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Sample records for cancer susceptibility gene

  1. Search for new breast cancer susceptibility genes

    NARCIS (Netherlands)

    Oldenburg, Rogier Abel

    2008-01-01

    This thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1 and BRCA2 breast cancer susceptibility genes. For the remaining families the genetic etiology is unknow

  2. 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...... was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.Conclusion:Our results suggest...

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Mapping Interactive Cancer Susceptibility Genes in Prostate Cancer

    Science.gov (United States)

    2007-04-01

    further analysis around this FHIT marker. Under the assumption of a recessive model, we attempted to narrow the disease interval by examining key meiotic ...examining key meiotic recombinants. A and B, physical map illustrating marker and FHIT exon locations. Solid bar, FHIT gene boundary; vertical bars, exons 5...gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 1996;84

  5. Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Notaridou, Maria; Quaye, Lydia; Dafou, Dimitra;

    2011-01-01

    Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines...

  6. 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.

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

    OpenAIRE

    Trubicka Joanna; Grabowska-Kłujszo Ewa; Suchy Janina; Masojć Bartłomiej; Serrano-Fernandez Pablo; Kurzawski Grzegorz; Cybulski Cezary; Górski Bohdan; Huzarski Tomasz; Byrski Tomasz; Gronwald Jacek; Złowocka Elżbieta; Kładny Józef; Banaszkiewicz Zbigniew; Wiśniowski Rafał

    2010-01-01

    Abstract Background 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. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be ...

  8. 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.......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....... 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...

  9. Toll-like receptors gene polymorphisms may confer increased susceptibility to breast cancer development.

    Science.gov (United States)

    Theodoropoulos, George E; Saridakis, Vasilios; Karantanos, Theodoros; Michalopoulos, Nikolaos V; Zagouri, Flora; Kontogianni, Panagiota; Lymperi, Maria; Gazouli, Maria; Zografos, George C

    2012-08-01

    Toll-like receptor (TLR) activation may be an important event in tumor cell immune evasion. TLR2 and TLR4 gene polymorphisms have been related to increased susceptibility to cancer development in various organs. 261 patients and 480 health individuals were investigated for genotype and allelic frequencies of a 22-bp nucleotide deletion (-196 to -174del) in the promoter of TLR2 gene as well as two polymorphisms causing amino acid substitutions (Asp299Gly and Thr399Ile) in TLR4 gene. As far as (-196 to -174del) in TLR2 gene is concerned ins/del and del/del genotypes and del allele were significantly more frequent in breast cancer patients compared to healthy controls. Considering Asp299Gly replacement of TLR4 gene, Gly carriers (Asp/Gly & Gly/Gly genotype) and Gly allele were overrepresented among the breast cancer cases. The -174 to -196del of TLR2 gene and Asp299Gly of TLR4 gene polymorphisms may confer an increased susceptibility to breast cancer development.

  10. Breast Cancer Susceptibility Genes in High Risk Women

    Science.gov (United States)

    2005-12-01

    232-7. 32. Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus [see comments]. Arthritis...duplicates do not have identical genotype and the cause for the discordancy ( systematic or isolated) will be determined. A second level of QC is provided...AM, Healey CS, Pharoah PD, Teare MD, Ponder BA, Easton DF. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiology

  11. Relationship between Polymorphism of Nicotinic Acetylcholine Receptor Gene CHRNA3 and Susceptibility of Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Shen Bo; Shi Meiqi; Mei Jinfeng; Hong Zhuan; Cao Guochun; Lu Jianwei; Feng Jifeng

    2013-01-01

    Objective:To investigate the relationship between polymorphism of nicotinic acetylcholine receptor gene CHRNA3 and susceptibility of lung cancer. Methods:Sixty hundred patients with lung cancer and 600 healthy people were respectively selected. TaqMan-MGB probe technique was applied to detect rs3743073 (T > G) genotypes at SNPs site on CHRNA3. The difference of genotype distribution among groups was compared, and its relationship with lung cancer was also investigated. Results:There was statistical signiifcance regarding the distributions of CHRNA3 rs3743073 (T>G) genotype and allele frequencies in patients with lung cancer and healthy people (P Conclusion:The risk of developing lung cancer in patients with rs3743073G mutant genotypes of CHRNA3 gene is increased markedly, especially in those more than 60 years old, males and smoking ones.

  12. 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.

  13. Transposon insertional mutagenesis in mice identifies human breast cancer susceptibility genes and signatures for stratification

    Science.gov (United States)

    Chen, Liming; Jenjaroenpun, Piroon; Pillai, Andrea Mun Ching; Ivshina, Anna V.; Ow, Ghim Siong; Efthimios, Motakis; Zhiqun, Tang; Lee, Song-Choon; Rogers, Keith; Ward, Jerrold M.; Mori, Seiichi; Adams, David J.; Jenkins, Nancy A.; Copeland, Neal G.; Ban, Kenneth Hon-Kim; Kuznetsov, Vladimir A.; Thiery, Jean Paul

    2017-01-01

    Robust prognostic gene signatures and therapeutic targets are difficult to derive from expression profiling because of the significant heterogeneity within breast cancer (BC) subtypes. Here, we performed forward genetic screening in mice using Sleeping Beauty transposon mutagenesis to identify candidate BC driver genes in an unbiased manner, using a stabilized N-terminal truncated β-catenin gene as a sensitizer. We identified 134 mouse susceptibility genes from 129 common insertion sites within 34 mammary tumors. Of these, 126 genes were orthologous to protein-coding genes in the human genome (hereafter, human BC susceptibility genes, hBCSGs), 70% of which are previously reported cancer-associated genes, and ∼16% are known BC suppressor genes. Network analysis revealed a gene hub consisting of E1A binding protein P300 (EP300), CD44 molecule (CD44), neurofibromin (NF1) and phosphatase and tensin homolog (PTEN), which are linked to a significant number of mutated hBCSGs. From our survival prediction analysis of the expression of human BC genes in 2,333 BC cases, we isolated a six-gene-pair classifier that stratifies BC patients with high confidence into prognostically distinct low-, moderate-, and high-risk subgroups. Furthermore, we proposed prognostic classifiers identifying three basal and three claudin-low tumor subgroups. Intriguingly, our hBCSGs are mostly unrelated to cell cycle/mitosis genes and are distinct from the prognostic signatures currently used for stratifying BC patients. Our findings illustrate the strength and validity of integrating functional mutagenesis screens in mice with human cancer transcriptomic data to identify highly prognostic BC subtyping biomarkers. PMID:28251929

  14. Association between CYP1B1 Gene Polymorphisms and Risk Factors and Susceptibility to Laryngeal Cancer

    OpenAIRE

    Yu, Peng-Ju; Chen, Wei-Guan; Feng, Quan-Lin; Chen, Wei; Jiang, Man-Jie; Li, Ze-Qing

    2015-01-01

    Background The aim of this study was to investigate the association between polymorphism of the cytochrome P450 1B1 (CYP1B1) gene, a metabolic enzyme gene, and the susceptibility to laryngeal cancer among the Chinese Han population. Material/Methods In a case-control study, we investigated polymorphisms in the CYP1B1 gene (rs10012, rs1056827, and rs1056836) with a real-time quantitative polymerase chain reaction (PCR) assay (TaqMan). The study was conducted with 300 Chinese Han patients with ...

  15. Inherited Susceptibility to Breast Cancer in Healthy Women: Mutation in Breast Cancer Genes, Immune Surveillance, and Psychological Distress

    Science.gov (United States)

    2005-10-01

    hypotheses were investigated: Hypothesis 1: Women with family histories of breast cancer are more emotionally distressed than women at normal risk... emotionally distressed than women at normal risk, particularly after notification that they carry a mutation in a primary susceptibility gene. o Healthy...Valdimarsdottir HB, Montgomery GH, Bovbjerg DH. Heightened cortisol responses to daily stress in working women at familial risk for breast cancer. Biological

  16. Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility.

    Science.gov (United States)

    Hosgood, H Dean; Cawthon, Richard; He, Xingzhou; Chanock, Stephen; Lan, Qing

    2009-11-01

    Telomeres are responsible for the protection of the chromosome ends and shortened telomere length has been associated with risk of multiple cancers. Genetic variation in telomere-related genes may alter cancer risk associated with telomere length. Using lung cancer cases (n=120) and population-based controls (n=110) from Xuanwei, China, we analyzed telomere length separately and in conjunction with single nucleotide polymorphisms in the telomere maintenance genes POT1, TERT, and TERF2, which we have previously reported were associated with risk of lung cancer in this study. POT1 rs10244817, TERT rs2075786, and TERF2 rs251796 were significantly associated with lung cancer (p(trend)telomere length was not significantly associated with risk of lung cancer (OR=1.58; 95% CI=0.79-3.18) when compared to the longest tertile of telomere length. When stratified by genotype, there was a suggestion of a dose-response relationship between tertiles of telomere length and risk of lung cancer among the POT1 rs10244817 common variant carriers (OR (95% CI)=1.33 (0.47-3.75), 3.30 (1.14-9.56), respectively) but not among variant genotype carriers (p(interaction)=0.05). Our findings provide evidence that telomere length and genetic variation in telomere maintenance genes may be associated with risk of lung cancer susceptibility and warrant replication in larger studies.

  17. Polymorphism of the DNA repair gene XPA and susceptibility to lung cancer

    Institute of Scientific and Technical Information of China (English)

    Jinfu Zhu; Zhibin Hu; Hongxia Ma; Xiang Huo; Lin Xu; Jiannong Zhou; Hongbing Shen; Yijiang Chen

    2005-01-01

    Objective: To study the relationship between one polymorphism in the promoter of the DNA repair gene XPA and the susceptibility to lung cancer. Methods: Genotypes were determined by the PCR-restriction fragment length polymorphism (PCR-RFLP)method in 310 histologically-confirmed lung cancer cases and 341 age and sex frequency-matched cancer-free controls. Results: The XPA A23G genotype frequencies were 27.1% (AA), 42.9% (AG), and 30.0% (GG) in case patients and 21.1% (AA), 52.8% (AG),and 26.1% (GG) in control subjects. Multivariate logistic regression analysis revealed that individuals carrying at least one 23G variant allele (AG + GG genotypes) had a significantly decreased risk for lung cancer (adjusted OR = 0.66; 95% CI = 0.44- 0.98) compared with the wild-type genotype (23AA). Stratified analysis showed that the protective effect was more evident in subjects with a family history of cancer. Conclusion: These results suggest that the XPA A23G polymorphism may have a role in lung cancer susceptibility in this study population.

  18. 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.

