimation of the association, 27 clinical case-control studies (which met all the inclusion criteria) were included in this meta-analysis. A total of 8,539 cancer cases and 10,750 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs T allele odds ratio [OR] =0.87, 95% confidence interval [CI], 0.71–1.06), homozygote comparison (AA vs GG OR =1.12, 95% CI, 0.68–1.85), heterozygote comparison (AT vs TT OR =1.01, 95% CI, 0.81–1.26), dominant model (AA + AG vs GG OR =0.93, 95% CI, 0.85–1.02), and recessive model (AA vs AG + GG OR =1.01, 95% CI, 0.88–1.15), but a moderately significant association was found for AG vs GG (OR =0.241, 95% CI =0.17–0.35). Subgroup analysis based on ethnicity. Ethnicity analysis suggested that genetic polymorphisms in XRCC1 were not correlated with increased bladder cancer risk among Asians (all P>0.05). Therefore, we concluded that XRCC1 genetic polymorphism may not contribute to bladder cancer susceptibility in the present meta-analysis, and further well-designed studies with a large sample size are warranted to validate our conclusion. PMID:26869802

  9. Correlation between XRCC1 Arg399Gln genetic polymorphisms and susceptibility to bladder cancer: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Liu N

    2016-01-01

    Full Text Available Nannan Liu,1 Xiawei Fei,2 Yi Shen,1 Weifeng Shi,1 Jinhong Ma1 1Department of Clinical Laboratory, The Third Affiliated Hospital of Suzhou University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Urology Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China Abstract: The relationship between XRCC1 polymorphisms and bladder cancer has been widely studied. Here, our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in XRCC1 and susceptibility to bladder cancer. In order to derive a more precise estimation of the association, 27 clinical case-control studies (which met all the inclusion criteria were included in this meta-analysis. A total of 8,539 cancer cases and 10,750 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs T allele odds ratio [OR] =0.87, 95% confidence interval [CI], 0.71–1.06, homozygote comparison (AA vs GG OR =1.12, 95% CI, 0.68–1.85, heterozygote comparison (AT vs TT OR =1.01, 95% CI, 0.81–1.26, dominant model (AA + AG vs GG OR =0.93, 95% CI, 0.85–1.02, and recessive model (AA vs AG + GG OR =1.01, 95% CI, 0.88–1.15, but a moderately significant association was found for AG vs GG (OR =0.241, 95% CI =0.17–0.35. Subgroup analysis based on ethnicity. Ethnicity analysis suggested that genetic polymorphisms in XRCC1 were not correlated with increased bladder cancer risk among Asians (all P>0.05. Therefore, we concluded that XRCC1 genetic polymorphism may not contribute to bladder cancer susceptibility in the present meta-analysis, and further well-designed studies with a large sample size are warranted to validate our conclusion. Keywords: XRCC1, genetic polymorphism, susceptibility, bladder cancer, meta-analysis

  10. Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available Genome-wide association studies (GWASs have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii to replicate these SNPs in an independent set of breast cancer cases and controls; and iii to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412 in logistic regression that conferred elevated risks for breast cancer (P(interaction<7.3 × 10(-3. Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943 (P(permutation = 2.4 × 10(-3. SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P

  11. Genotype, phenotype and cancer: Role of low penetrance genes and environment in tumour susceptibility

    Indian Academy of Sciences (India)

    Ashwin Kotnis; Rajiv Sarin; Rita Mulherkar

    2005-02-01

    Role of heredity and lifestyle in sporadic cancers is well documented. Here we focus on the influence of low penetrance genes and habits, with emphasis on tobacco habit in causing head and neck cancers. Role of such gene-environment interaction can be well studied in individuals with multiple primary cancers. Thus such a biological model may elucidate that cancer causation is not solely due to genetic determinism but also significantly relies on lifestyle of the individual.

  12. A risk evaluation model of cervical cancer based on etiology and human leukocyte antigen allele susceptibility

    OpenAIRE

    Bicheng Hu; Ning Tao; Fanyu Zeng; Min Zhao; Lixin Qiu; Wen Chen; Yun Tan; Yun Wei; Xufeng Wu; Xinxing Wu

    2014-01-01

    Background: There are no reliable risk factors to accurately predict progression to cervical cancer in patients with chronic cervicitis infected with human papillomavirus (HPV). The aim of this study was to create a validated predictive model based on the risk factors for cervical cancer. A model to estimate the risk of cervical cancer may help select patients for intervention therapy in order to reduce the occurrence of cervical cancer after HPV infection. Methods: This retrospective anal...

  13. IκBα polymorphism at promoter region (rs2233408 influences the susceptibility of gastric cancer in Chinese

    Directory of Open Access Journals (Sweden)

    Sung Joseph JY

    2010-02-01

    Full Text Available Abstract Background Nuclear factor of kappa B inhibitor alpha (IκBα protein is implicated in regulating a variety of cellular process from inflammation to tumorigenesis. The objective of this study was to investigate the susceptibility of rs2233408 T/C genotype in the promoter region of IκBα to gastric cancer and the association of this polymorphism with clinicopathologic variables in gastric cancer patients. Methods A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 564 gastric cancer patients and 566 healthy controls were enrolled in this study. rs2233408 genotypes in IκBα were analyzed by TaqMan SNP genotyping assay. Results Both rs2233408 T homozygote (TT and T heterozygotes (TC and TT had significantly reduced gastric cancer risk (TT: OR = 0.250, 95% CI = 0.069-0.909, P = 0.035; TC and TT: OR = 0.721, 95% CI = 0.530-0.981, P = 0.037, compared with rs2233408 C homozygote (CC. rs2233408 T heterozygotes were significantly associated with reduced risk of intestinal-type gastric cancer with ORs of 0.648 (95% CI = 0.459-0.916, P = 0.014, but not with the diffuse or mix type of gastric cancer. The association between rs2233408 T heterozygotes and gastric cancer appeared more apparent in the older patients (age>40 (OR = 0.674, 95% CI = 0.484-0.939, P = 0.02. rs2233408 T heterozygotes was associated with non-cardiac gastric cancer (OR = 0.594, 95% CI = 0.411-0.859, P = 0.006, but not with cardiac gastric cancer. However, rs2233408 polymorphism was not associated with the prognosis of gastric cancer patients. Conclusions IκBα rs2233408 T heterozygotes were associated with reduced risk of gastric cancer, especially for the development of certain subtypes of gastric cancer in Chinese population.

  14. [Genome-wide association study(GWAS) and genetic risk of prostate cancer].

    Science.gov (United States)

    Nakagawa, Hidewaki; Akamatsu, Shusuke; Takata, Ryo

    2016-01-01

    It is evident that genetic factors play critical roles in prostate cancer development. GWAS (genome-wide association studies) in multiple ethnic groups have been identifying more than 100 loci or genes which was significantly associated with prostate cancer susceptibility. They include several loci at 8q24, prostate-specific gene, inflammation gene, and metabolism-related genes. Risk prediction for prostate cancer by combining multiple SNPs is still primitive and not sufficiently accurate for clinical use, but this model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA or very high risk of prostate cancer. PMID:26793876

  15. Association studies of ERCC1 polymorphisms with lung cancer susceptibility: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jinhong Zhu

    Full Text Available BACKGROUND: Excision repair cross-complimentary group 1 (ERCC1 is an essential component of the nucleotide excision repair system that is responsible for repairing damaged DNA. Functional genetic variations in the ERCC1 gene may alter DNA repair capacity and modulate cancer risk. The putative roles of ERCC1 gene polymorphisms in lung cancer susceptibility have been widely investigated. However, the results remain controversial. OBJECTIVES: An updated meta-analysis was conducted to explore whether lung cancer risk could be attributed to the following ERCC1 polymorphisms: rs11615 (T>C, rs3212986 (C>A, rs3212961 (A>C, rs3212948 (G>C, rs2298881 (C>A. METHODS: Several major databases (MEDLINE, EMBASE and Scopus and the Chinese Biomedical database were searched for eligible studies. Crude odds ratios (ORs with 95% confidence intervals (CIs were used to measure the strength of associations. RESULTS: Sixteen studies with 10,106 cases and 13,238 controls were included in this meta-analysis. Pooled ORs from 11 eligible studies (8,215 cases vs. 11,402 controls suggested a significant association of ERCC1 rs11615 with increased risk for lung cancer (homozygous: CC versus TT, OR = 1.24, 95% CI: 1.04-1.48, P = 0.02. However, such an association was disproportionately driven by a single study. Removal of that study led to null association. Moreover, initial analyses suggested that ERCC1 rs11615 exerts a more profound effect on the susceptibility of non-smokers to lung cancer than that of smokers. Moreover, no statistically significant association was found between remaining ERCC1 polymorphisms of interest and lung cancer risk, except for rs3212948 variation (heterozygous: CG vs.GG, OR = 0.78, 95% CI: 0.67-0.90, P = 0.001; dominant: CG/CC vs.GG, OR = 0.79, 95% CI: 0.69-0.91, P = 0.001. CONCLUSION: Overall, this meta-analysis suggests that ERCC1 rs3212948 G>C, but not others, is a lung cancer risk-associated polymorphism. Carefully

  16. Polymorphisms in miRNA binding site: new insight into small cell lung cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    Hong-yu LIU; Jun CHEN

    2011-01-01

    Lung cancer is a leading cause in cancer-related deaths with less than 15% five-year survival worldwide.Small cell lung cancer (SCLC),which accounts for about 15%-18% of lung cancer,carries the worst prognosis within the lung cancer patients.SCLC differs from other lung cancers,so called non-small cell lung cancers (NSCLCs),in the specifically clinical and biologic characteristics.It exhibits aggressive behavior,with rapid growth,early spread to distant sites.Although exquisite sensitive to chemotherapy and radiation,SCLC recurs rapidly with only 5% of patients surviving five years and frequent association with distinct paraneoplastic syndromes[1].

  17. Possible association of β2- and β3-adrenergic receptor gene polymorphisms with susceptibility to breast cancer

    International Nuclear Information System (INIS)

    The involvement of β2-adrenergic receptor (ADRB2) and β3-adrenergic receptor (ADRB3) in both adipocyte lipolysis and thermogenic activity suggests that polymorphisms in the encoding genes might be linked with interindividual variation in obesity, an important risk factor for postmenopausal breast cancer. In order to examine the hypothesis that genetic variations in ADRB2 and ADRB3 represent interindividual susceptibility factors for obesity and breast cancer, we conducted a hospital-based, case-control study in the Aichi Cancer Center, Japan. A self-administered questionnaire was given to 200 breast cancer patients and 182 control individuals, and pertinent information on lifestyle, family history and reproduction was collected. ADRB2 and ADRB3 genotypes were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism assessment. Twenty-five (12.4%) breast cancer patients and 32 (17.6%) control individuals were found to bear a glutamic acid (Glu) allele for the ADRB2 gene (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.38-1.18), and 60 (30.0%) breast cancer patients and 61 (33.5%) control individuals were found to bear an Arg allele for the ADRB3 gene (OR 0.85, 95% CI 0.55-1.31). A significantly lower risk was observed in those who carried the Glu ADRB2 allele and who reported first childbirth when they were younger than 25 years (OR 0.35; 95% CI 0.13-0.99). A potential association may exist between risk of breast cancer and polymorphisms in the ADRB2 and ADRB3 genes; further studies in larger samples and/or in different ethnic groups are warranted to investigate this potential association

  18. Special susceptibility of the child to certain radiation-induced cancers.

    OpenAIRE

    Miller, R. W.

    1995-01-01

    The carcinogenic effects of exposure to ionizing radiation vary markedly with age, as revealed by studies of Japanese atomic bomb survivors and of Marshall Islanders exposed to fallout from U.S. nuclear weapons tests in the South Pacific in 1954. An increase in cancers of adulthood after intrauterine exposure, as reported in 1988, has not been sustained. After childhood exposure, increases in leukemia, breast cancer, and thyroid cancer are well established. The carcinogenic effects of radiati...

  19. Next generation sequencing approaches to identify novel susceptibility genes for epithelial ovarian cancer

    OpenAIRE

    Hayward, J. D.

    2014-01-01

    Ovarian cancer is the fifth most common cancer in women in developed countries and is associated with poor survival due to late diagnoses. Strategies focusing on detecting the disease in the earliest stages and/or improving risk prediction may represent effective clinical intervention reducing disease burden. Women at the greatest risk of epithelial ovarian cancer (EOC) can be offered prophylactic risk-reducing salpingo-oopherectomy (RRSO), which is currently only offered to women with mutati...

  20. Gene-expression patterns in peripheral blood classify familial breast cancer susceptibility

    OpenAIRE

    Piccolo, Stephen R; Andrulis, Irene L; Cohen, Adam L.; Conner, Thomas; Moos, Philip J.; Spira, Avrum E; Buys, Saundra S.; Johnson, W. Evan; Bild, Andrea H

    2015-01-01

    Background Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk varian...

  1. Functional promoter -31G/C variant of Survivin gene predict prostate cancer susceptibility among Chinese: a case control study

    International Nuclear Information System (INIS)

    Abnormal expression of Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin), a novel member of the inhibitor of apoptosis protein (IAP) family, has implications in many types of cancer and is considered as a new therapeutic target. We suppose that genetic variant rs9904341 in the 5′ UTR region of survivin gene may be associated with the development and progression of prostate cancer (PCa) in Chinese population. TaqMan assay method was used to genotype the polymorphism in the hospital-based case–control analysis of 665 patients with PCa and 710 age-matched cancer-free controls. The genetic associations with the occurrence and progression of PCa were calculated by logistic regression. Our results indicated that compared with GG genotypes, there was a statistically significant increased risk of PCa associated with those with CC genotypes [odds ratios (ORs) = 1.57, 95%confidence intervals (CIs) = 1.17-2.13, P = 0.004]. Moreover, stratification analysis revealed that the association was more pronounced in subgroups of nondrinkers, nonsmokers and those without a family history of cancer (all P < 0.05). In addition, we observed that PSA ≥ 20 was more frequent in patients carrying GC/CC genotypes than in those with a wild type genotype. The functional survivin rs9904341 genetic variant may have a substantial influence on the PCa susceptibility and evolution

  2. Allelic variants of XRCC1 and XRCC3 repair genes and susceptibility of oral cancer in Brazilian patients

    DEFF Research Database (Denmark)

    Dos Reis, Mariana Bisarro; Losi-Guembarovski, Roberta; de Souza Fonseca Ribeiro, Enilze Maria; Cavalli, Iglenir João; Morita, Maria Celeste; Ramos, Gyl Henrique Albrecht; de Oliveira, Benedito Valdecir; Mizuno, Lauro Toyoshi; Rogatto, Silvia Regina; de Syllos Cólus, Ilce Mara

    2013-01-01

    genes have been found to be associated with oral cancer. The aim of this study was to investigate the relationship between the presence of allelic variants Arg194Trp (rs:1799782) and Arg399Gln (rs: 25487) of XRCC1 gene and Thr241Met (rs: 861539) of XRCC3 gene and susceptibility to oral cancer. We also...... variants of the XRCC1 gene within codon 194 (OR 0.82, 95% CI: 0.44-1.51) and codon 399 (OR 0.94, 95% CI: 0.59-1.50) and within the XRCC3 gene (OR 0.72; 95% CI: 0.45-1.16) were not associated with an increased risk of oral cancer. A combinational analysis of SNPs in both genes indicated no association. The......BACKGROUND: The capacity for DNA repair is essential in maintaining cellular functions and homeostasis; however, this capacity can be altered based on DNA sequence variations in DNA repair genes, which may contribute to the onset of cancer. Many single-nucleotide polymorphisms (SNPs) in repair...

  3. Risk modification of colorectal cancer susceptibility by interleukin-8-251T>A polymorphism in Malaysians

    Institute of Scientific and Technical Information of China (English)

    Mohd Aminudin Mustapha; Siti Nurfatimah Mohd Shahpudin; Ahmad Aizat Abdul Aziz; Ravindran Ankathil

    2012-01-01

    AIM:To investigate the allele and genotype frequencies and associated risk of interleukin (IL)-8-251T>A polymorphism on colorectal cancer (CRC) susceptibility risk.METHODS:Peripheral blood samples of 255 normal controls and 255 clinically and histopathologically confirmed CRC patients were genotyped for IL-8-251T>A polymorphism employing allele-specific polymerase chain reaction.The relative association of variant allele and genotypes with CRC susceptibility risk was determined by calculating the odds ratios (ORs).Corresponding x2 tests on the CRC patients and controls were carried out and 95% confidence intervals (CIs) were determined using Fisher's exact test.The allele frequencies and its risk association were calculated using FAMHAP,haplotype association analysis software.RESULTS:On comparing the frequencies of genotypes of patients and controls,the homozygous variant AA was significantly higher in CRC patients (P =0.002)compared to controls.Investigation on the association of the polymorphic genotypes with CRC susceptibility risk,showed that the homozygous variant IL-8-251AA had a significantly increased risk with OR 3.600 (95%CI:1.550-8.481,P =0.001).In the case of allele frequencies,variant allele A of IL-8-251 showed a significantly increased risk of CRC predisposition with OR 1.32(95% CI:1.03-1.69,P =0.003).CONCLUSION:Variant allele and genotype of IL-8 (-251T>A) was significantly associated with CRC susceptibility risk and could be considered as a high-risk variant for CRC predisposition.

  4. p53 codon 72 polymorphism and liver cancer susceptibility: A meta-analysis of epidemiologic studies

    Institute of Scientific and Technical Information of China (English)

    Xi Chen; Fei Liu; Bo Li; Yong-Gang Wei; Lv-Nan Yan; Tian-Fu Wen

    2011-01-01

    AIM: To evaluate the association between p53 codon 72 polymorphism and liver cancer risk by means of meta-analysis.METHODS: Two investigators independently searched the Medline, Embase and Chinese Biomedicine databas-es. Summary odds ratios and 95% CI for p53 codon 72 polymorphism and liver cancer were calculated in .xed-effects model (Mantel-Haenszel method) and random-effects model (DerSimonian and Laird method) when appropriate.RESULTS: This meta-analysis included 1115 liver can-cer cases and 1778 controls. The combined results based on all studies showed that there was a statisti-cally signi.cant link between Pro/Pro genotype and liver cancer, but not between Arg/Arg or Pro/Arg genotype and liver cancer. When stratifying for race, similar re-sults were obtained, i.e. patients with liver cancer had a signi.cantly higher frequency of Pro/Pro genotype than non-cancer patients among Asians. After stratifying the various studies by control source, gender, family history of liver cancer and chronic hepatitis virus infection, we found that (1) patients among hospital-based studies had a significantly higher frequency of Pro/Pro and a signi.cantly lower frequency of Arg/Arg genotype than individuals without cancer; (2) female patients with liver cancer had a significantly lower frequency of Arg/Arg and a higher frequency of Pro/Arg+Pro/Pro genotypes than female individuals without cancer; (3) subgroup analyses for family history of liver cancer did not re-veal any signi.cant association between p53 codon 72 polymorphism and liver cancer development; and (4) patients with negative hepatitis virus infection had a sig-ni.cantly higher frequency of Pro/Pro and a signi.cantly lower frequency of Arg/Arg genotype than individuals without cancer.CONCLUSION: This meta-analysis suggests that the p53 codon 72 polymorphism may be associated with liver cancer among Asians.

  5. Alcohol-related cancers and genetic susceptibility in Europe: the ARCAGE project: study samples and data collection.

    LENUS (Irish Health Repository)

    Lagiou, Pagona

    2009-02-01

    Cancers of the upper aerodigestive tract (UADT) include those of the oral cavity, pharynx (other than nasopharynx), larynx, and esophagus. Tobacco smoking and consumption of alcoholic beverages are established causes of UADT cancers, whereas reduced intake of vegetables and fruits are likely causes. The role of genetic predisposition and possible interactions of genetic with exogenous factors, however, have not been adequately studied. Moreover, the role of pattern of smoking and drinking, as well as the exact nature of the implicated dietary variables, has not been clarified. To address these issues, the International Agency for Research on Cancer initiated in 2002 the alcohol-related cancers and genetic susceptibility (ARCAGE) in Europe project, with the participation of 15 centers in 11 European countries. Information and biological data from a total of 2304 cases and 2227 controls have been collected and will be used in a series of analyses. A total of 166 single nucleotide polymorphisms of 76 genes are being studied for genetic associations with UADT cancers. We report here the methodology of the ARCAGE project, main demographic and lifestyle characteristics of the cases and controls, as well as the distribution of cases by histology and subsite. About 80% of cases were males and fewer than 20% of all cases occurred before the age of 50 years. Overall, the most common subsite was larynx, followed by oral cavity, oropharynx, esophagus and hypopharynx. Close to 90% of UADT cancers were squamous cell carcinomas. A clear preponderance of smokers and alcohol drinkers among UADT cases compared with controls was observed.

  6. 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

    Science.gov (United States)

    Warren, Helen; Dudbridge, Frank; Fletcher, Olivia; Orr, Nick; Johnson, Nichola; Hopper, John L.; Apicella, Carmel; Southey, Melissa C.; Mahmoodi, Maryam; Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten; Braaf, Linda M.; Muir, Kenneth R.; Lophatananon, Artitaya; Chaiwerawattana, Arkom; Wiangnon, Surapon; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Schulz-Wendtland, Ruediger; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Mulot, Claire; Bojesen, Stig E; Nielsen, Sune F.; Flyger, Henrik; Nordestgaard, Børge G; Milne, Roger L.; Benítez, Javier; Arias-Pérez, José-Ignacio; Zamora, M. Pilar; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Langheinz, Anne; Meindl, Alfons; Golatta, Michael; Bartram, Claus R.; Schmutzler, Rita K.; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Bogdanova, Natalia; Antonenkova, Natalia; Rogov, Yuriy; Bermisheva, Marina; Prokofyeva, Darya; Zinnatullina, Guzel; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Kataja, Vesa; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Lambrechts, Diether; Smeets, Ann; Paridaens, Robert; Weltens, Caroline; Flesch-Janys, Dieter; Buck, Katharina; Behrens, Sabine; Peterlongo, Paolo; Bernard, Loris; Manoukian, Siranoush; Radice, Paolo; Couch, Fergus J.; Vachon, Celine; Wang, Xianshu; Olson, Janet; Giles, Graham; Baglietto, Laura; McLean, Cariona A.; Severi, Gianluca; John, Esther M.; Miron, Alexander; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Mulligan, Anna Marie; Weerasooriya, Nayana; Devilee, Peter; Tollenaar, Robert A.E.M.; Martens, John W.M.; Seynaeve, Caroline M.; Hooning, Maartje J.; Hollestelle, Antoinette; Jager, Agnes; Tilanus-Linthorst, Madeleine M.A.; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Cox, Angela; Cross, Simon S.; Brock, Ian W.; Reed, Malcolm W.R.; Pharoah, Paul; Blows, Fiona M.; Dunning, Alison M.; Ghoussaini, Maya; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk; Easton, Douglas F.; Humphreys, Manjeet; Wang, Qin; Peto, Julian; dos-Santos-Silva, Isabel

    2013-01-01

    Background Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10–29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10–143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10–22) but less strongly, if at all, with ER-negative (ER–) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10–6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact The findings further support the view that genetic susceptibility varies according to tumor subtype. PMID:22859399

  7. Exploration of risk taking behaviors and perceived susceptibility of colorectal cancer among Malaysian adults: a community based cross-sectional study

    OpenAIRE

    Al-Dubai, S. A. R.; Ganasegeran, K.; Alabsi, A. M.; Shah, S. A.; Razali, F. M. M.; Arokiasamy, J. T.

    2014-01-01

    Background: Perceived susceptibility to an illness has been shown to affect Health-risk behavior. The objective of the present study was to determine the risk taking behaviors and the demographic predictors of perceived susceptibility to colorectal cancer in a population-based sample. Methods: A cross-sectional study was carried out among 305 Malaysian adults in six major districts, selected from urban, semi-urban, and rural settings in one state in Malaysia. A self-administered questionnaire...

  8. Common variants at 19p13 are associated with susceptibility to ovarian cancer

    DEFF Research Database (Denmark)

    Bolton, Kelly L; Tyrer, Jonathan; Song, Honglin;

    2010-01-01

    Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available s...

  9. Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis

    DEFF Research Database (Denmark)

    Cunningham, J M; Vierkant, R A; Sellers, T A;

    2009-01-01

    BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin...... ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in...... a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell...

  10. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Schildkraut, Joellen M; Goode, Ellen L; Clyde, Merlise A;

    2009-01-01

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2......,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in.......07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated...

  11. Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis

    Directory of Open Access Journals (Sweden)

    Liu Jiyong

    2006-05-01

    Full Text Available Abstract Background Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk. Methods To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population. Results We found that the distribution of TS3'-UTR (1494del6 genotype frequencies were significantly different between the cases and controls (P = 0.026. Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35–0.97 but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82–1.46. Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks. Conclusion These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the

  12. Impacts of microRNA gene polymorphisms on the susceptibility of environmental factors leading to carcinogenesis in oral cancer.

    Directory of Open Access Journals (Sweden)

    Yin-Hung Chu

    Full Text Available BACKGROUND: MicroRNAs (miRNAs have been regarded as a critical factor in targeting oncogenes or tumor suppressor genes in tumorigenesis. The genetic predisposition of miRNAs-signaling pathways related to the development of oral squamous cell carcinoma (OSCC remains unresolved. This study examined the associations of polymorphisms with four miRNAs with the susceptibility and clinicopathological characteristics of OSCC. METHODOLOGY/PRINCIPAL FINDINGS: A total of 895 male subjects, including 425 controls and 470 male oral cancer patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a, miRNA196, miRNA499 and miRNA149 genetic polymorphisms between the control group and the case group. This study determined that a significant association of miRNA499 with CC genotype, as compared to the subjects with TT genotype, had a higher risk (AOR = 4.52, 95% CI = 1.24-16.48 of OSCC. Moreover, an impact of those four miRNAs gene polymorphism on the susceptibility of betel nut and tobacco consumption leading to oral cancer was also revealed. We found a protective effect between clinical stage development (AOR = 0.58, 95% CI = 0.36-0.94 and the tumor size growth (AOR = 0.47, 95% CI = 0.28-0.79 in younger patients (age<60. CONCLUSIONS: Our results suggest that genetic polymorphism of miRNA499 is associated with oral carcinogenesis, and the interaction of the miRNAs genetic polymorphism and environmental carcinogens is also related to an increased risk of oral cancer in Taiwanese.