  19. XPG Gene Polymorphisms Contribute to Colorectal Cancer Susceptibility: A Two-Stage Case-Control Study

    Science.gov (United States)

    Hua, Rui-Xi; Zhuo, Zhen-Jian; Zhu, Jinhong; Zhang, Shao-Dan; Xue, Wen-Qiong; Zhang, Jiang-Bo; Xu, Hong-Mei; Li, Xi-Zhao; Zhang, Pei-Fen; He, Jing; Jia, Wei-Hua

    2016-01-01

    Previous studies have reported that xeroderma pigmentosum group G (XPG) gene polymorphisms may modulate colorectal cancer (CRC) susceptibility. In this study, we performed a two-stage case-control study to comprehensively investigate the associations of five polymorphisms in the XPG gene with CRC risk in 1,901 cases and 1,976 controls from Southern China, including rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601 G>A. After combining data from two stages, we found that three of the studied polymorphisms (rs2094258 C>T, rs751402 C>T, and rs873601 G>A) were significantly associated with CRC susceptibility. After adjustment for age and gender, multivariate logistic regression analysis indicated that carriers of the rs2094258 T alleles had an increased CRC risk [CT vs. CC: adjusted odds ratio (OR)=1.17, 95% confidence interval (CI)=1.01-1.36; TT vs. CC: adjusted OR=1.49, 95% CI=1.18-1.89; TT vs. CT/CC: adjusted OR=1.38, 95% CI=1.10-1.72]. Likely, rs873601 A allele also conferred increased CRC susceptibility. In contrast, a protective association was identified between rs751402 C>T polymorphism and the risk of CRC. In summary, our results indicated that these three polymorphisms were found to associate with CRC susceptibility in a Southern Chinese population.

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

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    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.

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

    Science.gov (United States)

    2010-01-01

    Background 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. Methods 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. Results 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. Conclusion 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. PMID:20701755

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

    Directory of Open Access Journals (Sweden)

    Trubicka Joanna

    2010-08-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion 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.

  3. Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript.

    Science.gov (United States)

    Kote-Jarai, Z; Amin Al Olama, A; Leongamornlert, D; Tymrakiewicz, M; Saunders, E; Guy, M; Giles, G G; Severi, G; Southey, M; Hopper, J L; Sit, K C; Harris, J M; Batra, J; Spurdle, A B; Clements, J A; Hamdy, F; Neal, D; Donovan, J; Muir, K; Pharoah, P D P; Chanock, S J; Brown, N; Benlloch, S; Castro, E; Mahmud, N; O'Brien, L; Hall, A; Sawyer, E; Wilkinson, R; Easton, D F; Eeles, R A

    2011-06-01

    Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.

  4. Mutations in BRCA1 and BRCA2 in breast cancer families: Are there more breast cancer-susceptibility genes?

    Energy Technology Data Exchange (ETDEWEB)

    Serova, O.M.; Mazoyer, S.; Putet, N. [CNRS, Lyon (France)] [and others

    1997-03-01

    To estimate the proportion of breast cancer families due to BRCA1 or BRCA2, we performed mutation screening of the entire coding regions of both genes supplemented with linkage analysis of 31 families, 8 containing male breast cancers and 23 site-specific female breast cancer. A combination of protein-truncation test and SSCP or heteroduplex analyses was used for mutation screening complemented, where possible, by the analysis of expression level of BRCA1 and BRCA2 alleles. Six of the eight families with male breast cancer revealed frameshift mutations, two in BRCA1 and four in BRCA2. Although most families with female site-specific breast cancers were thought to be due to mutations in either BRCA1 or BRCA2, we identified only eight mutations in our series of 23 site-specific female breast cancer families (34%), four in BRCA1 and four in BRCA2. According to the posterior probabilities calculated for mutation-negative families, based on linkage data and mutation screening results, we would expect 8-10 site-specific female breast cancer families of our series to be due to neither BRCA1 nor BRCA2. Thus, our results suggest the existence of at least one more major breast cancer-susceptibility gene. 24 refs., 1 fig., 3 tabs.

  5. 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.

  6. Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan

    Directory of Open Access Journals (Sweden)

    Ling-I Hsu

    2015-01-01

    Full Text Available Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1, reactive oxygen species (ROS related metabolic genes (NQO1, EPHX1, and HO-1, and DNA repair genes (XRCC1, XPD, hOGG1, and ATM together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR and 95% confidence interval (CI using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01–8.83; OR = 2.04, 95% CI = 0.99–4.27; OR = 1.74, 95% CI = 1.00–3.02, resp.. However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated.

  7. 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.

  8. 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.

  9. A Review of Whole-Exome Sequencing Efforts Toward Hereditary Breast Cancer Susceptibility Gene Discovery.

    Science.gov (United States)

    Chandler, Madison R; Bilgili, Erin P; Merner, Nancy D

    2016-09-01

    Inherited genetic risk factors contribute toward breast cancer (BC) onset. BC risk variants can be divided into three categories of penetrance (high, moderate, and low) that reflect the probability of developing the disease. Traditional BC susceptibility gene discovery approaches that searched for high- and moderate-risk variants in familial BC cases have had limited success; to date, these risk variants explain only ∼30% of familial BC cases. Next-generation sequencing technologies can be used to search for novel high and moderate BC risk variants, and this manuscript reviews 12 familial BC whole-exome sequencing efforts. Study design, filtering strategies, and segregation and validation analyses are discussed. Overall, only a modest number of novel BC risk genes were identified, and 90% and 97% of the exome-sequenced families and cases, respectively, had no BC risk variants reported. It is important to learn from these studies and consider alternate strategies in order to make further advances. The discovery of new BC susceptibility genes is critical for improved risk assessment and to provide insight toward disease mechanisms for the development of more effective therapies.

  10. Association between the APC gene D1822V variant and the genetic susceptibility of colorectal cancer.

    Science.gov (United States)

    Feng, Maohui; Fang, Xiping; Yang, Qian; Ouyang, Gang; Chen, Daping; Ma, Xiang; Li, Huachi; Xie, Wei

    2014-07-01

    Adenomatous polyposis coli (APC) gene polymorphisms are believed to contribute to tumor susceptibility. However, the association between genetic variants (A/T) in the APC gene D1822V polymorphism and colorectal cancer (CRC) susceptibility remains unknown. To determine this association, a case-control study was performed. The genotype of the APC gene D1822V variants was analyzed by DNA sequencing in blood samples collected from 196 patients with CRC and 279 healthy subjects. There were no significant associations between the case and control groups in the distribution of AT [odds ratio (OR), 0.604; 95% confidence interval (CI), 0.355-1.029) and TT genotypes (OR, 0.438; 95% CI, 0.045-4.247) relative to the AA genotype. The ratio of the T allele was significantly lower (P=0.047) in the case group compared with the control group (OR, 0.611; 95% CI, 0.374-0.997), indicating that the T allele conferred a protective effect in CRC. The frequency of the AT genotype among the subjects diagnosed at >45 years of age was lower than those diagnosed at a younger age (P<0.05). The present study demonstrates that the T allele of the D1822V polymorphism may exert a protective effect against CRC, however, these findings require further validation in a larger sample size.

  11. Increased radiosensitivity as an indicator of genes conferring breast cancer susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Varga, D.; Kreienberg, R.; Deissler, H.; Sauer, G. [Dept. of Gynecology and Obstetrics, Univ. of Ulm Medical School (Germany); Vogel, W.; Bender, A.; Surowy, H.; Maier, C. [Dept. of Genetics, Univ. of Ulm Medical School (Germany)

    2007-12-15

    Purpose: This paper briefly summarizes the research on increased radiosensitivity in breast cancer patients measured by the micronucleus test (MNT) and its association to genetic variants in DNA repair genes. More preliminary data are presented on the distribution of chromosomes and chromosome fragments in micronuclei (MN) in order to gain more information on clastogenic and aneugenic effects and better understand the phenotype of increased radiosensitivity. Material and Methods: Reports of relevant studies obtained from a search of PubMed and studies referenced in those reports were reviewed. In four patients with high MN frequency (three cancer patients, one control) and four probands with low MN frequency, the presence of chromosome fragments or whole chromosomes in MN was determined by fluorescence in situ hybridization analysis for chromosomes 1, 7, and 17. Results: An increased MN frequency in breast cancer patients compared to controls has consistently been reported with high significance. Higher MN frequencies were observed in 20-50% of breast cancer patients. Chromosomal fragments of chromosome 17, but not of chromosomes 1 and 7 were more frequent in the probands with high MN frequency than in those with low frequency (p = 0.045). Conclusion: The MNT detects a cellular phenotype common to a portion of sporadic breast cancer patients. This phenotype is very likely to be genetically determined. For the genetic dissection of breast cancer susceptibility this phenotype may turn out to be more efficient than breast cancer itself. Additional parameters which can be measured simultaneously with the MN frequency may be able to further enhance its usefulness. (orig.)

  12. 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.

  13. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Ngoc-Han Ha

    2016-09-01

    Full Text Available Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ and low metastatic (MOLF/EiJ mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL SNPs with disease-free survival, consistent with the mouse studies.

  14. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer

    Science.gov (United States)

    Ha, Ngoc-Han; Long, Jirong; Cai, Qiuyin; Shu, Xiao Ou

    2016-01-01

    Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies. PMID:27656887

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

    Directory of Open Access Journals (Sweden)

    Ling Bai

    2016-04-01

    Full Text Available 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.

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

    NARCIS (Netherlands)

    Lawrenson, K.; Li, Q.; Kar, S.; Seo, J.H.; Tyrer, J.; Spindler, T.J.; Lee, J. van der; Chen, Y; Karst, A.; Drapkin, R.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Baker, H.; Bandera, E.V.; Bean, Y.; Beckmann, M.W.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Bogdanova, N.; Brinton, L.A.; Brooks-Wilson, A.; Bruinsma, F.; Butzow, R.; Campbell, I.G.; Carty, K.; Chang-Claude, J.; Chenevix-Trench, G.; Chen, A; Chen, Z.; Cook, L.S.; Cramer, D.W; Cunningham, J.M.; Cybulski, C.; Dansonka-Mieszkowska, A.; Dennis, J.; Dicks, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Easton, D.T.; Edwards, R.P.; Eilber, U.; Ekici, A.B.; Fasching, P.A.; Fridley, B.L.; Gao, Y.T.; Gentry-Maharaj, A.; Giles, G.G.; Glasspool, R.; Goode, E.L.; Goodman, M.T.; Grownwald, J.; Harrington, P.; Harter, P.; Hasmad, H.N.; Hein, A.; Heitz, F.; Hildebrandt, M.A.; Hillemanns, P.; Hogdall, E.; Hogdall, C.; Hosono, S.; Iversen, E.S.; Jakubowska, A.; James, P.; Jensen, A.; Ji, B.T.; Karlan, B.Y.; Kjaer, S. Kruger; Kelemen, L.E.; Kellar, M.; Kelley, J.L.; Kiemeney, L.A.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, A.W.; Lele, S.; Leminen, A.; Lester, J.; Levine, D.A.; Liang, D.; Lissowska, J.; Lu, K.; Lubinski, J.; Lundvall, L.; Massuger, L.F.; Matsuo, K.; McGuire, V.; McLaughlin, J.R.; Nevanlinna, H.; McNeish, I.; Menon, U.; Modugno, F.

    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 associat

  17. 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.

  18. Association of XPC Gene Polymorphisms with Susceptibility to Prostate Cancer: Evidence from 3,936 Subjects

    Science.gov (United States)

    Zou, Yan-Feng; Tao, Jin-Hui; Ye, Qian-Ling; Pan, Hai-Feng; Pan, Fa-Ming; Su, Hong

    2013-01-01

    Aim: Polymorphisms of xeroderma pigmentosum complementation group C (XPC) are thought to have significant effects on prostate cancer (PCa) risk. The aim of our study was to evaluate the impact of XPC gene polymorphisms on PCa risk by using a meta-analysis. Methods: Data were collected from the following electronic databases: PubMed, EMBASE, Elsevier Science Direct, Cochrane Library, and CNKI, with the last report up to April 30, 2013. Odds ratios with 95% confidence intervals were used to assess the strength of the association. Results: A total of five separate case–control studies (1966 cases and 1970 controls) were included in this meta-analysis. Meta-analysis was performed for the rs2228001 and PAT+/−polymorphisms. We did not detect a significant association between rs2228001 polymorphism and PCa (p>0.05). Similar results were found in stratification analyses by ethnicity and tumor stage. We detected a significant association of PAT+/−polymorphism with PCa (p0.05). Conclusion: These analyses suggest that XPC gene PAT+/−polymorphism, but not rs2228001, likely contributes to susceptibility to PCa. PMID:24093803

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

    Directory of Open Access Journals (Sweden)

    Helal Ahmed N

    2010-06-01

    Full Text Available Abstract Background 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. Methods 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. Results 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

  20. Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array

    DEFF Research Database (Denmark)

    Saunders, Edward J; Dadaev, Tokhir; Leongamornlert, Daniel A

    2016-01-01

    BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants...... identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated...... Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using...

  1. Identification of Variants in Breast Cancer Susceptibility Genes and Determination of Functional and Clinical Significance of Novel Mutations

    Science.gov (United States)

    2014-10-01

    likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1) MSH2 (1), and MUTYH (double...included 26 study genes plus BRCA1 and BRCA2 and were: 1) high penetrance breast cancer susceptibility genes (CDH1, PTEN, STK11, TP53 ); 2) genes known...for management, namely TP53 (4), CDKN2A (1) MSH2 (1), and MUTYH (double heterozygote). Twenty- four patients (8.6%) had deleterious or likely

  2. 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.

  3. 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

  4. 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

    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 presence of the allelic variants of these two genes had no statistically significant effect on tumor differentiation, lymph node invasion or tumor size. CONCLUSIONS: These results suggest that allelic variants of XRCC1 and XRCC3 are not suitable markers for susceptibility to carcinomas of the oral cavity...

  5. 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

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

    Science.gov (United States)

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

    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

  7. Association study of nicotinic acetylcholine receptor genes identifies a novel lung cancer susceptibility locus near CHRNA1 in African-Americans

    OpenAIRE

    Walsh, Kyle M.; Christopher I Amos; Wenzlaff, Angela S.; Gorlov, Ivan P; Sison, Jennette D.; Wu, Xifeng; Spitz, Margaret R; Hansen, Helen M.; Lu, Emily Y.; Wei, Chongjuan; Zhang, Huifeng; Chen, Wei; Lloyd, Stacy M.; Frazier, Marsha L.; Paige M Bracci

    2012-01-01

    Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-America...

  8. 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...

  9. 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.

  10. Polymorphisms in the AR and PSA genes as markers of susceptibility and aggressiveness in prostate cancer

    DEFF Research Database (Denmark)

    Kuasne, Hellen; Rodrigues, Iara Sant'Ana; Fuganti, Paulo Emílio;

    2010-01-01

    The study of genes involved in androgen pathway can contribute to a better knowledge of prostate cancer. Our aim was to examine if polymorphisms in prostate-specific antigen (PSA) and androgen receptor (AR) genes were involved in prostate cancer risk and aggressiveness. Genotypes were determined...... by PCR-RFLP (PSA) or using a 377 ABI DNA Sequencer (AR). PSA(G/G) genotype (OR = 1.78, 95% CI = 1.06–2.99) and AR short CAG repeats (OR = 1.89, 95% CI = 1.21–2.96) increased risk for prostate cancer and were related with tumor aggressiveness. About 38.3% of tumors showed microsatellite instability....... In conclusion, polymorphisms in these genes may be indicated as potential biomarkers for prostate cancer....

  11. 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.

  12. Association of Matrix Metalloproteinase-9 and p53 Gene Polymorphisms with Genetic Susceptibility to No-small-cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    ZHAO Ying-hao; MA Tong-hui; ZHENG Yong-chen; ZHANG Kun; YANG Jing-bo; YANG Long-fei; YANG Zhi-guang; SHAO Guo-guang

    2011-01-01

    Matrix metalloproteinase-9(MMP-9) and p53 genes play an essential role in the multi-step process of tumorigenesis in lung cancer. Single nucleotide polymorphisms(SNPs) of MMP-9 and p53 genes are associated with the risk and progression of many cancers. In this study, we evaluated the association of the R279Q polymo rphism of MMP-9 or the A1/A2 polymorphism of p53 gene with the risk of no-small-cell lung cancer(NSCLC) in Hah population of Northeast China. We examined the frequency of SNPs in the two kinds of genes of 50 patients with NSCLC and 50 cancer-free controls frequency-matched by age and sex. Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) technique was used to determine the genotypes. The results indicate that the 279RR genotype in MMP-9 gene and the A1/A2 genotype in p53 gene show a significantly increased risk of NSCLC. Therefore,the MMP-9 279RR and p53 A1/A2 genotypes may be used as markers for susceptibility to NSCLC in Han population of Northeast China.

  13. The TLR4 gene polymorphisms and susceptibility to cancer: a systematic review and meta-analysis.

    Science.gov (United States)

    Zhang, Kui; Zhou, Bin; Wang, Yanyun; Rao, Li; Zhang, Lin

    2013-03-01

    Growing studies revealed the association between polymorphisms in Toll-like receptor 4 (TLR4) and susceptibility to cancer, however, the results remained inconsistent. To assess the effect of six selected SNPs (rs1927914, rs4986790, rs4986791, rs11536889, rs1927911 and rs2149356) in TLR4 on cancer, we conducted a meta-analysis, up to February 2012, 22 case-control studies were available. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR4 and cancer risk were estimated. Our meta-analysis identified that two SNPs (rs4986790 and rs4986791) in TLR4 were associated with increased cancer risk (for rs4986790: OR=1.24, 95% CI=1.01-1.52 in dominant model; OR=1.24, 95% CI=1.02-1.52 in overdominant model; for rs4986791: OR=1.81, 95% CI=1.18-2.77 in allele comparison; OR=1.79, 95% CI=1.15-2.80 in dominant model; OR=1.70, 95% CI=1.09-2.67 in overdominant model) and one SNP (rs1927911) in TLR4 was associated with decreased cancer risk (for rs1927911: OR=0.63, 95% CI=0.41-0.99 in allele comparison; OR=0.57, 95% CI=0.35-0.95 in dominant model; OR=0.67, 95% CI=0.46-0.97 in codominant model). Moreover, in terms of stratified analyses by cancer type for SNP rs4986790, significantly elevated risk was observed to be associated with G allele in gastric cancer and 'other cancers'. These findings indicate that polymorphisms in TLR4 may play a role, although modest, in cancer development.

  14. 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...... 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 adhesion...

  15. Polymorphisms of GSTM1 and CYP1A1 genes and their genetic susceptibility to prostate cancer in Chinese men

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Background Variation in prostate cancer incidence between different racial groups has been well documented,for which genetic polymorphisms are hypothesized to be an explanation.We evaluated the association between polymorphisms in the cytochrome P-450 CYP1A1(CYP1A1)and glutathione S-transferase M1(GSTM1)genes and genetic susceptibility to prostate cancer in Chinese men.Methods Two hundred and eight prostate cancer patients and 230 age matched controls were enrolled in this study.All DNA samples from peripheral blood lymphocytes were genotyped for common genetic polymorphisms of the CYP1A1 and GSTM1 genes using the oligonucleotide microarray(DNA chip)technique and the polymorphism results confirmed by sequencing.The different polymorphisms in prostate cancer patients were also analyzed according to age at diagnosis,prostate specific antigen level,cancer stage and grade(Gleason score).Results The prevalence of the GSTM1(0/0)genotype was significantly higher in prostate cancer patients(58.2%)than in controls(41.7%,P<0.05).Further analysis demonstrated that the prostate cancer patients with a GSTM1(0/0)genotype were younger than those with the GSTM1(+/+)genotype(P=0.024).No significant differences in the frequency distributions of CYP1A1 polymorphisms were observed between prostate cancer patients and controls.Conclusion GSTM1(0/0)gene polymorphism may be linked to prostate cancer risk and early age of onset in Chinese.

  16. Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

    NARCIS (Netherlands)

    Litchfield, Kevin; Levy, Max; Dudakia, Darshna; Proszek, Paula; Shipley, Claire; Basten, Sander; Rapley, Elizabeth; Bishop, D Timothy; Reid, Alison; Huddart, Robert; Broderick, Peter; Castro, David Gonzalez de; O'Connor, Simon; Giles, Rachel H; Houlston, Richard S; Turnbull, Clare

    2016-01-01

    Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare

  17. Contribution of DNA double-strand break repair gene XRCC3 genotypes to oral cancer susceptibility in Taiwan.

    Science.gov (United States)

    Tsai, Chia-Wen; Chang, Wen-Shin; Liu, Juhn-Cherng; Tsai, Ming-Hsui; Lin, Cheng-Chieh; Bau, Da-Tian

    2014-06-01

    The DNA repair gene X-ray repair cross complementing protein 3 (XRCC3) is thought to play a major role in double-strand break repair and in maintaining genomic stability. Very possibly, defective double-strand break repair of cells can lead to carcinogenesis. Therefore, a case-control study was performed to reveal the contribution of XRCC3 genotypes to individual oral cancer susceptibility. In this hospital-based research, the association of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotypes with oral cancer risk in a Taiwanese population was investigated. In total, 788 patients with oral cancer and 956 age- and gender-matched healthy controls were genotyped. The results showed that there was significant differential distribution among oral cancer and controls in the genotypic (p=0.001428) and allelic (p=0.0013) frequencies of XRCC3 rs861539. As for the other polymorphisms, there was no difference between case and control groups. In gene-lifestyle interaction analysis, we have provided the first evidence showing that there is an obvious joint effect of XRCC3 rs861539 genotype with individual areca chewing habits on oral cancer risk. In conclusion, the T allele of XRCC3 rs861539, which has an interaction with areca chewing habit in oral carcinogenesis, may be an early marker for oral cancer in Taiwanese.

  18. Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility.