  13. A comprehensive review on host genetic susceptibility to human papillomavirus infection and progression to cervical cancer

    Directory of Open Access Journals (Sweden)

    Koushik Chattopadhyay

    2011-01-01

    Full Text Available Cervical cancer is the second most common cancer in women worldwide. This is caused by oncogenic types of human papillomavirus (HPV infection. Although large numbers of young sexually active women get HPV-infected, only a small fraction develop cervical cancer. This points to different co-factors for regression of HPV infection or progression to cervical cancer. Host genetic factors play an important role in the outcome of such complex or multifactor diseases such as cervical cancer and are also known to regulate the rate of disease progression. The aim of this review is to compile the advances in the field of host genetics of cervical cancer. MEDLINE database was searched using the terms, ′HPV′, ′cervical′, ′CIN′, ′polymorphism(s′, ′cervical′ + FNx01the name of the geneFNx01 and ′HPV′ + FNx01the name of the geneFNx01. This review focuses on the major host genes reported to affect the progression to cervical cancer in HPV infected individuals.

  14. Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

    OpenAIRE

    Schildkraut, J M; Goode, E.L.; Clyde, M. A.; Iversen, E. S.; Moorman, P. G.; Berchuck, A.; Marks, J R; Lissowska, J; Brinton, L.; Peplonska, B.; Cunningham, J. M.; Vierkant, R A; Rider, D. N.; Chenevix-Trench, G; Webb, P M

    2009-01-01

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independ...

  15. Plasminogen Activator Inhibitor-1 and Susceptibility to Lung Cancer: A Population Genetics Perspective

    OpenAIRE

    Bayramoglu, Aysegul; Gunes, Hasan Veysi; Metintas, Muzaffer; Degirmenci, Irfan; Guler, Halil Ibrahim; Ustuner, Cengiz; Musmul, Ahmet

    2014-01-01

    Aim: The aim of this study was to investigate the polymorphism frequency of plasminogen activator inhibitor-1 (PAI-1) (rs1799889) 4G/5G in patients with lung cancer. Methods: In this study, 286 genomic DNAs (154 lung cancer patients+132 subjects without lung cancer) were analyzed. Polymorphisms were determined by using the polymerase chain reaction (PCR) method, with 4G and 5G allele-specific primers. PCR products were assessed by a charge-coupled device camera and exposed to 2% agarose gel e...

  16. Lung Cancer Susceptibility and hOGG1 Ser326Cys Polymorphism: A Meta-Analysis

    International Nuclear Information System (INIS)

    Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. In this study, we tried to assess reported studies of association between polymorphism of human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys and lung cancer. We conducted MEDLINE, Current Contents and Web of Science searches using 'hOGG1', 'lung cancer' and 'polymorphism' as keywords to search for papers published (from January 1995 through August 2010). Data were combined using both a fixed effects (the inverse variance-weighted method) and a random effects (DerSimonian and Laird method) models. The Cochran Q test was used for the assessment of heterogeneity. Publication bias was assessed by both Begg’s and Egger’s tests. We identified 20 case-control studies in 21 different ethnic populations. As two studies were not in the Hardy-Weinberg equilibrium, 18 case-control studies in 19 different ethnic populations (7,792 cases and 9,358 controls) were included in our meta-analysis. Summary frequencies of the Cys allele among Caucasians and Asians based on the random effects model were 20.9% (95% confidence interval (CI) = 18.9–22.9) and 46.1% (95% CI = 40.2–52.0), respectively. The distribution of the Cys allele was significantly different between Asians and Caucasians (P < 0.001). The Cys/Cys genotype was significantly associated with lung cancer risk in Asian populations (odds ratio = 1.27, 95% CI = 1.09–1.48) but not in Caucasian populations. This ethnic difference in lung cancer risk may be due to environmental factors such as cigarette smoking and dietary factors. Although the summary risk for developing lung cancer may not be large, lung cancer is such a common malignancy that even a small increase

  17. Glutathione S-transferase M1, T1 and P1 polymorphisms: susceptibility and outcome in lung cancer patients.

    Science.gov (United States)

    Sreeja, Leelakumari; Syamala, Vani; Hariharan, Sreedharan; Syamala, Volga S; Raveendran, Praveenkumar B; Sivanandan, C D; Madhavan, Jayaprakash; Ankathil, Ravindran

    2008-01-01

    The glutathione S-transferases (GSTs) are a superfamily of genes whose products are phase II enzymes, catalyzing the conjugation of reactive intermediates to soluble glutathione. Some of the GSTs are polymorphic and may play a role in lung cancer susceptibility. We investigated whether genetic polymorphisms of GSTM1, GSTP1 and GSTT1 genes modulated lung cancer risk and affect survival among lung cancer patients. We determined the GST genotypes in 422 study subjects, using polymerase chain reaction (PCR) and reverse PCR and restriction fragment length polymorphism (RFLP). Logistic Regression analysis was carried out to find the association of various polymorphisms and GSTs and lung cancer. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function. Cox Proportional Hazard models were used to estimate hazard ratios (HR) for deaths. GSTT1 -/- genotype conferred a higher odds ratio of 2.9 (P = 0.001) compared to the GSTT1+/+. So also, the GSTP1 GG genotype too had higher risk compared to the GSTP1 AA genotype (OR = 2.3, P = 0.033). When the combined GST M1, GSTT1 and GSTP1 genotypes were examined, patients with the combinations GSTM1 null and GSTT1 null had a significant OR of 3.6. So also the combinations GSTT1-/- GSTP1 AA (P = 0.005) and GSTT1-/- GSTP1 AG/GG (P = 0.001) came out to be significant. There were some significant interactions between GST genotypes with tobacco smoking and also for clinicopathological factors. Regarding survival analysis, no association of GSTM1 or GSTP1 genes with survival was noted. The GSTT1 -/- genotype along with stage was significantly associated with overall survival and found to be an independent prognostic factors for shorter lung cancer survival. PMID:18472644

  18. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium.

    Science.gov (United States)

    Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Toyokuni, Shinnya; Hori, Masaru; Kikkawa, Fumitaka

    2016-06-01

    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma‑activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment. PMID:27035127

  19. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study

    DEFF Research Database (Denmark)

    Milne, Roger L; Gaudet, Mia M; Spurdle, Amanda B;

    2010-01-01

    Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in th...

  20. Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Chistiakov, Dimitry A. (Dept. of Pathology, Univ. of Pittsburgh, Pittsburgh (US)); Voronova, Natalia V. (Dept. of Molecular Diagnostics, National Research Center GosNIIgenetika, Moscow (RU)); Chistiakov, Pavel A. (Dept. of Radiology, Cancer Research Center, Moscow (RU))

    2008-06-15

    Ionizing radiation is a well established carcinogen for human cells. At low doses, radiation exposure mainly results in generation of double strand breaks (DSBs). Radiation-related DSBs could be directly linked to the formation of chromosomal rearrangements as has been proven for radiation-induced thyroid tumors. Repair of DSBs presumably involves two main pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). A number of known inherited syndromes, such as ataxia telangiectasia, ataxia-telangiectasia like-disorder, radiosensitive severe combined immunodeficiency, Nijmegen breakage syndrome, and LIG4 deficiency are associated with increased radiosensitivity and/or cancer risk. Many of them are caused by mutations in DNA repair genes. Recent studies also suggest that variations in the DNA repair capacity in the general population may influence cancer susceptibility. In this paper, we summarize the current status of DNA repair proteins as potential targets for radiation-induced cancer risk. We will focus on genetic alterations in genes involved in HR- and NHEJ-mediated repair of DSBs, which could influence predisposition to radiation-related cancer and thereby explain interindividual differences in radiosensitivity or radioresistance in a general population

  1. Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

    International Nuclear Information System (INIS)

    The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A

  2. Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Lintell Nicholas A

    2009-09-01

    Full Text Available Abstract Background The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1 underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. Methods The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. Conclusion This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S to Phe (F changes a hydrophilic residue (S to a hydrophobic residue (F and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5

  3. C60(Nd) nanoparticles enhance chemotherapeutic susceptibility of cancer cells by modulation of autophagy

    International Nuclear Information System (INIS)

    Autophagy, an evolutionally conserved intracellular process degrading cytoplasmic proteins and organelles for recycling, has become one of the most remarkable strategies applied in cancer research. The fullerene C60 nanoparticle (nC60) has been shown to induce autophagy and sensitize chemotherapeutic killing of cancer cells, but the details still remain unknown. Here we show that a water-dispersed nanoparticle solution of derivatized fullerene C60, C60(Nd) nanoparticles (nC60(Nd)), has greater potential in inducing autophagy and sensitizing chemotherapeutic killing of both normal and drug-resistant cancer cells than nC60 does in an autophagy-dependent fashion. Additionally we further demonstrated that autophagy induced by nC60/C60(Nd) and Rapamycin had completely different roles in cancer chemotherapy. Our results, for the first time, revealed a novel and more potent derivative of the C60 nanoparticle in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation, which may ultimately lead to novel therapeutic strategies in cancer therapy.

  4. C60(Nd) nanoparticles enhance chemotherapeutic susceptibility of cancer cells by modulation of autophagy

    Science.gov (United States)

    Wei, Pengfei; Zhang, Li; Lu, Yang; Man, Na; Wen, Longping

    2010-12-01

    Autophagy, an evolutionally conserved intracellular process degrading cytoplasmic proteins and organelles for recycling, has become one of the most remarkable strategies applied in cancer research. The fullerene C60 nanoparticle (nC60) has been shown to induce autophagy and sensitize chemotherapeutic killing of cancer cells, but the details still remain unknown. Here we show that a water-dispersed nanoparticle solution of derivatized fullerene C60, C60(Nd) nanoparticles (nC60(Nd)), has greater potential in inducing autophagy and sensitizing chemotherapeutic killing of both normal and drug-resistant cancer cells than nC60 does in an autophagy-dependent fashion. Additionally we further demonstrated that autophagy induced by nC60/C60(Nd) and Rapamycin had completely different roles in cancer chemotherapy. Our results, for the first time, revealed a novel and more potent derivative of the C60 nanoparticle in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation, which may ultimately lead to novel therapeutic strategies in cancer therapy.

  5. Fine mapping of chromosome 15q25.1 lung cancer susceptibility in African-Americans

    OpenAIRE

    Hansen, Helen M.; Xiao, Yuanyuan; Rice, Terri; Bracci, Paige M.; Wrensch, Margaret R.; Sison, Jennette D.; Chang, Jeffery S.; Smirnov, Ivan V.; Patoka, Joseph; Seldin, Michael F; Quesenberry, Charles P.; Kelsey, Karl T.; Wiencke, John K.

    2010-01-01

    Several genome-wide association studies identified the chr15q25.1 region, which includes three nicotinic cholinergic receptor genes (CHRNA5-B4) and the cell proliferation gene (PSMA4), for its association with lung cancer risk in Caucasians. A haplotype and its tagging single nucleotide polymorphisms (SNPs) encompassing six genes from IREB2 to CHRNB4 were most strongly associated with lung cancer risk (OR = 1.3; P < 10−20). In order to narrow the region of association and identify potential c...

  6. Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the Breast Cancer Association Consortium: a combined case-control study.

    OpenAIRE

    Milne, Roger L.; Gaudet, Mia M.; Spurdle, Amanda B.; Fasching, Peter A.; Couch, Fergus J.; Benitez, Javier; Arias Perez, Jose Ignacio; Zamora, Maria Pilar; Malats, Nuria; dos Santos Silva, Isabel; Gibson, Lorna J.; Fletcher, Olivia; Johnson, Nichola; Anton-Culver, Hoda; Ziogas, Argyrios

    2010-01-01

    Abstract Introduction Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Methods We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of liv...

  7. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

    OpenAIRE

    Milne, Roger L; Burwinkel, Barbara; Michailidou, Kyriaki; Arias-Perez, Jose-Ignacio; Zamora, M. Pilar; Men?ndez-Rodr?guez, Primitiva; Hardisson, David; Mendiola, Marta; Gonz?lez-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Dennis, Joe; WANG, QIN; Bolla, Manjeet K; Swerdlow, Anthony

    2014-01-01

    BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community?s Seventh Framework Programme under grant agreement n8 223175 (HEALTH-F2?2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ?CIHR Team in Familial Risks of Breast Can...

  8. Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

    DEFF Research Database (Denmark)

    Quaye, L; Song, H; Ramus, S J;

    2009-01-01

    Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five onc...

  9. Meta-Analysis of Mismatch Repair Polymorphisms within the Cogent Consortium for Colorectal Cancer Susceptibility

    Czech Academy of Sciences Publication Activity Database

    Picelli, S.; Bermejo, J. L.; Chang-Claude, J.; Hoffmeister, M.; Fernandez-Rozadilla, C.; Carracedo, A.; Castells, A.; Castellví-Bel, S.; Naccarati, Alessio; Pardini, Barbara; Vodičková, Ludmila; Müller, H.; Talseth-Palmer, B. A.; Stibbard, G.; Peterlongo, P.; Nici, C.; Veneroni, S.; Li, L.; Casey, G.; Tenesa, A.; Farrington, S.M.; Tomlinson, I.; Moreno, V.; van Wezel, T.; Wijnen, J.; Dunlop, M.; Radice, P.; Scott, R. J.; Vodička, Pavel; Ruiz-Ponte, C.; Brenner, H.; Buch, S.; Völzke, H.; Hampe, J.; Schafmayer, C.; Lindblom, A.

    2013-01-01

    Roč. 8, č. 9 (2013), e72091. E-ISSN 1932-6203 R&D Projects: GA ČR GAP304/10/1286; GA ČR GA310/07/1430 Institutional support: RVO:68378041 Keywords : colerectal cancer * The EPICOLON Consortium Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.534, year: 2013

  10. The role of genetic breast cancer susceptibility variants as prognostic factors

    DEFF Research Database (Denmark)

    Fasching, Peter A; Pharoah, Paul D P; Cox, Angela;

    2012-01-01

    Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 ...

  11. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M;

    2011-01-01

    Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among...

  12. Polymorphisms in the Human Cytochrome P450 and Arylamine N-Acetyltransferase: Susceptibility to Head and Neck Cancers

    Directory of Open Access Journals (Sweden)

    Rim Khlifi

    2013-01-01

    Full Text Available The occurrence of head and neck cancer (HNC is associated with smoking and alcohol drinking. Tobacco smoking exposes smokers to a series of carcinogenic chemicals. Cytochrome P450 enzymes (CYP450s, such as CYP1A1, CYP1B1, and CYP2D6, usually metabolize carcinogens to their inactive derivatives, but they occasionally convert the chemicals to more potent carcinogens. In addition, via CYP450 (CYP2E1 oxidase, alcohol is metabolized to acetaldehyde, a highly toxic compound, which plays an important role in carcinogenesis. Furthermore, two N-acetyltransferase isozymes (NATs, NAT1 and NAT2, are polymorphic and catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens. Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC. It has been suggested that such polymorphisms may be linked to cancer susceptibility. In this paper, we select four cytochrome P450 enzymes (CYP1A1, CYP1BA1, CYP2D6, and CYP2E1, and two N-acetyltransferase isozymes (NAT1 and NAT2 in order to summarize and analyze findings from the literature related to HNC risk by focusing on (i the interaction between these genes and the environment, (ii the impact of genetic defect on protein activity and/or expression, and (iii the eventual involvement of race in such associations.

  13. Hereditary breast cancer: ever more pieces to the polygenic puzzle

    OpenAIRE

    Bogdanova, Natalia; Helbig, Sonja; Dörk, Thilo

    2013-01-01

    Several susceptibility genes differentially impact on the lifetime risk for breast cancer. Technological advances over the past years have enabled the detection of genetic risk factors through high-throughput screening of large breast cancer case–control series. High- to intermediate penetrance alleles have now been identified in more than 20 genes involved in DNA damage signalling and repair, and more than 70 low-penetrance loci have been discovered through recent genome-wide association stu...

  14. Combined and interactive effects of environmental and GWAS-identified risk factors in ovarian cancer

    DEFF Research Database (Denmark)

    Pearce, Celeste Leigh; Rossing, Mary Anne; Lee, Alice W;

    2013-01-01

    There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied....

  15. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

    DEFF Research Database (Denmark)

    Stacey, Simon N; Sulem, Patrick; Jonasdottir, Aslaug;

    2011-01-01

    ' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10......(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).......To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery...

  16. Shared ancestral susceptibility to colorectal cancer and other nutrition related diseases

    Czech Academy of Sciences Publication Activity Database

    Huhn, S.; Bevier, M.; Rudolph, A.; Pardini, Barbara; Naccarati, Alessio; Hein, R.; Hoffmeister, M.; Vodičková, Ludmila; Novotný, J.; Brenner, H.; Chang-Claude, J.; Vodička, Pavel; Hemminki, K.; Försti, A.

    2012-01-01

    Roč. 13, č. 1 (2012), s. 94. ISSN 1471-2350 R&D Projects: GA ČR GAP304/10/1286; GA ČR GAP304/12/1585 Institutional research plan: CEZ:AV0Z50390512 Institutional support: RVO:68378041 Keywords : colorectal cancer * nutrition * complex diseases Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.536, year: 2012

  17. Single Nucleotide Polymorphisms within Interferon Signaling Pathway Genes Are Associated with Colorectal Cancer Susceptibility and Survival

    Czech Academy of Sciences Publication Activity Database

    Lu, S.; Pardini, B.; Cheng, B.; Naccarati, A.; Huhn, S.; Vymetálková, Veronika; Vodičková, Ludmila; Buchler, T.; Hemminki, K.; Vodička, Pavel; Försti, A.

    2014-01-01

    Roč. 9, č. 10 (2014), e11161. E-ISSN 1932-6203 R&D Projects: GA ČR GAP304/10/1286; GA ČR(CZ) GAP304/12/1585 Grant ostatní: GA MŠk(CZ) COST Action BM1206 Institutional support: RVO:68378041 Keywords : colorectal cancer * interferon * nutrition Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.234, year: 2014

  18. Detection and impact on cancer causation of persons exhibiting abnormal susceptibility to carcinogenic agents

    International Nuclear Information System (INIS)

    The so-called 'late biological effects', like cancer and genetic consequences and cytotoxic effects (cell killing, at higher doses), were once thought to be an inevitable consequence of a given level of exposure, whether to background radiation, to chemicals in our biosphere, or form spontaneous damage, the 'wear and tear' of living. The measurement of exposure, which results in living organisms in the formation of a related amount of DNA damage, became a surrogate for the end-effects that constitute risk. This may not be entirely appropriate. The concept of 'equal exposure -- equal risk' assumes a homogeneous response of individuals. However, there are subgroups within the human population of persons whose cultured cells exhibit abnormal sensitivity to specific carcinogenic agents and who may be at increased risk of cancer induced by these of similar agents. Modern molecular biology has shown that the majority of the damage in DNA is repaired by enzymatic DNA repair processes that restitute or ameliorate the lesions and restore normal DNA structure and function. In this view, it is not the initial damage that is of consequence but rather the residual damage left after the repair processes have acted. Since the vast majority of the initial DNA damage undergoes repair normally, variation in the efficiency of these processes in different persons may affect the actual risk of exposure. The human side of the cancer causation formula, that is, considerable importance. To understand how human DNA repair processes function, our laboratories at Chalk River have studied 'mutant' human cell strains in tissue culture. Generally, these DNA repair-defective cell strains are derived from individual donors with heritable disorders that are associated with carcinogen-hypersensitivity and cancer-proneness. Such studies, together with related epidemiological research, have highlighted the importance of this new 'human' factor in carcinogenesis

  19. Breast cancer in women with x-ray exposure: models of dose, time, and host susceptibility

    International Nuclear Information System (INIS)

    Acute postpartum mastitis (APM) is an inflammatory/infectious condition of the breast, occurring commonly at childbirth or during lactation. A series of 600 women who received x-ray therapy for APM during the 1940s or 1950s have been followed up by mail questionnaire, with medical verification of pertinent conditions, to ascertain their incidence of breast cancer. The groups have been followed for up to 45 years, with an average of 29 years. The relative risk of breast cancer, adjusted for age and interval since irradiation (or an equivalent entry definition for controls) was 3.2 for the irradiated breasts. The dose-response curve appeared to be essentially linear, except for a diminution of risk at high doses (≥ 700 rad). The fact that there were no breasts with doses between zero and 50 rad, however, means it was not possible to evaluate the curvature with the maximum contrast between low and high doses. The dose fractionation analyses showed that the number of dose fractions or the number of days between fractions had no apparent effect upon breast cancer risk, but there was a suggestion that lower doses per fraction led to a higher risk, which runs counter to what one would expect based on radiobiological theory. However, a Cox regression analysis, controlling for total breast dose, did not yield a significant effect for any of the fractionation variables

  20. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

    OpenAIRE

    Amankwah, E.K.; Wang, Q; Schildkraut, J.M.; Tsai, Y.Y.; Ramus, S.J.; Fridley, B L; Beesley, J.; Johnatty, S E; Webb, P. M.; Chenevix-Trench, G; Dale, L.C.; D. Lambrechts; Amant, F.; Despierre, E.; Vergote, I.

    2011-01-01

    Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a conso...

  1. Meta-analysis of loci associated with age at natural menopause in African-American women

    OpenAIRE

    Chen, Christina T. L.; Liu, Ching-Ti; Chen, Gary K.; Andrews, Jeanette S.; Arnold, Alice M.; Dreyfus, Jill; Franceschini, Nora; Garcia, Melissa E.; Kerr, Kathleen F.; Li, Guo; Lohman, Kurt K.; Musani, Solomon K.; Michael A Nalls; Raffel, Leslie J.; Smith, Jennifer

    2014-01-01

    Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a G...

  2. Differential expression of miR-1, a putative tumor suppressing microRNA, in cancer resistant and cancer susceptible mice

    Directory of Open Access Journals (Sweden)

    Jessica L. Fleming

    2013-04-01

    Full Text Available Mus spretus mice are highly resistant to several types of cancer compared to Mus musculus mice. To determine whether differences in microRNA (miRNA expression account for some of the differences in observed skin cancer susceptibility between the strains, we performed miRNA expression profiling of skin RNA for over 300 miRNAs. Five miRNAs, miR-1, miR-124a-3, miR-133a, miR-134, miR-206, were differentially expressed by array and/or qPCR. miR-1 was previously shown to have tumor suppressing abilities in multiple tumor types. We found miR-1 expression to be lower in mouse cutaneous squamous cell carcinomas (cSCCs compared to normal skin. Based on the literature and our expression data, we performed detailed studies on predicted miR-1 targets and evaluated the effect of miR-1 expression on two murine cSCC cell lines, A5 and B9. Following transfection of miR-1, we found decreased mRNA expression of three validated miR-1 targets, Met, Twf1 and Ets1 and one novel target Bag4. Decreased expression of Ets1 was confirmed by Western analysis and by 3’ reporter luciferase assays containing wildtype and mutated Ets1 3’UTR. We evaluated the effect of miR-1 on multiple tumor phenotypes including apoptosis, proliferation, cell cycle and migration. In A5 cells, expression of miR-1 led to decreased proliferation compared to a control miR. miR-1 expression also led to increased apoptosis at later time points (72 and 96 h and to a decrease in cells in S-phase. In summary, we identified five miRNAs with differential expression between cancer resistant and cancer susceptible mice and found that miR-1, a candidate tumor suppressor, has targets with defined roles in tumorigenesis.

  3. Mitochondrial DNA haplogroups and susceptibility to prostate cancer in a colombian population.

    Science.gov (United States)

    Cano, D; Gomez, C F; Ospina, N; Cajigas, J A; Groot, H; Andrade, R E; Torres, M M

    2014-01-01

    Prostate cancer (PC) is one of the most common cancers and the second leading cause of mortality from cancer in Colombian men. Mitochondrial DNA (mtDNA) haplogroups have been associated with the risk of PC. Several studies have demonstrated dramatic differences regarding the risk of PC among men from different ethnic backgrounds. The present study was aimed at assessing the relationship between mtDNA haplogroups and PC. The mitochondrial DNA hypervariable segment I (HSV-1) was sequenced in a population-based study covering 168 cases (CA) and 140 unrelated healthy individuals as a control group (CG). A total of 92 different mtDNA sequences were found in CA and 59 were found in the CG. According to the geographical origin attributed to each mtDNA haplogroup, 82% of the mtDNA sequences found in both groups were Native Americans (A, B, C, and D). The most frequent was A (41.1%CA-42.1%CG), followed by B (22.0%CA-21.4%CG), C (12.0%CA-11.4%CG), and D (6%CA-10.0%CG). A lower percentage of European haplogroups (U, H, K, J, M, T, and HV) were also found (13.1%CA-12.9%CG), likewise African haplogroups (L0, L1, L2, and L3) (6.5%CA-2.1%CG). There were no statistically significant differences between the distribution of mtDNA haplogroups in CA and the CG in this study. PMID:24616820

  4. Incorporating epistasis interaction of genetic susceptibility single nucleotide polymorphisms in a lung cancer risk prediction model.