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    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

  19. Lys751Gln polymorphism in ERCC2 gene is associated with lung cancer susceptibility in the Chinese population

    Institute of Scientific and Technical Information of China (English)

    Liang Geyu; Pu Yuepu; Yin Lihong

    2007-01-01

    The excision repair cross-complementing group 2 (ERCC2) gene encodes a DNA repair protein, which is absolutely necessary in nucleotide excision repair. A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity. Therefore, we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymorphism in the development of lung cancer in the Chinese population. The genotype of ERCC2 gene was analyzed by di-allele-specific-amplification with artificially modified primers (diASA-AMP) in 200 original lung cancer cases and 200 controls. The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype. Furthermore,the mutant genotype of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung adenocarcinoma. However, no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study. The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for susceptibility of lung cancer in the Chinese population.

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

    Directory of Open Access Journals (Sweden)

    Sharon E Johnatty

    2010-07-01

    Full Text Available 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 involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC. In the discovery stage, cases with epithelial ovarian cancer (n=675 and controls (n=1,162 were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5. However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03. Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24 p=0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus.

  1. 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.

  2. 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.

  3. Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis

    Science.gov (United States)

    Closa, Adria; Cordero, David; Sanz-Pamplona, Rebeca; Solé, Xavier; Crous-Bou, Marta; Paré-Brunet, Laia; Berenguer, Antoni; Guino, Elisabet; Lopez-Doriga, Adriana; Guardiola, Jordi; Biondo, Sebastiano; Salazar, Ramon; Moreno, Victor

    2014-01-01

    In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein–protein interaction networks. PMID:24760461

  4. Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

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    Sinilnikova Olga

    2011-05-01

    Full Text Available Abstract Background The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods We implemented an assay based on high-resolution melting (HRM curve analysis and developed an analysis tool for DAE assessment. Results We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.

  5. DNA repair gene XRCC3 241Met variant and breast cancer susceptibility of Azeri population in Iranian

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    Gohari-Lasaki Sahar

    2015-01-01

    Full Text Available DNA-repair systems are essential for repairing damage that occurs when there is recombination between homologous chromosomes. The gene XRCC3 (X-ray cross complementing group 3 encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. The Thr241Met XRCC3-18067C>T, rs861539 substitution, a C to T transition at codon 241 in exon7, thus plays critical roles in cancer development. The aim of this study was association between XRCC3 Thr241Met polymorphism and risk of sporadic breast cancer in Azari population. We analysed DNA samples from 100 sporadic breast cancer patients and 100 healthy women, for XRCC3 Thr241Met polymorphism using PCR-RFLP. Genotype specific risks were tested using chi-test with 95% confident intervals. Frequency of Thr/Thr at codon 241was 69% in controls and 70% in patients, Thr/Met frequency was 22% in controls and 13 % in patients, the Met/Met genotype was 9% incontrols and 17% in patients. No correlation between the genotype and allele distribution and increased susceptibility for breast Cancer. Our results suggested that in pre-menopausal women, breast cancer riskis not significantly associated with rs861539 in Azari population.

  6. Locating a Prostate Cancer Susceptibility Gene on the X Chromosome by Linkage Disequilibrium Mapping Using Three Founder Populations in Quebec and Switzerland

    Science.gov (United States)

    2006-09-01

    Non-medullary thyroid cancer: attempts to locate susceptibility genes by linkage in two Canadian families with goitre and non-medullary thyroid...Ashkenazi Jewish population Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas. March 12, 1998 Title: Familial multinodular goitre ...Appliqués du FRSQ Montreal, Quebec October 24, 1997 Title: A gene for familial multinodular goitre maps to chromosome 14q Annual Congress of the

  7. 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 amo...

  8. 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...

  9. 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.

  10. Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case-control analysis

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    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

  11. IL6 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review.

    Science.gov (United States)

    Yu, Yong; Wang, Wenjun; Zhai, Song; Dang, Shuangsuo; Sun, Mingzhu

    2012-08-01

    A number of case-control studies were conducted to investigate the association of IL6 gene polymorphisms with colorectal cancer (CRC). However, the results were not always consistent. We performed a systematic review and meta-analysis to examine the association between the IL6 gene polymorphisms and CRC. Data were collected from the following electronic databases: PubMed, EMBASE, Web of Science, BIOSIS Previews, HuGENet, and Chinese Biomedical Literature Database, with the last report up to July 2011. A total of 17 studies involving 4 SNPs were included (16 for rs1800795, 2 for rs1800796, 2 for rs1800797, and 1 for rs13306435). Overall, no significant association of these polymorphisms with CRC was found in heterozygote comparisons as well as homozygote comparison, dominant genetic model and recessive model. In subgroup analysis, among studies using population-based controls, fulfilling Hardy-Weinberg equilibrium, or using Taqman genotyping method, we did not find any significant association. However, the rs1800795 C allele was significantly associated with reduced risk for CRC among persons who regularly or currently took NSAIDs (four studies, OR = 0.750; 95 % CI, 0.64-0.88; P = 0.474 for heterogeneity test), and with increased risk for CRC among persons who drank (one study, OR = 1.97; 95 % CI, 1.32-2.94). Individuals with the rs1800795 C allele in the IL6 gene have a significantly lower risk of CRC, but in the setting of NSAIDs use. Further studies are merited to assess the association between the IL6 gene polymorphisms and CRC risk among persons who take NSAIDs, drink or smoke, etc.

  12. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility.

    Science.gov (United States)

    Kumar, Pradeep; Yadav, Upendra; Rai, Vandana

    2015-12-01

    There are several evidences supporting the role of 5-10 methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in breast cancer (BC). Case control association studies on breast cancer have been repeatedly performed over the last two decades, but results are inconsistent. We performed a meta-analysis to confirm the association between MTHFR C677T polymorphism and BC risk. The articles were retrieved by searching the PubMed, Google Scholar, and Springer Link databases. Crude odds ratios (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between C677T polymorphism and BC. Publication bias was assessed by Egger's and Begg-Mazumdar tests. Meta-analysis was performed with Open Meta Analyst. Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03-1.13, p = < 0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02-1.09, p = < 0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06-1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01-1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03-1.22, p = 0.005). In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06-1.51; p = 0.009) in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99-1.14; p = 0.05).

  13. 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; Silva, Isabel dos Santos; 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; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; 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 environmental risk factors.

  14. Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families.

    Science.gov (United States)

    Guénard, Frédéric; Labrie, Yvan; Ouellette, Geneviève; Beauparlant, Charles Joly; Bessette, Paul; Chiquette, Jocelyne; Laframboise, Rachel; Lépine, Jean; Lespérance, Bernard; Pichette, Roxane; Plante, Marie; Durocher, Francine

    2007-01-01

    Cowden syndrome is a disease associated with an increase in breast cancer susceptibility. Alleles in PTEN and other breast cancer susceptibility genes would be responsible for approximately 25% of the familial component of breast cancer risk, BRCA1 and BRCA2 being the two major genes responsible for this inherited risk. In order to evaluate the proportion of high-risk French Canadian non-BRCA1/BRCA2 breast/ovarian cancer families potentially harboring a PTEN germline mutation, the whole coding and flanking intronic sequences were analyzed in a series of 98 breast cancer cases. Although no germline mutation has been identified in the coding region, our study led to the identification of four intronic variants. Further investigations were performed to analyze the effect of these variants, alone and/or in combination, on splicing and PTEN protein levels. Despite suggestive evidence emerging from in silico analyses, the presence of these intronic variants do not seem to alter RNA splicing or PTEN protein levels. In addition, as loss of PTEN or part of it has been reported, Western blot analysis has also been performed. No major deletion could be identified in our cohort. Therefore, assuming a Poisson distribution for the frequency of deleterious mutation in our cohort, if the frequency of such deleterious mutation was 2%, we would have had a 90% or greater chance of observing at least one such mutation. These results suggest that PTEN germline mutations are rare and are unlikely to account for a significant proportion of familial breast cancer cases in the French Canadian population.

  15. 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...

  16. 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...

  17. 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...

  18. Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County

    Directory of Open Access Journals (Sweden)

    Yang Fang

    2011-06-01

    Full Text Available Abstract Background The purpose of this study was to evaluate the association of multi-genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC and the possibility of predicting those at higher risk. Methods A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH, 262 patients with esophageal squamous cell dysplasia (ESCD, 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants. Results The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG of the two combined genotypes was 1.83 (95%CI: 1.55-2.16, indicating a strong genetic association with the risk of carcinogenic progression in the esophagus. Conclusions The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk.

  19. The hOGG1 Ser326Cys gene polymorphism and susceptibility for bladder cancer: a meta-analysis

    Science.gov (United States)

    Wenjuan, Cao; Jianzhong, Lu; Chong, Li; Yanjun, Gao; Keqing, Lu; Hanzhang, Wang; Zhiping, Wang

    2016-01-01

    ABSTRACT Objective: To assess the susceptibility of the hOGG1 genetic polymorphism for bladder cancer and evaluate the impact of smoking exposure. Materials and Methods: Articles included in PubMed, Medline and Springer databases were retrieved using the following key words: “human 8-oxoguanine DNA glycosylase”, “OGG”, “OGG1”, “hOGG1”, “genetic variation”, “polymorphism” , “bladder cancer”, and “bladder carcinoma” to Meta-analysis was performed to detect whether there were differences between the bladder cancer group and the control group about the distribution of genotypes of the hOGG1 gene. Results: The results showed that there are no significant associations between the hOGG1 326Cys polymorphism and bladder cancer: GG vs. CC (OR: 1.09, 95% CI: 0.85–1.40, p=0.480); GC vs. CC (OR: 1.05, 95% CI: 0.85–1.28, p=0.662); GG+GC vs. CC (OR: 1.04, 95% CI: 0.89–1.21, p=0.619); GG vs. GC+CC(OR: 1.02, 95% CI: 0.78–1.33, p=0.888); G vs. C (OR: 1.01, 95% CI: 0.91–1.13, p=0.818). In the smoker population, no significant associations between the hOGG1 326Cys polymorphism and bladder cancer were observed for all the models. However, individuals carrying the hOGG1 Cys326Cys genotype have increased risk for bladder cancer compared to those carrying the hOGG1 Ser326Ser genotype in the non-smoker Asian population. Conclusion: The hOGG1 326Cys polymorphisms aren't a risk factor for bladder cancer, especially in the smoker population. But GG genotype is a risk factor for bladder cancer to the non-smoker Asian population compared with CC genotype. PMID:27583352

  20. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  1. 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.

  2. The Nuclear Death Domain Protein p84N5; A Candidate Breast Cancer Susceptibility Gene

    Science.gov (United States)

    2007-05-01

    maintained in RPMI supplemented with 10% FBS and 0.2 unit/mL of pork insulin. SKBP-3 cells were maintained in McCoy’s 5a medium supplemented with 15... Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long term

  3. 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

  4. '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.

  5. Locus-Specific Databases and Recommendations to Strengthen Their Contribution to the Classification of Variants in Cancer Susceptibility Genes

    NARCIS (Netherlands)

    Greenblatt, Marc S.; Brody, Lawrence C.; Foulkes, William D.; Genuardi, Maurizio; Hofstra, Robert M. W.; Olivier, Magali; Plon, Sharon E.; Sijmons, Rolf H.; Sinilnikova, Olga; Spurdle, Amanda B.