    Science.gov (United States)

    Marcus, Michael W; Raji, Olaide Y; Duffy, Stephen W; Young, Robert P; Hopkins, Raewyn J; Field, John K

    2016-07-01

    Incorporation of genetic variants such as single nucleotide polymorphisms (SNPs) into risk prediction models may account for a substantial fraction of attributable disease risk. Genetic data, from 2385 subjects recruited into the Liverpool Lung Project (LLP) between 2000 and 2008, consisting of 20 SNPs independently validated in a candidate-gene discovery study was used. Multifactor dimensionality reduction (MDR) and random forest (RF) were used to explore evidence of epistasis among 20 replicated SNPs. Multivariable logistic regression was used to identify similar risk predictors for lung cancer in the LLP risk model for the epidemiological model and extended model with SNPs. Both models were internally validated using the bootstrap method and model performance was assessed using area under the curve (AUC) and net reclassification improvement (NRI). Using MDR and RF, the overall best classifier of lung cancer status were SNPs rs1799732 (DRD2), rs5744256 (IL-18), rs2306022 (ITGA11) with training accuracy of 0.6592 and a testing accuracy of 0.6572 and a cross-validation consistency of 10/10 with permutation testing Pmodel was 0.75 (95% CI 0.73-0.77). When epistatic data were incorporated in the extended model, the AUC increased to 0.81 (95% CI 0.79-0.83) which corresponds to 8% increase in AUC (DeLong's test P=2.2e-16); 17.5% by NRI. After correction for optimism, the AUC was 0.73 for the epidemiological model and 0.79 for the extended model. Our results showed modest improvement in lung cancer risk prediction when the SNP epistasis factor was added. PMID:27121382

  5. Susceptibility of cancer cells to β-lapachone is enhanced by ionizing radiation

    International Nuclear Information System (INIS)

    Purpose: To reveal the interaction between β-lapachone (β-lap) and ionizing radiation (IR) in causing clonogenic death in cancer cells and to elucidate the potential usefulness of β-lap treatment in combination with radiotherapy of cancer. Methods and materials: FSaII tumor cells of C3H mice were used. The cytotoxicity of β-lap alone or in combination with IR in vitro was determined using clonogenic survival assay method. The IR-induced changes in the expression and the enzymatic activity of NAD(P)H:quinone oxidoreductase (NQO1), a mediator of β-lap cytotoxicity, were elucidated and the relationship between the NQO1 level and the sensitivity of cells to β-lap was investigated. The combined effect of IR and β-lap to suppress tumor growth was studied using FSaII tumors grown subcutaneously in the thigh of C3H mice. Results: β-Lap caused clonogenic death of FSaII tumor cells in vitro in a dose- and time-dependent manner. When cells were treated first with β-lap and then exposed to IR in vitro, the resultant cell death was only additive. On the contrary, exposing cells to IR at 2.5 Gy first and then treating the cells with β-lap killed the cells in a synergistic manner. Importantly, the 2.5 Gy cells were sensitive to β-lap as long as 10 h after irradiation, which was long after the sublethal radiation damage was repaired. Irradiation of FSaII cells in vitro with 2.5 Gy significantly increased the expression and enzymatic activity of NQO1. The growth delay of FSaII tumors caused by an intraperitoneal injection of β-lap in combination with 20 Gy irradiation of tumor was significantly greater than that caused by β-lap or 20 Gy irradiation alone. Conclusion: The sensitivity of cells to β-lap is dependent on NQO1 activity. IR caused a long-lasting increase in NQO1 activity in cancer cells, thereby sensitizing cells to β-lap and treatment of experimental mouse tumors with IR and β-lap suppressed tumor growth in a synergistic manner. The combination of

  6. Radiation-induced oesophagitis in lung cancer patients. Is susceptibility for neutropenia a risk factor?

    Energy Technology Data Exchange (ETDEWEB)

    Ruysscher, D. de [MAASTRO Clinic, Maastricht (Netherlands). Dept. of Radiation Oncology; Meerbeeck, J. van [Ghent Univ. Hospital (Belgium). Dept. of Respiratory Medicine; Vandecasteele, K. [Ghent Univ. Hospital (BE). Dept. of Radiation Oncology] (and others)

    2012-07-15

    Background: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking. Methods and patients: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy. Results: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023). Conclusion: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus

  7. The accumulation of DNA demethylation in Sat α in normal gastric tissues with Helicobacter pylori infection renders susceptibility to gastric cancer in some individuals.

    Science.gov (United States)

    Saito, Masaaki; Suzuki, Koichi; Maeda, Takafumi; Kato, Takaharu; Kamiyama, Hidenori; Koizumi, Kei; Miyaki, Yuichiro; Okada, Shinichiro; Kiyozaki, Hirokazu; Konishi, Fumio

    2012-06-01

    Helicobacter pylori (HP) infection is widely recognized as a risk factor for gastric cancer, but only a minority of infected individuals develop gastric cancer. The aim of this study was to determine whether DNA demethylation in non-cancerous gastric mucosa (NGM) significantly enhances susceptibility to gastric cancer. A total of 165 healthy volunteers, including 83 HP-positive and 82-negative individuals, as well as 83 patients with single and 18 with synchronous double gastric cancer (GC) were enrolled in this study. The relative demethylation levels (RDLs) of repetitive sequences, including Alu, LINE-1 and Sat α, were quantified by real-time methylation-specific polymerase chain reaction. The Alu RDL did not exhibit any differences within each respective group, whereas LINE-1 RDL was significantly elevated in cancer tissues compared with the NGM in the other groups (P<0.001). Our results indicated that a gradual increase in Sat α RDL correlated with HP infection and cancer development. Sat α RDL was significantly elevated in the NGM in HP-positive compared with HP-negative (P<0.001), and significantly elevated in cancer tissues (P<0.001). Although the Sat α RDL of the NGM in the total population increased in an age-dependent manner, it was significantly increased in a fraction of younger GC patients (<45 years) compared with all of the others (45 years or older, P=0.0391). In addition, double GC exhibited a significantly higher Sat α RDL in the NGM compared with single GC (P=0.0014). In these two fractions, Sat α RDL in the NGM exhibited an inverse correlation with age. In conclusion, the present study demonstrated that the accumulation of DNA demethylation in Sat α RDL in the NGM with HP infection potentially renders susceptibility to gastric cancer in a fraction of GC patients younger than 45 years or in patients with multiple cancers. PMID:22426602

  8. Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.

    Science.gov (United States)

    Liu, Pengyuan; Lu, Yan; Liu, Hongbo; Wen, Weidong; Jia, Dongmei; Wang, Yian; You, Ming

    2012-01-01

    To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. PMID:22127497

  9. Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility.

    Directory of Open Access Journals (Sweden)

    Joshua M Uronis

    Full Text Available It is well established that the intestinal microbiota plays a key role in the pathogenesis of Crohn's disease (CD and ulcerative colitis (UC collectively referred to as inflammatory bowel disease (IBD. Epidemiological studies have provided strong evidence that IBD patients bear increased risk for the development of colorectal cancer (CRC. However, the impact of the microbiota on the development of colitis-associated cancer (CAC remains largely unknown. In this study, we established a new model of CAC using azoxymethane (AOM-exposed, conventionalized-Il10(-/- mice and have explored the contribution of the host intestinal microbiota and MyD88 signaling to the development of CAC. We show that 8/13 (62% of AOM-Il10(-/- mice developed colon tumors compared to only 3/15 (20% of AOM- wild-type (WT mice. Conventionalized AOM-Il10(-/- mice developed spontaneous colitis and colorectal carcinomas while AOM-WT mice were colitis-free and developed only rare adenomas. Importantly, tumor multiplicity directly correlated with the presence of colitis. Il10(-/- mice mono-associated with the mildly colitogenic bacterium Bacteroides vulgatus displayed significantly reduced colitis and colorectal tumor multiplicity compared to Il10(-/- mice. Germ-free AOM-treated Il10(-/- mice showed normal colon histology and were devoid of tumors. Il10(-/-; Myd88(-/- mice treated with AOM displayed reduced expression of Il12p40 and Tnfalpha mRNA and showed no signs of tumor development. We present the first direct demonstration that manipulation of the intestinal microbiota alters the development of CAC. The TLR/MyD88 pathway is essential for microbiota-induced development of CAC. Unlike findings obtained using the AOM/DSS model, we demonstrate that the severity of chronic colitis directly correlates to colorectal tumor development and that bacterial-induced inflammation drives progression from adenoma to invasive carcinoma.

  10. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.

    Directory of Open Access Journals (Sweden)

    Kerstin B Meyer

    2008-05-01

    Full Text Available The recent whole-genome scan for breast cancer has revealed the FGFR2 (fibroblast growth factor receptor 2 gene as a locus associated with a small, but highly significant, increase in the risk of developing breast cancer. Using fine-scale genetic mapping of the region, it has been possible to narrow the causative locus to a haplotype of eight strongly linked single nucleotide polymorphisms (SNPs spanning a region of 7.5 kilobases (kb in the second intron of the FGFR2 gene. Here we describe a functional analysis to define the causative SNP, and we propose a model for a disease mechanism. Using gene expression microarray data, we observed a trend of increased FGFR2 expression in the rare homozygotes. This trend was confirmed using real-time (RT PCR, with the difference between the rare and the common homozygotes yielding a Wilcox p-value of 0.028. To elucidate which SNPs might be responsible for this difference, we examined protein-DNA interactions for the eight most strongly disease-associated SNPs in different breast cell lines. We identify two cis-regulatory SNPs that alter binding affinity for transcription factors Oct-1/Runx2 and C/EBPbeta, and we demonstrate that both sites are occupied in vivo. In transient transfection experiments, the two SNPs can synergize giving rise to increased FGFR2 expression. We propose a model in which the Oct-1/Runx2 and C/EBPbeta binding sites in the disease-associated allele are able to lead to an increase in FGFR2 gene expression, thereby increasing the propensity for tumour formation.

  11. Species distribution and antimicrobial susceptibility of gram-negative aerobic bacteria in hospitalized cancer patients

    Directory of Open Access Journals (Sweden)

    El-Sharif Amany

    2009-02-01

    Full Text Available Abstract Background Nosocomial infections pose significant threats to hospitalized patients, especially the immunocompromised ones, such as cancer patients. Methods This study examined the microbial spectrum of gram-negative bacteria in various infection sites in patients with leukemia and solid tumors. The antimicrobial resistance patterns of the isolated bacteria were studied. Results The most frequently isolated gram-negative bacteria were Klebsiella pneumonia (31.2% followed by Escherichia coli (22.2%. We report the isolation and identification of a number of less-frequent gram negative bacteria (Chromobacterium violacum, Burkholderia cepacia, Kluyvera ascorbata, Stenotrophomonas maltophilia, Yersinia pseudotuberculosis, and Salmonella arizona. Most of the gram-negative isolates from Respiratory Tract Infections (RTI, Gastro-intestinal Tract Infections (GITI, Urinary Tract Infections (UTI, and Bloodstream Infections (BSI were obtained from leukemic patients. All gram-negative isolates from Skin Infections (SI were obtained from solid-tumor patients. In both leukemic and solid-tumor patients, gram-negative bacteria causing UTI were mainly Escherichia coli and Klebsiella pneumoniae, while gram-negative bacteria causing RTI were mainly Klebsiella pneumoniae. Escherichia coli was the main gram-negative pathogen causing BSI in solid-tumor patients and GITI in leukemic patients. Isolates of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, and Acinetobacter species were resistant to most antibiotics tested. There was significant imipenem -resistance in Acinetobacter (40.9%, Pseudomonas (40%, and Enterobacter (22.2% species, and noticeable imipinem-resistance in Klebsiella (13.9% and Escherichia coli (8%. Conclusion This is the first study to report the evolution of imipenem-resistant gram-negative strains in Egypt. Mortality rates were higher in cancer patients with nosocomial Pseudomonas infections than any other bacterial infections

  12. Genetic variant in CD44 confer susceptibility to acute skin reaction in breast cancer patients undergoing radiotherapy

    International Nuclear Information System (INIS)

    Heterogeneity in toxicity to normal tissue is observed in 10% of cancer patients after radiotherapy (RT) which limits the therapeutic outcome. Response to RT is manifested from alterations in gene of vivid pathways involving DNA damage-repair, inflammatory cytokine, cell cycle regulation, antioxidant response etc. Therefore, the common sequence variants in these radioresponsive genes may modify the severity of normal tissue toxicity and identification of the same may have clinical relevance as a predictive biomarker. The present study was aimed to evaluate the potential modifying role of genetic variants in NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, LIG3, SH3GL1, BAXS, XRCC1, MAD2L2 and TGFBR3 on the individual susceptibility to RT induced acute skin reactions. All the 132 breast cancer patients were treated with a total dose of 50 Gy in case of mastectomy and 60 Gy in breast conservation surgery. The severity of skin damage was scored according to the Radiation Therapy Oncology Group (RTOG) criteria and the toxicity scores were dichotomized as non-over-responders (NOR; RTOG<2) and over-responders (NOR;RTOG>2) for analysis. Out of the 132 subjects, 44 were ORs. Among the 20 studied SNPs of indicated genes, the rs8193 (CD44) polymorphism lying in the miRNA binding site was significantly (p<0.05) associated with the RT induced adverse skin reactions. The non-coding CD44 3'-UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by freeing the target mRNAs from being repressed. Therefore, though the role of CD44 in radiosensitivity is unknown, the change in the miRNA binding to CD44mRNA transcripts may regulate expression of several genes involved in pathophysiology of normal tissue radiosensitivity leading to the observed outcome. (author)

  13. Hereditary breast cancer: ever more pieces to the polygenic puzzle.

    Science.gov (United States)

    Bogdanova, Natalia; Helbig, Sonja; Dörk, Thilo

    2013-01-01

    Several susceptibility genes differentially impact on the lifetime risk for breast cancer. Technological advances over the past years have enabled the detection of genetic risk factors through high-throughput screening of large breast cancer case-control series. High- to intermediate penetrance alleles have now been identified in more than 20 genes involved in DNA damage signalling and repair, and more than 70 low-penetrance loci have been discovered through recent genome-wide association studies. In addition to classical germ-line mutation and single-nucleotide polymorphism, copy number variation and somatic mosaicism have been proposed as potential predisposing mechanisms. Many of the identified loci also appear to influence breast tumour characteristics such as estrogen receptor status. In this review, we briefly summarize present knowledge about breast cancer susceptibility genes and discuss their implications for risk prediction and clinical practice. PMID:24025454

  14. Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression

    International Nuclear Information System (INIS)

    The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer. A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines. Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines. This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression

  15. Role of genetic susceptibility in development of treatment-related adverse outcomes in cancer survivors.

    Science.gov (United States)

    Bhatia, Smita

    2011-10-01

    Clear and unambiguous associations have been established between therapeutic exposures and specific complications. However, considerable interindividual variability is observed in the risk of developing an outcome for a given therapeutic exposure. Genetic predisposition and especially its interaction with therapeutic exposures can potentially exacerbate the toxic effect of treatment on normal tissues and organ systems, and can possibly explain the interindividual variability. This article provides a brief overview of the current knowledge about the role of genomic variation in the development of therapy-related complications. Relatively common outcomes with strong associations with therapeutic exposures, including cardiomyopathy, obesity, osteonecrosis, ototoxicity, and subsequent malignancies are discussed here. To develop a deeper understanding of the molecular underpinnings of therapy-related complications, comprehensive and near-complete collection of clinically annotated samples is critical. Methodologic issues such as study design, definition of the endpoints or phenotypes, identification of appropriate and adequately sized study population together with a reliable plan for collecting and maintaining high-quality DNA, and selection of an appropriate approach or platform for genotyping are also discussed. Understanding the etiopathogenetic pathways that lead to the morbidity is critical to developing targeted prevention and intervention strategies, optimizing risk-based health care of cancer survivors, thus minimizing chronic morbidities and improving quality of life. PMID:21980013

  16. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...