    2008-01-01

    Locus-specific databases (LSDBs) are curated collections of sequence variants in genes associated with disease. LSDBs of cancer-related genes often serve as a critical resource to researchers, diagnostic laboratories, clinicians, and others in the cancer genetics community. LSDBs are poised to play

  6. Genetic association between the cyclin-dependent kinase inhibitor gene p27/Kip1 polymorphism (rs34330) and cancer susceptibility: a meta-analysis

    Science.gov (United States)

    Cheng, Xiao-Ke; Wang, Xue-Jun; Li, Xiao-Dong; Ren, Xue-Qun

    2017-01-01

    The p27 rs34330 (-79C/T) polymorphism has been widely studied for human cancer susceptibility. The current findings, however, still remained controversial. Therefore, we performed the meta-analysis to provide a more accurate result. Eligible studies were identified from PubMed database up to June 2015. The association of p27 rs34330 polymorphism and cancer susceptibility was estimated with odds ratios and corresponding 95% confidence intervals. The meta-analysis was performed with Stata 12. A total of ten studies with 11,214 cases and more than 8,776 controls were included in the meta-analysis (including breast, lung, thyroid, endometrial, and hepatocellular cancer). In pooled analysis, p27 gene rs34330 polymorphism significantly increased the cancer susceptibility. Subgroup analysis indicated that the elevated risk was observed under all the genetic models for Asians and under three genetic models for Caucasians. Results of sensitivity analysis were similar to the overall results. The results suggested that the p27 rs34330 polymorphism increased the cancer susceptibility, especially in Asians. Further well-designed and large sample size studies are warranted to verify the conclusion. PMID:28317869

  7. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

    NARCIS (Netherlands)

    Rafnar, T.; Vermeulen, H.H.M.; Sulem, P.; Thorleifsson, G.; Aben, K.K.H.; Witjes, J.A.; Grotenhuis, A.J.; Verhaegh, G.W.C.T.; Hulsbergen- van de Kaa, C.A.; Besenbacher, S.; Gudbjartsson, D.; Stacey, S.N.; Gudmundsson, J.; Johannsdottir, H.; Bjarnason, H.; Zanon, C.; Helgadottir, H.; Jonasson, J.G.; Tryggvadottir, L.; Jonsson, E.; Geirsson, G.; Nikulasson, S.; Petursdottir, V.; Bishop, D.T.; Chung-Sak, S.; Choudhury, A.; Elliott, F.; Barrett, J.H.; Knowles, M.A.; Verdier, P. de; Ryk, C.; Lindblom, A.; Rudnai, P.; Gurzau, E.; Koppova, K.; Vineis, P.; Polidoro, S.; Guarrera, S.; Sacerdote, C.; Panadero, A.; Sanz-Velez, J.I.; Sanchez, M.; Valdivia, G.; Garcia-Prats, M.D.; Hengstler, J.G.; Selinski, S.; Gerullis, H.; Ovsiannikov, D.; Khezri, A.; Aminsharifi, A.; Malekzadeh, M.; Berg, L.H. van den; Ophoff, R.A.; Veldink, J.H.; Zeegers, M.P.; Kellen, E.; Fostinelli, J.; Andreoli, D.; Arici, C.; Porru, S.; Buntinx, F.; Ghaderi, A.; Golka, K.; Mayordomo, J.I.; Matullo, G.; Kumar, R.; Steineck, G.; Kiltie, A.E.; Kong, A.; Thorsteinsdottir, U.; Stefansson, K.; Kiemeney, L.A.L.M.

    2011-01-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European G

  8. European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene.

    Science.gov (United States)

    Rafnar, Thorunn; Vermeulen, Sita H; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K; Witjes, J Alfred; Grotenhuis, Anne J; Verhaegh, Gerald W; Hulsbergen-van de Kaa, Christina A; Besenbacher, Soren; Gudbjartsson, Daniel; Stacey, Simon N; Gudmundsson, Julius; Johannsdottir, Hrefna; Bjarnason, Hjordis; Zanon, Carlo; Helgadottir, Hafdis; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Jonsson, Eirikur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Bishop, D Timothy; Chung-Sak, Sei; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H; Knowles, Margaret A; de Verdier, Petra J; Ryk, Charlotta; Lindblom, Annika; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Panadero, Angeles; Sanz-Velez, José I; Sanchez, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D; Hengstler, Jan G; Selinski, Silvia; Gerullis, Holger; Ovsiannikov, Daniel; Khezri, Abdolaziz; Aminsharifi, Alireza; Malekzadeh, Mahyar; van den Berg, Leonard H; Ophoff, Roel A; Veldink, Jan H; Zeegers, Maurice P; Kellen, Eliane; Fostinelli, Jacopo; Andreoli, Daniele; Arici, Cecilia; Porru, Stefano; Buntinx, Frank; Ghaderi, Abbas; Golka, Klaus; Mayordomo, José I; Matullo, Giuseppe; Kumar, Rajiv; Steineck, Gunnar; Kiltie, Anne E; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; Kiemeney, Lambertus A

    2011-11-01

    Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.

  9. Identification of Ovarian Cancer Susceptibility Genes Involved in Stromal-Epithelial Interactions

    Science.gov (United States)

    2009-02-01

    Mayo Clinic (Ellen Goode)) by Mass Array for 22 SNPs in CSF1, DDR2 , FN1, ITGA6, ITGAV, LCN2, MMP26, MMP3, MMP7, PANX1, PLOD2, PODXL, PTEN, PTTG1,TERT...Ovarian Cancer Association Consortium, as well as a further 19 SNPs in PTTG1, CSF1, PLOD2, FGF2, TIMP3, DDR2 , FN1, MMP7, PANX1, PTEN, ITGAV and LCN2

  10. A functional polymorphism in the NKG2D gene modulates NK-cell cytotoxicity and is associated with susceptibility to Human Papilloma Virus-related cancers.

    Science.gov (United States)

    Espinoza, J Luis; Nguyen, Viet H; Ichimura, Hiroshi; Pham, Trang T T; Nguyen, Cuong H; Pham, Thuc V; Elbadry, Mahmoud I; Yoshioka, Katsuji; Tanaka, Junji; Trung, Ly Q; Takami, Akiyoshi; Nakao, Shinji

    2016-12-20

    Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and is etiologically linked to several cancers, including cervical and genital cancers. NKG2D, an activating receptor expressed by NK cells, plays an important role in cancer immune-surveillance. We analyzed the impact of a NKG2D gene variant, rs1049174, on the incidence of HPV-related cancers in Vietnamese patients and utilized various molecular approaches to elucidate the mechanisms of NKG2D receptor regulation by rs1049174. In a group of 123 patients with HPV+ anogenital cancers, the low cytotoxicity allele LNK was significantly associated with increased cancer susceptibility (p = 0.016). Similar results were also observed in a group of 153 women with cervical cancer (p = 0.05). In functional studies, NK cells from individuals with LNK genotype showed a lower NKG2D expression and displayed less efficient NKG2D-mediated functions than NK cells with HNK genotype. Notably, the rs1049174 variant occurs within a targeting site for miR-1245, a negative regulator of NKG2D expression. Compared with the higher cytotoxicity allele HNK, the LNK allele was more efficiently targeted by miR-1245 and thus determined lower NKG2D expression in NK cells with the LNK genotype. The NKG2D variants may influence cancer immunosurveillance and thus determine susceptibility to various malignancies, including HPV-induced cancers.

  11. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.

    Directory of Open Access Journals (Sweden)

    Ella R Thompson

    2012-09-01

    Full Text Available Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.

  12. Roles of Breast Cancer Susceptibility Genes BRCA’s in Mammary Epithelial Cell Differentiation

    Science.gov (United States)

    2006-03-01

    associated factor 3 - 3.0 IFNAR1 AA133989 interferon (alpha, beta and omega) receptor 1 -3.1 PDXK AW449022 pyridoxal ( pyridoxine , vitamin B6...IFNAR1 AA133989 Interferon (, , and ) receptor 1 3.1 PDXK AW449022 Pyridoxal ( pyridoxine , vitamin B6) kinase 4.0 HTATIP2 BC002439 HIV-1 Tat...evaluate the risk of breast cancer. N Engl J Med 336, 1409-1415. 26 Cullmann, G., Fien, K., Kobayashi, R., and Stillman, B. (1995). Characterization

  13. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

    Science.gov (United States)

    Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes

    2009-09-01

    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

  14. Methylenetetrahydrofolate reductase gene C677T polymorphism and breast cancer risk: Evidence for genetic susceptibility

    Directory of Open Access Journals (Sweden)

    Pradeep Kumar

    2015-12-01

    Total 75 studies with 31,315 cases and 35, 608 controls were found suitable for the inclusion in the present meta-analysis. The results of meta-analysis suggested that there were moderate significant association between C677T polymorphism and BC risk using overall comparisons in five genetic models (T vs. C: OR = 1.08, 95% CI = 1.03–1.13, p = <0.001; TT + CT vs. CC: OR = 1.06, 95% CI = 1.02–1.09, p = <0.001; TT vs. CC: OR = 1.17, 95% CI = 1.06–1.28, p = 0.001; CT vs. CC OR = 1.05, 95% CI = 1.01–1.08, p = 0.005; TT vs. CT + CC: OR = 1.12, 95% CI = 1.03–1.22, p = 0.005. In conclusion, results of present meta-analysis showed modest association between MTHFR C677T polymorphism with breast cancer in total studies. However, sub-group analysis results based on ethnicity showed strong significant association between TT genotype and breast cancer (TT vs. CC; OR°=°1.26; 95% CI: 1.06–1.51; p = 0.009 in Asian population but in Caucasian population such association was not observed (TT vs. CC; OR°=°1.08; 95% CI: 0.99–1.14; p = 0.05.

  15. Association of MTOR and AKT Gene Polymorphisms with Susceptibility and Survival of Gastric Cancer.

    Directory of Open Access Journals (Sweden)

    Ying Piao

    Full Text Available The phosphoinositide 3-kinase (PI3K/protein kinase B (PKB, AKT/mammalian target of rapamycin (mTOR signaling pathway plays a critical role in angiogenesis and cell growth, proliferation, metabolism, migration, differentiation, and apoptosis. Genetic diversity in key factors of this pathway may influence protein function and signal transduction, contributing to disease initiation and progression. Studies suggest that MTOR rs1064261 and AKT rs1130233 polymorphisms are associated with risk and/or prognosis of multiple cancer types. However, this relationship with gastric cancer (GC remains unclear. The aim of this study was to investigate the role of MTOR and AKT polymorphisms in the risk and prognosis of GC.The Sequenom MassARRAY platform was used to genotype 1842 individuals for MTOR rs1064261 T→C and AKT rs1130233 G→A polymorphisms. ELISA was used to detect Helicobacter pylori antibodies in serum. Immunohistochemical analysis was used to detect total and phosphorylated MTOR and AKT proteins.The MTOR rs1064261 (TC+CC genotype and the AKT rs1130233 (GA+AA genotype were associated with increased risk of GC in men (P = 0.049, P = 0.030. In H. pylori-negative individuals, the AKT rs1130233 GA and (GA+AA genotypes were related to increased risk of atrophic gastritis (AG; P = 0.012, P = 0.024. Notably, the AKT rs1130233 (GA+AA genotype demonstrated significant interactions with H. pylori in disease progression from healthy controls (CON to AG (P = 0.013 and from AG to GC (P = 0.049. Additionally, for individuals with the AKT rs1130233 variant, those in the H. pylori-positive group had higher levels of phosphorylated AKT (p-AKT expression. The AKT rs1130233 genotype was found to be associated with clinicopathological parameters including lymph node metastasis and alcohol drinking (P<0.05.MTOR rs1064261and AKT rs1130233 polymorphisms were associated with increased GC risk in males and increased AG risk in H. pylori-negative individuals. A significant

  16. Metabolic polymorphisms and cancer susceptibility.

    Science.gov (United States)

    Smith, G; Stanley, L A; Sim, E; Strange, R C; Wolf, C R

    1995-01-01

    The vast majority of cancers arise as a consequence of exposure to environmental agents that are toxic or mutagenic. In response to this, all higher organisms have evolved complex mechanisms by which they can protect themselves from environmental challenge. In many cases, this involves an adaptive response in which the levels of expression of enzymes active in the metabolism and detoxification of the foreign chemical are induced. The best characterized of these enzyme systems are the cytochrome P450s, the GSTs and the NATs. An unfortunate consequence of many of these reactions, however, is the creation of a toxic or mutagenic reaction product from chemicals that require metabolic activation before realizing their full carcinogenic potential. Altered expression of one or more of these drug metabolizing enzymes can therefore be predicted to have profound toxicological consequences. Genetic polymorphisms with well defined associated phenotypes have now been characterized in P450, GST and NAT genes. Indeed, many of these polymorphisms have been associated with decreased or increased metabolism of many tumour promoters and chemical carcinogens and hence offer protection against or increased susceptibility to many distinct tumour types.

  17. Polymorphisms in stromal genes and susceptibility to serous epithelial ovarian cancer: a report from the Ovarian Cancer Association Consortium.

    Directory of Open Access Journals (Sweden)

    Ernest K Amankwah

    Full Text Available 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 homogeneous (P(heterogeneity≥0.13 and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P(trend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P(heterogeneity≤0.03, which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P(interaction≤0.003, age at diagnosis (P(interaction = 0.04, and year of diagnosis (P(interaction = 0.05 in the five studies with available information (1,044 cases, 2,469 controls. We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.

  18. Association of CYP1B1 gene polymorphisms with susceptibility to endometrial cancer: a meta-analysis.

    Science.gov (United States)

    Wang, Fang; Zou, Yan-Feng; Sun, Guo-Ping; Su, Hong; Huang, Fen

    2011-03-01

    The objective of this meta-analysis was to quantitatively summarize the association of CYP1B1 gene polymorphisms and endometrial cancer risk. Data were collected from the following electronic databases: PubMed,Elsevier Science Direct, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure and Wanfang, with the last report up to June 2010. Meta-analysis was conducted in a fixed/random effect model. Out of the 715 papers retrieved 12 studies (3605 cases and 5692 controls) on the association of CYP1B1 gene polymorphisms with endometrial cancer risk in different ethnic groups were identified. Meta-analysis was performed for CYP1B1 gene polymorphisms: R48G (C/G, five studies), L432V (C/G, 12 studies), N453S (A/G, four studies), and A119S (G/T, five studies). We did not detect any association of CYP1B1 gene A119S polymorphism with endometrial cancer. An association of CYP1B1 gene R48G polymorphism with endometrial cancer was found [GG vs. GC+CC: odds ratio (OR)=0.55, 95% confidence interval (CI): 0.42-0.73, PCYP1B1 gene L432V polymorphism was associated with a significantly increased risk of endometrial cancer (G vs. C: OR=1.23, 95% CI: 1.06-1.43, P=0.007; GC+GG vs. CC:OR=1.24, 95% CI: 1.08-1.43, P=0.003; GC vs. CC: OR=1.16, 95% CI: 1.04-1.29, P=0.009). Moreover, we detected the association of CYP1B1 gene N453S polymorphism with endometrial cancer (G vs. A: OR=0.82,95% CI: 0.72-0.94, P=0.005; GA vs. AA: OR=0.81, 95% CI: 0.69-0.95, P=0.01). In conclusion, this meta-analysis provides strong evidence that CYP1B1 gene R48G, L432V, and N453S polymorphisms are associated with endometrial cancer risk, but not A119S.

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

    Science.gov (United States)

    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; Hartge, Patricia; Hoover, Robert N.; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P.; LaCroix, Andrea; Mandelson, Margaret T.; Petersen, Gloria; Zheng, Wei; Agalliu, Ilir; Albanes, Demetrius; Boutron-Ruault, Marie-Christine; Bracci, Paige M.; Buring, Julie E.; Canzian, Federico; Chang, Kenneth; Chanock, Stephen J.; Cotterchio, Michelle; Gaziano, J.Michael; Giovannucci, Edward L.; Goggins, Michael; Hallmans, Göran; Hankinson, Susan E.; Hoffman Bolton, Judith A.; Hunter, David J.; Hutchinson, Amy; Jacobs, Kevin B.; Jenab, Mazda; Khaw, Kay-Tee; Kraft, Peter; Krogh, Vittorio; Kurtz, Robert C.; McWilliams, Robert R.; Mendelsohn, Julie B.; Patel, Alpa V.; Rabe, Kari G.; Riboli, Elio; Shu, Xiao-Ou; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Virtamo, Jarmo; Visvanathan, Kala; Watters, Joanne; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Stolzenberg-Solomon, Rachael Z.

    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 cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer. PMID:22523087

  20. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

    Science.gov (United States)

    Kabisch, Maria; Lorenzo Bermejo, Justo; Dünnebier, Thomas; Ying, Shibo; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Shah, Mitul; Perkins, Barbara J.; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Lambrechts, Diether; Neven, Patrick; Peeters, Stephanie; Weltens, Caroline; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Purrington, Kristen; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; dos-Santos-Silva, Isabel; Johnson, Nichola; Fletcher, Olivia; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten; Hogervorst, Frans B.L.; Li, Jingmei; Brand, Judith S.; Humphreys, Keith; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Burwinkel, Barbara; Marmé, Frederik; Yang, Rongxi; Bugert, Peter; González-Neira, Anna; Benitez, Javier; Pilar Zamora, M.; Arias Perez, Jose I.; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Le Marchand, Loic; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J.; Hollestelle, Antoinette; Kriege, Mieke; Koppert, Linetta B.; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Slettedahl, Seth; Toland, Amanda E.; Vachon, Celine; Yannoukakos, Drakoulis; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J.; Swerdlow, Anthony; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Brüning, Thomas; Ko, Yon-Dschun; Radice, Paolo; Peterlongo, Paolo; Scuvera, Giulietta; Fortuzzi, Stefano; Bogdanova, Natalia; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Zheng, Wei; Shrubsole, Martha J.; Cai, Qiuyin; Torres, Diana; Anton-Culver, Hoda; Kristensen, Vessela; Bacot, François; Tessier, Daniel C.; Vincent, Daniel; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel; Simard, Jacques; Chenevix-Trench, Georgia; Hall, Per; Pharoah, Paul D.P.; Dunning, Alison M.; Easton, Douglas F.; Hamann, Ute

    2015-01-01

    The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. PMID:25586992

  1. A Regulatory Polymorphism at Position -309 in PTPRCAP Is Associated with Susceptibility to Diffuse-type Gastric Cancer and Gene Expression

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    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.

  2. ENVIRONMENTAL FACTORS AFFECTING BREAST CANCER SUSCEPTIBILITY

    Science.gov (United States)

    Environmental Factors Affecting Breast Cancer SusceptibilitySuzanne. E. FentonUS EPA, ORD, MD-67 NHEERL, Reproductive Toxicology Division, Research Triangle Park, NC 27711.Breast cancer is still the most common malignancy afflicting women in the Western world. Alt...

  3. 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

  4. Susceptibility genes in movement disorders.

    Science.gov (United States)

    Scholz, Sonja; Singleton, Andrew

    2008-05-15

    During the last years, remarkable progress in our understanding of molecular genetic mechanisms underlying movement disorders has been achieved. The successes of linkage studies, followed by positional cloning, have dominated the last decade and several genes underlying monogenic disorders have been discovered. The pathobiological understanding garnered from these mutations has laid the foundation for much of the search for genetic loci that confer risk for, rather than cause, disease. With the introduction of whole genome association studies as a novel tool to investigate genetic variation underlying common, complex diseases, a new era in neurogenomics has just begun. As the field rapidly moves forward several new challenges and critical questions in clinical care have to be addressed. In this review, we summarize recent advances in the discovery of susceptibility loci underlying major movement disorders, explain the newest methodologies and tools employed for finding and characterizing genes and discuss how insights into the molecular genetic basis of neurological disorders will impact therapeutic concepts in patient care.

  5. An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

    Science.gov (United States)

    Rudolph, Anja; Milne, Roger L.; Truong, Thérèse; Knight, Julia A.; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Munday, Hannah R.; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S.; Olson, Janet; Vachon, Celine M.; Hallberg, Emily; Castelao, J. Esteban; Carracedo, Angel; Torres, Maria; Li, Jingmei; Humphreys, Keith; Cordina-Duverger, Emilie; Menegaux, Florence; Flyger, Henrik; Nordestgaard, Børge G.; Nielsen, Sune F.; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Engelhardt, Ellen G.; Broeks, Annegien; Rutgers, Emiel J.; Glendon, Gord; Mulligan, Anna Marie; Cross, Simon; Reed, Malcolm; Gonzalez-Neira, Anna; Perez, José Ignacio Arias; Provenzano, Elena; Apicella, Carmel; Southey, Melissa C.; Spurdle, Amanda; Investigators, kConFab; Group, AOCS; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; McLean, Catriona; Baglietto, Laura; Chanock, Stephen J.; Lissowska, Jolanta; Sherman, Mark E.; Brüning, Thomas; Hamann, Ute; Ko, Yon-Dschun; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Mannermaa, Arto; Swerdlow, Anthony; Giles, Graham G.; Brenner, Hermann; Fasching, Peter A.; Chenevix-Trench, Georgia; Hopper, John; Benítez, Javier; Cox, Angela; Andrulis, Irene L.; Lambrechts, Diether; Gago-Dominguez, Manuela; Couch, Fergus; Czene, Kamila; Bojesen, Stig E.; Easton, Doug F.; Schmidt, Marjanka K.; Guénel, Pascal; Hall, Per; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Chang-Claude, Jenny

    2014-01-01

    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 estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4). In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. PMID:25227710

  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.