  17. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, A.M.; Couch, F.J.; Barrowdale, D.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Robson, M.; Sherman, M.; Spurdle, A.B.; Wappenschmidt, B.; Lee, A.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Janavicius, R.; Hansen, T.V.; Nielsen, F.C.; Ejlertsen, B.; Osorio, A.; Munoz-Repeto, I.; Duran, M.; Godino, J.; Pertesi, M.; Benitez, J.; Peterlongo, P.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Cattaneo, E.; Bonanni, B.; Viel, A.; Pasini, B.; Papi, L.; Ottini, L.; Savarese, A.; Bernard, L.; Radice, P.; Hamann, U.; Verheus, M.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Nelen, M.R.; Kets, C.M.; Seynaeve, C.; Tilanus-Linthorst, M.M.; Luijt, R.B. van der; Os, T.V.; Rookus, M.; Frost, D.; Jones, J.L.; Evans, D.G.; Lalloo, F.; Eeles, R.; Izatt, L.; Adlard, J.; Davidson, R.; Cook, J.; Donaldson, A.; Dorkins, H.; Gregory, H.; Eason, J.; Houghton, C.; Barwell, J.; Side, L.E.; McCann, E.; Murray, A.; Peock, S.; Godwin, A.K.; Schmutzler, R.K.; Rhiem, K.; Engel, C.; Meindl, A.; Ruehl, I.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Kast, K.; Preisler-Adams, S.; Varon-Mateeva, R.; Schoenbuchner, I.; Fiebig, B.; Heinritz, W.; Schafer, D.; Gevensleben, H.; Caux-Moncoutier, V.; Fassy-Colcombet, M.; Cornelis, F.; Mazoyer, S.; Leone, M.; Boutry-Kryza, N.; Hardouin, A.; Berthet, P.; Muller, D.; Fricker, J.P.; Mortemousque, I.; Pujol, P.

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes i

  18. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, Anna Marie; Couch, Fergus J.; Barrowdale, Daniel; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Robson, Mark; Sherman, Mark; Spurdle, Amanda B.; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Janavicius, Ramunas; Hansen, Thomas V. O.; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Munoz-Repeto, Ivan; Duran, Mercedes; Godino, Javier; Pertesi, Maroulio; Benitez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Nelen, Marcel R.; Kets, C. Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M. A.; van der Luijt, Rob B.; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J. Louise; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E.; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K.; Schmutzler, Rita K.; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schaefer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, Francois; Mazoyer, Sylvie; Leone, Melanie; Boutry-Kryza, Nadia; Hardouin, Agnes; Berthet, Pascaline; Muller, Daniele; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomaki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B.; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Ganz, Patricia A.; Tomlinson, Gail E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F.; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L.; Greene, Mark H.; Imyanitov, Evgeny; O'Malley, Frances P.; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E.; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L.; Beattie, Mary; Pharoah, Paul D. P.; Moysich, Kirsten B.; Nathanson, Katherine L.; Karlan, Beth Y.; Gross, Jenny; John, Esther M.; Daly, Mary B.; Buys, Saundra M.; Southey, Melissa C.; Hopper, John L.; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F.; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F.; Andrulis, Irene L.; Antoniou, Antonis C.

    2011-01-01

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 an

  19. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium

    DEFF Research Database (Denmark)

    Amankwah, Ernest K; Wang, Qinggang; Schildkraut, Joellen M;

    2011-01-01

    Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among...... Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and...... replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P(heterogeneity)≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P(trend) = 0.001 to 0.03). Results from replication set 2 were statistically...

  20. Single nucleotide polymorphisms within interferon signaling pathway genes are associated with colorectal cancer susceptibility and survival.

    Directory of Open Access Journals (Sweden)

    Shun Lu

    Full Text Available Interferon (IFN signaling has been suggested to play an important role in colorectal carcinogenesis. Our study aimed to examine potentially functional genetic variants in interferon regulatory factor 3 (IRF3, IRF5, IRF7, type I and type II IFN and their receptor genes with respect to colorectal cancer (CRC risk and clinical outcome. Altogether 74 single nucleotide polymorphisms (SNPs were covered by the 34 SNPs genotyped in a hospital-based case-control study of 1327 CRC cases and 758 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 483 patients. Seven SNPs in IFNA1, IFNA13, IFNA21, IFNK, IFNAR1 and IFNGR1 were associated with CRC risk. After multiple testing correction, the associations with the SNPs rs2856968 (IFNAR1 and rs2234711 (IFNGR1 remained formally significant (P = 0.0015 and P<0.0001, respectively. Multivariable survival analyses showed that the SNP rs6475526 (IFNA7/IFNA14 was associated with overall survival of the patients (P = 0.041 and event-free survival among patients without distant metastasis at the time of diagnosis, P = 0.034. The hazard ratios (HRs for rs6475526 remained statistically significant even after adjustment for age, gender, grade and stage (P = 0.029 and P = 0.036, respectively, suggesting that rs6475526 is an independent prognostic marker for CRC. Our data suggest that genetic variation in the IFN signaling pathway genes may play a role in the etiology and survival of CRC and further studies are warranted.

  1. Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Gracia-Aznarez

    Full Text Available The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10 diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.

  2. Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7)

    DEFF Research Database (Denmark)

    Boedtkjer, Ebbe; Moreira, José M. A.; Mele, Marco;

    2013-01-01

    Genome-wide association studies recently linked the locus for Na(+) ,HCO(3) (-) -cotransporter NBCn1 (SLC4A7) to breast cancer susceptibility, yet functional insights have been lacking. To determine whether NBCn1, by transporting HCO(3) (-) into cells, may dispose of acid produced during high...

  3. Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1

    DEFF Research Database (Denmark)

    Skoglund, J; Djureinovic, T; Zhou, X-L;

    2006-01-01

    dominantly inherited colorectal cancer risk. Recently, a locus on chromosome 9q22.2-31.2 was identified by linkage analysis in sib pairs with colorectal cancer or adenoma. METHODS: Linkage analysis for the suggested locus on chromosome 9 was carried out in an extended Swedish family. This family had...... previously been investigated but following the identification of adenomas in several previously unaffected family members, these subjects were now considered to be gene carriers. RESULTS: In the present study, we found linkage of adenoma and colorectal cancer to chromosome 9q22.32-31.1 with a multipoint LOD...... score of 2.4. We were also able to define the region for this locus to 7.9 cM between the markers D9S280 and D9S277. CONCLUSIONS: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region....

  4. Susceptibility Testing

    Science.gov (United States)

    ... page helpful? Also known as: Sensitivity Testing; Drug Resistance Testing; Culture and Sensitivity; C & S; Antimicrobial Susceptibility Formal name: Bacterial and Fungal Susceptibility Testing Related tests: Urine Culture ; ...

  5. Association of cellular and molecular responses in the rat mammary gland to 17β-estradiol with susceptibility to mammary cancer

    International Nuclear Information System (INIS)

    We are using ACI and BN rats, which differ markedly in their susceptibility to 17β-estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks. Mammary gland morphology and histology were examined by whole mount and hematoxylin and eosin (H&E) staining. Cell proliferation and epithelial density were evaluated by quantitative immunohistochemistry. Apoptosis was evaluated by quantitative western blotting and flow cytometry. Mammary gland differentiation was examined by immunohistochemistry. Gene expression was evaluated by microarray, qRT-PCR and quantitative western blotting assays. Extracellular matrix (ECM) associated collagen was evaluated by Picrosirius Red staining and Second Harmonic Generation (SHG) microscopy. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the ECM. Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in

  6. Low-dose radiation enhances susceptibility to cisplatin in resistant ovarian cancer cells via downregulation of ERCC1 and Bcl-2

    Institute of Scientific and Technical Information of China (English)

    Xiaoran Liu; Donghai Liang; Tao Jiang; Qing Dong; Hongsheng Yu 

    2016-01-01

    Objective Ovarian cancer is one of the leading causes of mortality in patients with malignant gyneco-logical tumors. After surgical intervention for ovarian cancer, cisplatin (DDP)-based chemotherapy is the first-line treatment. However, a major chal enge to treating ovarian cancer is the development of chemore-sistance. Thus, the first aim of this study was to determine whether low-dose radiation could enhance the susceptibility of resistant ovarian cancer cel s to DDP. The second aim was to provide new strategies for treating DDP-resistant ovarian cancer by examining its mechanism. Methods A cel counting kit-8 (CCK8) assay was performed to measure cel proliferation. Flow cytometry was utilized to quantify the apoptosis of DDP-resistant ovarian cancer cel s (SKOV3/DDP) using Annexin V and propidium iodide staining. Real-time quantitative (qPCR) was used to analyze the messenger RNA (mRNA) expression levels of excision repair cross complementing-group 1 (ERCC1) and B-cel lymphoma 2 (Bcl-2) in SKOV3/DDP. Results The IC50 values of the control, conventional-dose, and low-dose groups were 9.367 ± 0.16, 9.289 ± 0.16, and 3.847 ± 0.15, respectively (P Conclusion Low-dose radiation enhanced the sensitivity of resistant ovarian cancer cel s to DDP, pos-sibly by decreasing the DNA repair capacity of tumor cel s and promoting apoptosis.

  7. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

    OpenAIRE

    Wang, Zhaoming; Zhu, Bin; Zhang, Mingfeng; Parikh, Hemang; Jia, Jinping; Chung, Charles C.; Sampson, Joshua N.; Hoskins, Jason W.; Hutchinson, Amy; Burdette, Laurie; Ibrahim, Abdisamad; Hautman, Christopher; Raj, Preethi S.; Abnet, Christian C.; Adjei, Andrew A.

    2014-01-01

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based...

  8. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women

    OpenAIRE

    Barnholtz-Sloan, Jill S; Shetty, Priya B; Guan, Xiaowei; Nyante, Sarah J; Luo, Jingchun; Brennan, Donal J.; Millikan, Robert C.

    2010-01-01

    Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry ...

  9. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...... subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers....

  10. A novel functional TagSNP Rs7560488 in the DNMT3A1 promoter is associated with susceptibility to gastric cancer by modulating promoter activity.

    Directory of Open Access Journals (Sweden)

    Huazhang Wu

    Full Text Available DNA-methyltransferase (DNMT-3A which contains DNMT3A1 and DNMT3A2 isoforms have been suggested to play a crucial role in carcinogenesis and showed aberrant expression in most cancers. Accumulated evidences also indicated that single nucleotide polymorphisms (SNP in DNMT genes were associated with susceptibility to different tumors. We hypothesized that genetic variants in DNMT3A1 promoter region are associated with gastric cancer risk. We selected the tagSNPs from the HapMap database for the Chinese and genotyped in a case-control study to evaluate the association with gastric cancer (GC in a Chinese population. We identified that the functional tagSNP rs7560488 T>C associated with a significantly increased risk of GC. In vitro functional analysis by luciferase reporter assay and EMSA indicated that the tagSNP rs7560488 T>C substantially altered transcriptional activity of DNMT3A1 gene via influencing the binding of some transcriptional factors, although a definite transcriptional factor remains to be established. Compared with TT homozygotes, subjects who were TC heterozygotes and CC homozygotes exhibited a reduced expression of DNMT3A1. Furthermore, stratified analysis showed that individuals who harbor TC or CC genotypes less than 60 years old were more susceptible to GC. Our results suggest that the genetic variations in the DNMT3A1 promoter contribute to the susceptibility to GC and also provide an insight that tagSNP rs7560488 T>C may be a promising biomarker for predicting GC genetic susceptibility and a valuable information in GC pathogenesis.