  7. The Role of MicroRNAs in Cancer Susceptibility

    Directory of Open Access Journals (Sweden)

    Rodolfo Iuliano

    2013-01-01

    Full Text Available Single nucleotide polymorphisms (SNPs are germline variations interspersed in the human genome. These subtle changes of DNA sequence can influence the susceptibility to various pathologies including cancer. The functional meaning of SNPs is not always clear, being, the majority of them, localized in noncoding regions. The discovery of microRNAs, tiny noncoding RNAs able to bind the 3′ untranslated region (UTR of target genes and to consequently downregulate their expression, has provided a functional explanation of how some SNPs positioned in noncoding regions contribute to cancer susceptibility. In this paper we summarize the current knowledge of the effect on cancer susceptibility of SNPs included in regions related with miRNA-dependent pathways. Hereditary cancer comes up from mutations that occur in high-penetrant predisposing tumor genes. However, a considerable part of inherited cancers arises from multiple low-penetrant predisposing gene variants that influence the behavior of cancer insurgence. Despite the established significance of such polymorphic variants in cancer predisposition, sometimes their functional role remains unknown. The discovery of a new group of genes called microRNAs (miRNAs opened an avenue for the functional interpretation of polymorphisms involved in cancer predisposition.

  8. Positional mapping and candidate gene analysis of the mouse Ccs3 locus that regulates differential susceptibility to carcinogen-induced colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Charles Meunier

    Full Text Available The Ccs3 locus on mouse chromosome 3 regulates differential susceptibility of A/J (A, susceptible and C57BL/6J (B6, resistant mouse strains to chemically-induced colorectal cancer (CRC. Here, we report the high-resolution positional mapping of the gene underlying the Ccs3 effect. Using phenotype/genotype correlation in a series of 33 AcB/BcA recombinant congenic mouse strains, as well as in groups of backcross populations bearing unique recombinant chromosomes for the interval, and in subcongenic strains, we have delineated the maximum size of the Ccs3 physical interval to a ∼2.15 Mb segment. This interval contains 12 annotated transcripts. Sequencing of positional candidates in A and B6 identified many either low-priority coding changes or non-protein coding variants. We found a unique copy number variant (CNV in intron 15 of the Nfkb1 gene. The CNV consists of two copies of a 54 bp sequence immediately adjacent to the exon 15 splice site, while only one copy is found in CRC-susceptible A. The Nfkb1 protein (p105/p50 expression is much reduced in A tumors compared to normal A colonic epithelium as analyzed by immunohistochemistry. Studies in primary macrophages from A and B6 mice demonstrate a marked differential activation of the NfκB pathway by lipopolysaccharide (kinetics of stimulation and maximum levels of phosphorylated IκBα, with a more robust activation being associated with resistance to CRC. NfκB has been previously implicated in regulating homeostasis and inflammatory response in the intestinal mucosa. The interval contains another positional candidate Slc39a8 that is differentially expressed in A vs B6 colons, and that has recently been associated in CRC tumor aggressiveness in humans.

  9. 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

    the 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...

  10. Glutathione S-transferase P1, gene-gene interaction, and lung cancer susceptibility in the Chinese population: An updated meta-analysis and review

    Directory of Open Access Journals (Sweden)

    Xue-Ming Li

    2015-01-01

    Full Text Available Aim of Study: To assess the impact of glutathione S-transferase P1 (GSTP1 Ile105Val polymorphism on the risk of lung cancer in the Chinese population, an updated meta-analysis and review was performed. Materials and Methods: Relevant studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine published through January 22, 2015. The odds ratios (ORs and 95% confidence intervals (CIs were calculated to estimate the strength of the associations. Results: A total of 13 case-control studies, including 2026 lung cancer cases and 2451 controls, were included in this meta-analysis. Overall, significantly increased lung cancer risk was associated with the variant genotypes of GSTP1 polymorphism in the Chinese population (GG vs. AA: OR = 1.36, 95% CI = 1.01-1.84. In subgroup analyses stratified by geographic area and source of controls, the significant results were found in population-based studies (GG vs. AA: OR = 1.62, 95% CI: 1.13-2.31; GG vs. AG: OR = 1.49, 95% CI: 1.03-2.16; GG vs. AA + AG: OR = 1.55, 95% CI: 1.12-2.26. A gene-gene interaction analysis showed that there was an interaction for individuals with combination of GSTM1 (or GSTT1 null genotype and GSTP1 (AG + GG mutant genotype for lung cancer risk in Chinese. Conclusion: This meta-analysis suggests that GSTP1 Ile105Val polymorphism may increase the risk of lung cancer in the Chinese population.

  11. Characterization of TRZ1, a yeast homolog of the human candidate prostate cancer susceptibility gene ELAC2 encoding tRNase Z

    Directory of Open Access Journals (Sweden)

    Chen Yuan

    2005-05-01

    Full Text Available Abstract Background In humans, mutation of ELAC2 is associated with an increased risk of prostate cancer. ELAC2 has been shown to have tRNase Z activity and is associated with the γ-tubulin complex. Results In this work, we show that the yeast homolog of ELAC2, encoded by TRZ1 (tRNase Z 1, is involved genetically in RNA processing. The temperature sensitivity of a trz1 mutant can be rescued by multiple copies of REX2, which encodes a protein with RNA 3' processing activity, suggesting a role of Trz1p in RNA processing in vivo. Trz1p has two putative nucleotide triphosphate-binding motifs (P-loop and a conserved histidine motif. The histidine motif and the putative nucleotide binding motif at the C-domain are important for Trz1p function because mutant proteins bearing changes to the critical residues in these motifs are unable to rescue deletion of TRZ1. The growth defect exhibited by trz1 yeast is not complemented by the heterologous ELAC2, suggesting that Trz1p may have additional functions in yeast. Conclusion Our results provide genetic evidence that prostate cancer susceptibility gene ELAC2 may be involved in RNA processing, especially rRNA processing and mitochondrial function.

  12. Identification of genetic polymorphisms in DNA repair xenoderma pigmentosum group D gene and its association with head and neck cancer susceptibility in rural Indian population: a hospital based case-control study from south-western Maharashtra, India

    Directory of Open Access Journals (Sweden)

    Kailas D. Datkhile

    2016-06-01

    Conclusions: This study indicates that polymorphisms in cd199 of XPD gene could play a role in modifying genetic susceptibility of individual to head and neck cancer in Maharashtra patients. Thus, the case-control study suggest that selected DNA repair genes represent genetic determinants in oral carcinogenesis along with other risk factors in the rural Indian population. [Int J Res Med Sci 2016; 4(6.000: 1997-2005

  13. An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

    OpenAIRE

    Rudolph, Anja; Milne, Roger L; Truong, Thérèse; Knight, Julia A; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Alison M Dunning; Shah, Mitul; Munday, Hannah R.; Darabi, Hatef

    2014-01-01

    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 estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC.

  14. Introduction to cancer genetic susceptibility syndromes.

    Science.gov (United States)

    McGee, Rose B; Nichols, Kim E

    2016-12-02

    The last 30 years have witnessed tremendous advances in our understanding of the cancer genetic susceptibility syndromes, including those that predispose to hematopoietic malignancies. The identification and characterization of families affected by these syndromes is enhancing our knowledge of the oncologic and nononcologic manifestations associated with predisposing germ line mutations and providing insights into the underlying disease mechanisms. Here, we provide an overview of the cancer genetic susceptibility syndromes, focusing on aspects relevant to the evaluation of patients with leukemia and lymphoma. Guidance is provided to facilitate recognition of these syndromes by hematologists/oncologists, including descriptions of the family history features, tumor genotype, and physical or developmental findings that should raise concern for an underlying cancer genetic syndrome. The clinical implications and management challenges associated with cancer susceptibility syndromes are also discussed.

  15. 29. LACK OF ASSOCIATION OF AH RECEPTOR GENE POLYMORPHISM WITH SUSCEPTIBILITY TO BLADDER CANCER IN SHANGHAI POPULATION

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@The diversity in genetic background largely predetermine the individual susceptibility towards health risk related to xenobiotic exposure. The receptors of signal transduction mechanism are involved in the modulation of toxicological outcome of xenobiotics. The survey of distribution of different polymorphic forms of Ah receptor in Chinese population and probing into their possible association with health risk related with xenobiotic exposure will not only contribute to a better understanding of mechanism of imperilment, but also inspire a clue for a further

  16. Subtle variations in Pten dose determine cancer susceptibility.

    Science.gov (United States)

    Alimonti, Andrea; Carracedo, Arkaitz; Clohessy, John G; Trotman, Lloyd C; Nardella, Caterina; Egia, Ainara; Salmena, Leonardo; Sampieri, Katia; Haveman, William J; Brogi, Edi; Richardson, Andrea L; Zhang, Jiangwen; Pandolfi, Pier Paolo

    2010-05-01

    Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes. Here we analyze Pten hypermorphic mice (Pten(hy/+)), expressing 80% normal levels of Pten. Pten(hy/+) mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

  17. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

    DEFF Research Database (Denmark)

    Shen, Hui; Fridley, Brooke L; Song, Honglin

    2013-01-01

    HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we ...

  18. Association of single nucleotide polymorphisms in CYP1B1 and COMT genes with breast cancer susceptibility in Indian women.

    Science.gov (United States)

    Yadav, Sharawan; Singhal, Naveen Kumar; Singh, Virendra; Rastogi, Neeraj; Srivastava, Pramod Kumar; Singh, Mahendra Pratap

    2009-01-01

    Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu(432)Val and/or COMT Val(158)Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val(158)Val) in combination with CYP1B1 heterozygous variant (Leu(432)Val) [OR: 0.21; 95% CI (0.05-0.82), p value; 0.021] and COMT heterozygous variant (Val(158)Met) in combination with CYP1B1 wild type (Leu(432)Leu) [OR: 0.29; 95% CI (0.08-0.96), p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.

  19. Association of Single Nucleotide Polymorphisms in CYP1B1 and COMT Genes with Breast Cancer Susceptibility in Indian Women

    Directory of Open Access Journals (Sweden)

    Sharawan Yadav

    2009-01-01

    Full Text Available Cytochrome P450 1B1 (CYP1B1 and catechol-$O$-methyltransferase (COMT enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu to valine (Val at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met at codon 158 decreases the catalytic activity of COMT. The present study was performed to evaluate the associations of CYP1B1 Leu432Val and/or COMT Val158Met polymorphisms with total, premenopausal and postmenopausal breast cancer risks in Indian women. COMT and CYP1B1 polymorphisms in controls and breast cancer patients were analyzed employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP followed by gel electrophoresis. Although CYP1B1 and COMT genotypes did not exhibit statistically significant association with breast cancer risks when analyzed individually, COMT wild type (Val158Val in combination with CYP1B1 heterozygous variant (Leu432Val [OR: 0.21; 95% CI (0.05–0.82, p value; 0.021] and COMT heterozygous variant (Val158Met in combination with CYP1B1 wild type (Leu432Leu [OR: 0.29; 95% CI (0.08–0.96, p value; 0.042] showed significant protective association with premenopausal breast cancer risk. The results demonstrate that CYP1B1 wild type in combination with COMT heterozygous or their inverse combination offer protection against breast cancer in premenopausal Indian women.