  11. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index

    Science.gov (United States)

    Speliotes, Elizabeth K.; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian’an; Mägi, Reedik; Randall, Joshua C.; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segré, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpeläinen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tõnu; Feitosa, Mary F.; Kutalik, Zoltán; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Åsa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R.B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I.F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proença, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S.; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N.M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J.C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Gräßler, Jürgen; Greenawalt, Danielle M.; Groves, Christopher J.; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; König, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaløy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J.; Lecoeur, Cecile; Lehtimäki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O’Donnell, Christopher J.; O’Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Paré, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietiläinen, Kirsi H.; Platou, Carl G.P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstråle, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S.; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J.; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Tönjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B.J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Voight, Benjamin F.; Waite, Lindsay L.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kähönen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Collins, Francis S.; Cupples, L. Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Grönberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B.; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter E.H.; Shuldiner, Alan R.; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André; Valle, Timo T.; Wabitsch, Martin; Waeber, Gérard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Zillikens, M. Carola; Chatterjee, Nilanjan; McCarroll, Steven A.; Purcell, Shaun; Schadt, Eric E.; Visscher, Peter M.; Assimes, Themistocles L.; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O’Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H.-Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Gonçalo R.; Barroso, Inês; Boehnke, Michael; Stefansson, Kari; North, Kari E.; McCarthy, Mark I.; Hirschhorn, Joel N.; Ingelsson, Erik; Loos, Ruth J.F.

    2010-01-01

    Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation. PMID:20935630

  12. A Regulatory Polymorphism at Position -309 in PTPRCAP Is Associated with Susceptibility to Diffuse-type Gastric Cancer and Gene Expression

    Directory of Open Access Journals (Sweden)

    Hyoungseok Ju

    2009-12-01

    Full Text Available PTPRCAP (CD45-AP is a positive regulator of protein tyrosine phosphatase PTPRC (CD45, which activates Src family kinases implicated in tumorigenesis. Single-nucleotide polymorphism (SNP rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer in the current case-control study. The minor-allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = .0021, n = 252, but not to intestinal-type (P = .30, n = 178, versus the major-allele homozygote, when comparing unrelated Korean patients with healthy controls (n = 406. Nine other SNPs were in nearly perfect linkage disequilibrium (r2 ≥ 0.97 with this SNP, exhibiting the same association, and spread out for 26 kb on chromosome 11q13.1 covering RPS6KB2, PTPRCAP, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (0, 1, and 2 of the risk-haplotype (P = .0060 in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor-allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major-allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases.

  13. Higher susceptibility of NOD/LtSz-scid Il2rg−/− NSG mice to xenotransplanted lung cancer cell lines

    International Nuclear Information System (INIS)

    No lung cancer xenograft model using non-obese diabetic (NOD)-scid Il2rg−/− mice has been reported. The purpose of this study is to select a suitable mouse strain as a xenogenic host for testing tumorigenicity of lung cancer. We directly compared the susceptibility of four immunodeficient mouse strains, c-nu, C.B-17 scid, NOD-scid, and NOD/LtSz-scid Il2rg−/− (NSG) mice, for tumor formation from xenotransplanted lung cancer cell lines. Various numbers (101–105 cells/head) of two lung cancer cell lines, A549 and EBC1, were subcutaneously inoculated and tumor sizes were measured every week up to 12 weeks. When 104 EBC1 cells were inoculated, no tumor formation was observed in BALB/c-nu or C.B-17 scid mice. Tumors developed in two of the five NOD-scid mice (40%) and in all the five NSG mice (100%). When 103 EBC1 cells were injected, no tumors developed in any strain other than NSG mice, while tumorigenesis was achieved in all the five NSG mice (100%, P=0.0079) within 9 weeks. NSG mice similarly showed higher susceptibility to xenotransplantation of A549 cells. Tumor formation was observed only in NSG mice after inoculation of 103 or fewer A549 cells (40% vs 0% in 15 NSG mice compared with others, respectively, P=0.0169). We confirmed that the engrafted tumors originated from inoculated human lung cancer cells by immunohistochemical staining with human cytokeratin and vimentin. NSG mice may be the most suitable strain for testing tumorigenicity of lung cancer, especially if only a few cells are available

  14. Confirmation of novel type 1 diabetes risk loci in families

    DEFF Research Database (Denmark)

    Cooper, J D; Howson, J M M; Smyth, D; Walker, N M; Stevens, Hanne; Yang, Jian; She, J-X; Eisenbarth, G S; Rewers, M; Todd, J A; Akolkar, B; Concannon, P; Erlich, H A; Julier, C; Morahan, G; Nerup, Jørn; Nierras, C; Pociot, F; Rich, Steve

    2012-01-01

    Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the...... Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study....

  15. 大规模单核苷酸多态性分析与肿瘤易感性%Large-scale Single Nucleotide Polymorphism Analysis and Cancer Susceptibility

    Institute of Scientific and Technical Information of China (English)

    王娟

    2007-01-01

    单核苷酸多态性(SNPs)是人类基因组中最常见的变异形式.作为第三代遗传标记,SNP在基因定位、克隆、遗传多态性方面具有广泛应用,特别是作为基因诊断标记在预防医学中具有十分重要的作用.近年来,随着人类基因组计划的发展,数以百万计的SNP被陆续发现,并可在公共数据库中免费获得.SNP数量的快速增加和SNP检测方法的发展,为其在肿瘤易感性领域的应用提供了可能.在本综述中,我们介绍了几种高通量检测SNP的分析方法,总结了大规模SNP分析技术在肿瘤易感性中的应用,介绍了目前人们对于不同人群中的SNP分析、肿瘤易感基因、个体肿瘤易感性的理解,以及研究SNP标记与肿瘤易感性关系时存在的难点.%Single nucleotide polymorphisms (SNPs) are the most common sources of variation between humans. As a kind of new genetic marker, SNPs are used extensively in gene location, clone and genetic polymorphisms. Specially, as diagnostic markers, the genetic SNPs play an important role in preventive medicine. In recent years, with the development of human genome project, millions of SNPs are reported and freely available in public databases. The rapid increase of SNP number and the development of detection methods for SNPs provide probability for the analysis of cancer susceptibility. In this review, we described main methods for high-throughput SNP analysis technologies. We summarized the application of SNPs analysis by large-scale analytic technologies in cancer susceptibility, the current understanding of SNP analysis in the different populations, tumor susceptibility genes and individual cancer susceptibility, as well as the obstacles in discovering the relationship between SNP analysis and cancer susceptibility underlying complex human traits.

  16. Genetic polymorphisms in MMP 2, 3, 7, and 9 genes and the susceptibility and clinical outcome of cervical cancer in a Chinese Han population.

    Science.gov (United States)

    Xie, Beibei; Zhang, Zhen; Wang, Hui; Chen, Zhaojie; Wang, Yongsheng; Liang, Huazheng; Yang, Gaoyuan; Yang, Xingsheng; Zhang, Haiyan

    2016-04-01

    Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumor progression, including the invasion and metastasis. However, there are no data about the role of MMP polymorphism in the development of cervical cancer. A hospital-based case-control study was conducted in 230 patients with cervical cancer and 230 healthy controls to investigate the possible association between the MMP2 rs243865, MMP3 rs3025058, MMP7 rs11568818, and MMP9 rs3918242 polymorphisms, respectively, and the risk of cervical cancer. Our results suggested that the MMP2 rs243865-1306 C/T was significantly associated with an increased risk of cervical cancer (CT vs. CC, OR = 1.46; 95 % CI 1.18-3.55; P = 0.032; TT vs. CC, OR = 1.72; 95 % CI 1.28-4.02; P = 0.031; CT + TT vs. CC, OR = 1.43; 95 % CI 1.21-3.44; P = 0.029). Similarly, the MMP7 rs11568818-181A/G genotypes can also elevate the risk of cervical cancer in all genetic models. However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms in cervical cancer patients were not significantly different from controls. Further analysis showed MMP2 rs243865 and MMP7 rs11568818 genotypes were associated with advanced tumor stages of cervical cancer patients. More interestingly, the MMP2 rs243865 and MMP7 rs11568818 genotype was statistically significantly associated with a poor survival in cervical cancer patients. Our results showed that the MMP2 rs243865 and MMP7 rs11568818 genotypes e were associated with increased susceptibility and development of cervical cancer in Chinese Han population. PMID:26526578

  17. Non-small cell lung cancer: current status of chemoradiation for locally advanced disease and an update on susceptibility and prevention

    International Nuclear Information System (INIS)

    Locally advanced, inoperable non-small cell lung cancer (NSCLC) afflicts 40,000 patients yearly. The traditional treatment has been radiation therapy (RT) alone with 5 year survival rates averaging around 5%. Recent reports of randomized clinical trials using combined radiochemotherapy suggest significant improvement in survival compared to RT alone. These trials are difficult to evaluate because of differences in dose, timing and sequencing of both the chemotherapy (CT) and the RT. Dr. Byhardt will give an overview of the significant chemoradiation trials, especially with respect to the factors associated with reduction of local failure and distant metastasis. Dr. Tishler will review the biologic rationale of these regimens and make some prognostications about the potential role of new chemotherapy agents, new developments in RT dose-time-fractionation, and new RT technology in future radiochemotherapy trials. While progress continues to be made using the more traditional cancer treatment modalities, investigations in NSCLC epidemiology and prevention are providing new insights regarding susceptibility, etiology, failure risk stratification, and potential avenues of therapeutic intervention. Dr. Spitz will discuss NSCLC as a paradigm of an environmentally induced disease in which host susceptibility may be determined by genetically determined modulation of environmental exposures. A mutagen sensitivity assay can determine individuals at high risk for developing NSCLC if exposed to carcinogens such as those in cigarette smoke. This susceptibility may have prognostic implications that could influence choice of therapy. Highly susceptible individuals can also be selected for special counseling, smoking cessation, with consideration given to chemoprevention. Dr. Gritz will review major work done in this area

  18. Remote Symbolic Computation of Loci

    Science.gov (United States)

    Abanades, Miguel A.; Escribano, Jesus; Botana, Francisco

    2010-01-01

    This article presents a web-based tool designed to compute certified equations and graphs of geometric loci specified using standard Dynamic Geometry Systems (DGS). Complementing the graphing abilities of the considered DGS, the equations of the loci produced by the application are remotely computed using symbolic algebraic techniques from the…

  19. Association of LEP G2548A and LEPR Q223R polymorphisms with cancer susceptibility: evidence from a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Jing He

    Full Text Available BACKGROUND: Numerous epidemiological studies have examined associations of genetic variations in LEP (G2548A, -2548 nucleotide upstream of the ATG start site and LEPR (Q223R, nonsynonymous SNP in exon 6 with cancer susceptibility; however, the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate such associations. METHODS: We searched published literature from MEDLINE, EMBASE, Web of Science and CBM for eligible publications. We also assessed genotype-based mRNA expression data from HapMap for rs7799039 (G2548A and rs1137101 (Q223R in normal cell lines derived from 270 subjects with different ethnicities. RESULTS: The final analysis included 16 published studies of 6569 cases and 8405 controls for the LEP G2548A and 19 studies of 7504 cases and 9581 controls for the LEPR Q223R. Overall, LEP G2548A was statistically significantly associated with an increased risk of overall cancer (AA vs. GG: OR=1.27, 95% CI=1.05-1.54; recessive model: OR=1.19, 95% CI=1.00-1.41. Further stratifications by cancer type showed an increased risk for prostate cancer (recessive model: OR=1.26, 95% CI=1.05-1.51 but not for other cancers. For LEPR Q223R, no statistical evidence for an association with risk of cancer was found for all; however, further stratification by ethnicity showed an increased risk for Africans but not for other ethnicities. No significantly differences in LEP and LEPR mRNA expression were found among genotypes or by ethnicity. CONCLUSIONS: Despite some limitations, this meta-analysis found some statistical evidence for an association between the LEP 2548AA genotype and overall risk of cancer, particularly for prostate cancer, but given this variant did not have an effect on mRNA expression, this association warrants additional validation in large and well-designed studies.

  20. Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells

    International Nuclear Information System (INIS)

    Microtubules are part of cell structures that play a role in regulating the migration of cancer cells. The cellular apoptosis susceptibility (CSE1L/CAS) protein is a microtubule-associated protein that is highly expressed in cancer. We report here that CSE1L regulates the association of α-tubulin with β-tubulin and promotes the migration of MCF-7 breast cancer cells. CSE1L was associated with α-tubulin and β-tubulin in GST (glutathione S-transferase) pull-down and immunoprecipitation assays. CSE1L-GFP (green fluorescence protein) fusion protein experiments showed that the N-terminal of CSE1L interacted with microtubules. Increased CSE1L expression resulted in decreased tyrosine phosphorylation of α-tubulin and β-tubulin, increased α-tubulin and β-tubulin association, and enhanced assembly of microtubules. Cell protrusions or pseudopodia are temporary extensions of the plasma membrane and are implicated in cancer cell migration and invasion. Increased CSE1L expression increased the extension of MCF-7 cell protrusions. In vitro migration assay showed that enhanced CSE1L expression increased the migration of MCF-7 cells. Our results indicate that CSE1L plays a role in regulating the extension of cell protrusions and promotes the migration of cancer cells.

  1. Clinical Significance of Long Non-Coding RNA CASC8 rs10505477 Polymorphism in Lung Cancer Susceptibility, Platinum-Based Chemotherapy Response, and Toxicity

    Directory of Open Access Journals (Sweden)

    Lei Hu

    2016-05-01

    Full Text Available Long non-coding RNA (lncRNA CASC8 rs10505477 polymorphism has been identified to be related to risk of many kinds of cancers, such as colorectal cancer, gastric cancer, and invasive ovarian cancer, and it may be involved in the prognosis of gastric cancer patients who have received platinum-based chemotherapy after surgical treatment. So far, there is no study investigating the clinical significance of lncRNA CASC8 rs10505477 in lung cancer susceptibility and treatment. In this study, we genotyped 498 lung cancer patients and 213 healthy control subjects to explore the correlation between the rs10505477 polymorphism and lung cancer risk in a Chinese population. Among the 498 patients, 467 were selected for the chemotherapy response and toxicity study. We found that the single nucleotide polymorphisms (SNP rs10505477 was greatly related to lung cancer risk in male and adenocarcinoma subgroups in recessive model (adjusted OR = 0.51, 95%CI = 0.29–0.90, p = 0.02; adjusted OR = 0.52, 95%CI = 0.30–0.89, p = 0.02, respectively. It was also closely correlated with platinum-based chemotherapy response in dominant model (adjusted OR = 1.58, 95%CI = 1.05–2.39, p = 0.03. Additionally, we observed that CASC8 rs10505477 polymorphism was significantly relevant to severe hematologic toxicity in non-small-cell lung cancer (NSCLC subgroup in dominant model (adjusted OR = 0.59, 95%CI = 0.35–0.98, p = 0.04 and in additive model (adjusted OR = 0.62, 95%CI = 0.43–0.90, p = 0.01. Furthermore, it was found that rs10505477 polymorphism was greatly associated with gastrointestinal toxicity in SCLC and cisplatin subgroups in dominant model (adjusted OR = 7.82, 95%CI = 1.36–45.07, p = 0.02; adjusted OR = 1.94, 95%CI = 1.07–3.53, p = 0.03, respectively. Thus, lncRNA CASC8 rs10505477 could serve as a possible risk marker for diagnosing lung cancer, and could be used to forecast the response and toxicity of platinum-based treatment in lung cancer patients.

  2. The analysis of a large Danish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 11q24

    DEFF Research Database (Denmark)

    Rudkjøbing, Laura Aviaja; Eiberg, Hans; Mikkelsen, Hanne Birte; Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise

    2015-01-01

    . Major rearrangements were excluded after karyotyping. The linkage analysis with SNP6 data revealed three candidate areas, on chromosome 2, 6 and 11 respectively, with a LOD score close to two and no negative LOD scores. After extended linkage analysis, the area on chromosome 6 was excluded, leaving...... areas on chromosome 2 and chromosome 11 with the highest possible LOD scores of 2.6. Two other studies have identified 11q24 as a candidate area for colorectal cancer susceptibility and this area is supported by our results....

  3. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gaudet, Mia M; Antoniou, Antonis C;

    2012-01-01

    Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mut...

  4. Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

    Science.gov (United States)

    Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley; Sinilnikova, Olga M.; Healey, Sue; Neuhausen, Susan L.; Ding, Yuan Chun; Rebbeck, Timothy R.; Weitzel, Jeffrey N.; Lynch, Henry T.; Isaacs, Claudine; Ganz, Patricia A.; Tomlinson, Gail; Olopade, Olufunmilayo I.; Couch, Fergus J.; Wang, Xianshu; Lindor, Noralane M.; Pankratz, Vernon S.; Radice, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Barile, Monica; Viel, Alessandra; Allavena, Anna; Dall’Olio, Valentina; Peterlongo, Paolo; Szabo, Csilla I.; Zikan, Michal; Claes, Kathleen; Poppe, Bruce; Foretova, Lenka; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Lejbkowicz, Flavio; Glendon, Gord; Ozcelik, Hilmi; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Sunde, Lone; Cruger, Dorthe; Jensen, Uffe Birk; Caligo, Maria; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Dubrovsky, Maya; Cohen, Shimrit; Borg, Ake; Jernström, Helena; Lindblom, Annika; Rantala, Johanna; Stenmark-Askmalm, Marie; Melin, Beatrice; Nathanson, Kate; Domchek, Susan; Jakubowska, Ania; Lubinski, Jan; Huzarski, Tomasz; Osorio, Ana; Lasa, Adriana; Durán, Mercedes; Tejada, Maria-Isabel; Godino, Javier; Benitez, Javier; Hamann, Ute; Kriege, Mieke; Hoogerbrugge, Nicoline; van der Luijt, Rob B; van Asperen, Christi J; Devilee, Peter; Meijers-Heijboer, E.J.; Blok, Marinus J; Aalfs, Cora M.; Hogervorst, Frans; Rookus, Matti; Cook, Margaret; Oliver, Clare; Frost, Debra; Conroy, Don; Evans, D. Gareth; Lalloo, Fiona; Pichert, Gabriella; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary E.; Walker, Lisa; Kennedy, M. John; Dorkins, Huw; Peock, Susan; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; de Pauw, Antoine; Mazoyer, Sylvie; Bonadona, Valérie; Lasset, Christine; Dreyfus, Hélène; Leroux, Dominique; Hardouin, Agnès; Berthet, Pascaline; Faivre, Laurence; Loustalot, Catherine; Noguchi, Tetsuro; Sobol, Hagay; Rouleau, Etienne; Nogues, Catherine; Frénay, Marc; Vénat-Bouvet, Laurence; Hopper, John L.; Daly, Mary B.; Terry, Mary B.; John, Esther M.; Buys, Saundra S.; Yassin, Yosuf; Miron, Alex; Goldgar, David; Singer, Christian F.; Dressler, Anne Catharina; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Hansen, Thomas V. O.; Jønson, Lars; Agnarsson, Bjarni A.; Kirchhoff, Tomas; Offit, Kenneth; Devlin, Vincent; Dutra-Clarke, Ana; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda Ewart; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Schmutzler, Rita; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Lochmann, Magdalena; Arnold, Norbert; Heidemann, Simone; Varon-Mateeva, Raymonda; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Preisler-Adams, Sabine; Kast, Karin; Schönbuchner, Ines; Caldes, Trinidad; de la Hoya, Miguel; Aittomäki, Kristiina; Nevanlinna, Heli; Simard, Jacques; Spurdle, Amanda B.; Holland, Helene; Chen, Xiaoqing; Platte, Radka; Chenevix-Trench, Georgia; Easton, Douglas F.

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  5. Fine mapping of dental fluorosis quantitative trait loci in mice

    OpenAIRE

    Everett, Eric T.; Yin, Zhaoyu; Yan, Dong; Zou, Fei

    2011-01-01

    Genetic factors underlie dental fluorosis (DF) susceptibility/resistance. The A/J (DF susceptible) and 129P3/J (DF resistant) strains have been previously used to detect quantitative trait loci (QTL) associated with DF on chromosomes (Chr) 2 and 11. In the present study increased marker density genotyping followed by interval mapping was performed to narrow the QTL intervals and improve the LOD scores. Narrower intervals on Chr 2 where LOD ≥ 6.0 (57–84 cM or ~51 Mb), LOD ≥ 7.0 (62–79 cM or ~3...

  6. In utero exposure of rats to high-fat diets perturbs gene expression profiles and cancer susceptibility of prepubertal mammary glands.

    Science.gov (United States)

    Govindarajah, Vinothini; Leung, Yuet-Kin; Ying, Jun; Gear, Robin; Bornschein, Robert L; Medvedovic, Mario; Ho, Shuk-Mei

    2016-03-01

    Human studies suggest that high-fat diets (HFDs) increase the risk of breast cancer. The 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis rat model is commonly used to evaluate the effects of lifestyle factors such as HFD on mammary tumor risk. Past studies focused primarily on the effects of continuous maternal exposure on the risk of offspring at the end of puberty (PND50). We assessed the effects of prenatal HFD exposure on cancer susceptibility in prepubertal mammary glands and identified key gene networks associated with such disruption. During pregnancy, dams were fed AIN-93G-based diets with isocaloric high olive oil, butterfat or safflower oil. The control group received AIN-93G. Female offspring were treated with DMBA on PND21. However, a significant increase in tumor volume and a trend of shortened tumor latency were observed in rats with HFD exposure against the controls (P=.048 and P=.067, respectively). Large-volume tumors harbored carcinoma in situ. Transcriptome profiling identified 43 differentially expressed genes in the mammary glands of the HFBUTTER group as compared with control. Rapid hormone signaling was the most dysregulated pathway. The diet also induced aberrant expression of Dnmt3a, Mbd1 and Mbd3, consistent with potential epigenetic disruption. Collectively, these findings provide the first evidence supporting susceptibility of prepubertal mammary glands to DMBA-induced tumorigenesis that can be modulated by dietary fat that involves aberrant gene expression and likely epigenetic dysregulation. PMID:26895667

  7. Artificial neural network-based exploration of gene-nutrient interactions in folate and xenobiotic metabolic pathways that modulate susceptibility to breast cancer.

    Science.gov (United States)

    Naushad, Shaik Mohammad; Janaki Ramaiah, M; Pavithrakumari, Manickam; Jayapriya, Jaganathan; Hussain, Tajamul; Alrokayan, Salman A; Gottumukkala, Suryanarayana Raju; Digumarti, Raghunadharao; Kutala, Vijay Kumar

    2016-04-15

    In the current study, an artificial neural network (ANN)-based breast cancer prediction model was developed from the data of folate and xenobiotic pathway genetic polymorphisms along with the nutritional and demographic variables to investigate how micronutrients modulate susceptibility to breast cancer. The developed ANN model explained 94.2% variability in breast cancer prediction. Fixed effect models of folate (400μg/day) and B12 (6μg/day) showed 33.3% and 11.3% risk reduction, respectively. Multifactor dimensionality reduction analysis showed the following interactions in responders to folate: RFC1 G80A×MTHFR C677T (primary), COMT H108L×CYP1A1 m2 (secondary), MTR A2756G (tertiary). The interactions among responders to B12 were RFC1G80A×cSHMT C1420T and CYP1A1 m2×CYP1A1 m4. ANN simulations revealed that increased folate might restore ER and PR expression and reduce the promoter CpG island methylation of extra cellular superoxide dismutase and BRCA1. Dietary intake of folate appears to confer protection against breast cancer through its modulating effects on ER and PR expression and methylation of EC-SOD and BRCA1. PMID:26784656

  8. Linkage disequilibrium mapping of a breast cancer susceptibility locus near RAI/PPPIRI3L/iASPP

    DEFF Research Database (Denmark)

    Nexø, Bjørn A.; Vogel, Ulla Birgitte; Olsen, Anja;

    2008-01-01

    Background: Previous results have suggested an association of the region of 19q13.3 with several forms of cancer. In the present study, we investigated 27 public markers within a previously identified 69 kb stretch of chromosome 19q for association with breast cancer by using linkage disequilibri...

  9. 'Hide-then-hit' to explain the importance of genotypic polymorphism of DNA repair genes in determining susceptibility to cancer

    Institute of Scientific and Technical Information of China (English)

    Pei-Ei Wu; Chen-Yang Shen

    2011-01-01

    Interindividual variations in DNA repair capacity/efficiency linked to the presence of polymorphisms in DNA repair-related genes have been suggested to account for different risk of developing cancers. In this review article, on the basis of breast cancer formation as a model, we propose a 'hide-then-hit' hypothesis indicating the importance of escaping checkpoint surveillance for sub-optimal DNA repair variants to cause cancer. Therefore, only cells with subtle defects in repair capacity arising from low-penetrance variants of DNA repair genes would have the opportunity to grow and accumulate the genetic changes needed for cancer formation, without triggering cell-cycle checkpoint surveillance. Furthermore, distinct from high-penetrance alleles, these polymorphic alleles of DNA repair genes would predispose carriers to a higher risk of developing cancer but would not necessarily cause cancer. To examine this,we simultaneously genotyped multiple SNPs of cell-cycle checkpoint genes and the DNA repair genes. Support for the hypothesis came from observations that breast cancer risk associated with variant genotypes of DNA repair genes became more significant in be confirmed by biological evidence in which a cause-effect relationship has to be established. However, based on this, possible gene-gene interaction is considered to play an important role in modifying the cancer risk associated with genotypic polymorphism of DNA repair gene in different study populations.

  10. Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

    DEFF Research Database (Denmark)

    Milne, Roger L; Goode, Ellen L; García-Closas, Montserrat;

    2011-01-01

    BACKGROUND: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Associatio...

  11. Library Spirit and Genius Loci

    DEFF Research Database (Denmark)

    Dahlkild, Nan

    2009-01-01

    The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style".......The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style"....

  12. Family history suggestive of an inherited susceptibility to breast cancer and treatment outcome in young women after breast-conserving therapy

    International Nuclear Information System (INIS)