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

    Science.gov (United States)

    Rudolph, Anja; Milne, Roger L; Truong, Thérèse; Knight, Julia A; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dunning, Alison M; Shah, Mitul; Munday, Hannah R; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S; Olson, Janet; Vachon, Celine M; Hallberg, Emily; Castelao, J Esteban; Carracedo, Angel; Torres, Maria; Li, Jingmei; Humphreys, Keith; Cordina-Duverger, Emilie; Menegaux, Florence; Flyger, Henrik; Nordestgaard, Børge G; Nielsen, Sune F; Yesilyurt, Betul T; Floris, Giuseppe; Leunen, Karin; Engelhardt, Ellen G; Broeks, Annegien; Rutgers, Emiel J; Glendon, Gord; Mulligan, Anna Marie; Cross, Simon; Reed, Malcolm; Gonzalez-Neira, Anna; Arias Perez, José Ignacio; Provenzano, Elena; Apicella, Carmel; Southey, Melissa C; Spurdle, Amanda; Häberle, Lothar; Beckmann, Matthias W; Ekici, Arif B; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; McLean, Catriona; Baglietto, Laura; Chanock, Stephen J; Lissowska, Jolanta; Sherman, Mark E; Brüning, Thomas; Hamann, Ute; Ko, Yon-Dschun; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M; Mannermaa, Arto; Swerdlow, Anthony; Giles, Graham G; Brenner, Hermann; Fasching, Peter A; Chenevix-Trench, Georgia; Hopper, John; Benítez, Javier; Cox, Angela; Andrulis, Irene L; Lambrechts, Diether; Gago-Dominguez, Manuela; Couch, Fergus; Czene, Kamila; Bojesen, Stig E; Easton, Doug F; Schmidt, Marjanka K; Guénel, Pascal; Hall, Per; Pharoah, Paul D P; Garcia-Closas, Montserrat; Chang-Claude, Jenny

    2015-03-15

    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 estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) factors and the observed potential interactions require confirmation in independent studies.

  1. Novel susceptibility genes in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Colin Noble; Elaine Nimmo; Daniel Gaya; Richard K Russell; Jack Satsangi

    2006-01-01

    The inflammatory bowel disease, Crohn's disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling,are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.

  2. 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

    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...

  3. Association of Single Nucleotide Polymorphisms in CYP1B1 and COMT Genes with Breast Cancer Susceptibility in Indian Women

    OpenAIRE

    Sharawan Yadav; Naveen Kumar Singhal; Virendra Singh; Neeraj Rastogi; Pramod Kumar Srivastava; Mahendra Pratap Singh

    2009-01-01

    Cytochrome P450 1B1 (CYP1B1) and catechol-$O$-methyltransferase (COMT) enzymes play critical roles in estrogen metabolism. Alterations in the catalytic activity of CYP1B1 and COMT enzymes have been found associated with altered breast cancer risk in postmenopausal women in many populations. The substitution of leucine (Leu) to valine (Val) at codon 432 increases the catalytic activity of CYP1B1, however, substitution of Val to methionine (Met) at codon 158 decreases the catalytic activity of ...

  4. Polygenic susceptibility to testicular cancer

    DEFF Research Database (Denmark)

    Litchfield, Kevin; Mitchell, Jonathan S; Shipley, Janet

    2015-01-01

    BACKGROUND: The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic...... known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme. RESULTS: The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having...

  5. Association of Polymorphism rs198977 in Human Kallikrein-2 Gene (KLK2 with Susceptibility of Prostate Cancer: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Lishan Wang

    Full Text Available To assess the association of polymorphism rs198977 in the human kallikrein-2 gene (KLK2 and risk of prostate cancer (PCa.Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI. Pooled odds ratios (ORs and 95% confidence intervals (95% CIs for rs198977 and PCa were calculated in a fixed-effects model (the Mantel-Haenszel method and a random-effects model (the DerSimonian and Laird method when appropriate.Six studies met the inclusion criteria in this meta-analysis, which included 5859 PCa cases and 4867 controls. Overall, rs198977 was associated with the PCa risk (TT+CT vs. CC, pooled OR = 1.163, 95% CI = 1.076-1.258, P-value <0.0001. When stratified by ethnicity, significant association was observed in Caucasian samples under both allele comparison (T vs. C, pooled OR = 1.152, 95% CI = 1.079-1.229, P-value <0.0001 and dominant model (TT+CT vs. CC, pooled OR = 1.197, 95% CI = 1.104-1.297, P-value <0.0001. In the overall analysis, a comparably significant increase in the frequency of allele T for rs198977 was detected between cases and controls in Caucasian.This meta-analysis suggests that rs198977 of KLK2 was associated with susceptibility of PCa in Caucasian and the allele T might increase the risk of PCa in Caucasian.

  6. 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;

    2010-01-01

    with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds...

  7. Inhibition of constitutively activated phosphoinositide 3-kinase/AKT pathway enhances antitumor activity of chemotherapeutic agents in breast cancer susceptibility gene 1-defective breast cancer cells.

    Science.gov (United States)

    Yi, Yong Weon; Kang, Hyo Jin; Kim, Hee Jeong; Hwang, Jae Seok; Wang, Antai; Bae, Insoo

    2013-09-01

    Loss or decrease of wild type BRCA1 function, by either mutation or reduced expression, has a role in hereditary and sporadic human breast and ovarian cancers. We report here that the PI3K/AKT pathway is constitutively active in BRCA1-defective human breast cancer cells. Levels of phospho-AKT are sustained even after serum starvation in breast cancer cells carrying deleterious BRCA1 mutations. Knockdown of BRCA1 in MCF7 cells increases the amount of phospho-AKT and sensitizes cells to small molecule protein kinase inhibitors (PKIs) targeting the PI3K/AKT pathway. Restoration of wild type BRCA1 inhibits the activated PI3K/AKT pathway and de-sensitizes cells to PKIs targeting this pathway in BRCA1 mutant breast cancer cells, regardless of PTEN mutations. In addition, clinical PI3K/mTOR inhibitors, PI-103, and BEZ235, showed anti-proliferative effects on BRCA1 mutant breast cancer cell lines and synergism in combination with chemotherapeutic drugs, cisplatin, doxorubicin, topotecan, and gemcitabine. BEZ235 synergizes with the anti-proliferative effects of gemcitabine by enhancing caspase-3/7 activity. Our results suggest that the PI3K/AKT pathway can be an important signaling pathway for the survival of BRCA1-defective breast cancer cells and pharmacological inhibition of this pathway is a plausible treatment for a subset of breast cancers.

  8. Pathways: Strategies for Susceptibility Genes in SLE

    Science.gov (United States)

    Kelley, James M.; Edberg, Jeffrey C.; Kimberly, Robert P.

    2010-01-01

    Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by an inappropriate immune response to nuclear antigens. Recent whole genome association and more focused studies have revealed numerous genes implicated in this disease process, including ITGAM, Fc gamma receptors, complement components, C-reactive protein, and others. One common feature of these molecules is their involvement in the immune opsonins pathway and phagocytic clearing of nuclear antigens and apoptotic debris which provide excessive exposure of lupus-related antigens to immune cells. Analysis of gene-gene interactions in the opsonin pathway and its relationship to SLE may provide a systems-based approach to identify additional candidate genes associated with disease able to account for a larger part of lupus susceptibility. PMID:20144911

  9. Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer.

    Directory of Open Access Journals (Sweden)

    Jae Jeong Yang

    Full Text Available OBJECTIVES: To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2 are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS: In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone were measured using the time-resolved fluoroimmunoassay. RESULTS: SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively. Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05. CONCLUSIONS: Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.

  10. 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; Ramaiah, M Janaki; 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 (400 μg/day) and B12 (6 μg/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.

  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;

    2010-01-01

    SNPs-PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616-were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-alleleor=0.5). However genotypes at TERT rs7726159 were associated...... with ovarian cancer risk in the smaller, five-study replication study (Pper-allele=0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04-1.24) p=0.003]. Our study adds...

  12. Subtle variations in Pten dose determine cancer susceptibility

    Science.gov (United States)

    Alimonti, Andrea; Carracedo, Arkaitz; Clohessy, John G; Trotman, Lloyd C; Nardella, Caterina; Egia, Ainara; Salmena, Leonardo; Sampieri, Katia; Haveman, William J; Brogi, Edi; Richardson, Andrea L; Zhang, Jiangwen; Pandolfi, Pier Paolo

    2010-01-01

    Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG)1. It has been hypothesized that subtle variations in TSG expression can promote cancer development2,3. However, this hypothesis has not yet been definitively supported in vivo. PTEN is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes4. Here, we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosis. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner. PMID:20400965

  13. Association of 677 C>T (rs1801133 and 1298 A>C (rs1801131 polymorphisms in the MTHFR gene and breast cancer susceptibility: a meta-analysis based on 57 individual studies.

    Directory of Open Access Journals (Sweden)

    Kai Li

    Full Text Available OBJECTIVE: The 677 C>T and 1298 A>C polymorphisms of methylenetetrahydrofolate reductase (MTHFR gene have been widely reported and considered to have a significant effect on breast cancer risk, but the results are inconsistent. A meta-analysis based on 57 eligible studies was carried out to clarify the role of MTHFR gene polymorphisms in breast cancer. METHODS AND RESULTS: Eligible articles were identified by searching databases including PubMed, Web of Science, EMBASE, CNKI and CBM for the period up to August 2012. Finally, a total of 57 studies were included in this meta-analysis. Crude ORs with 95% CIs were used to assess the association between the MTHFR polymorphisms and breast cancer risk. The pooled ORs were performed with additive model, dominant model and recessive model, respectively. Subgroup analysis was also performed by ethnicity. The statistical heterogeneity across studies was examined with χ2-based Q-test. A meta-analysis was performed using the Stata 12.0 software. Overall, the 677 C allele was significantly associated with breast cancer risk (OR = 0.942, 95%CI = 0.898 to 0.988 when compared with the 677 T allele in the additive model, and the same results were also revealed under other genetic models. Simultaneously, the 1298 A allele was not associated with the breast cancer susceptibility when compared with the 1298 C allele (OR = 0.993, 95%CI = 0.978 to 1.009. Furthermore, analyses under the dominant, recessive and the allele contrast model yielded similar results. CONCLUSIONS: The results of this meta-analysis suggest that 677 C>T polymorphism in the MTHFR gene may contribute to breast cancer development. However, the 1298 A>C polymorphism is not significantly associated with increased risks of breast cancer.

  14. Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Hatagima Ana

    2002-01-01

    Full Text Available Epidemiological studies have estimated that approximately 80% of all cancers are related to environmental factors. Individual cancer susceptibility can be the result of several host factors, including differences in metabolism, DNA repair, altered expression of tumor suppressor genes and proto-oncogenes, and nutritional status. Xenobiotic metabolism is the principal mechanism for maintaining homeostasis during the body's exposure to xenobiotics. The balance of xenobiotic absorption and elimination rates in metabolism can be important in the prevention of DNA damage by chemical carcinogens. Thus the ability to metabolize and eliminate xenobiotics can be considered one of the body's first protective mechanisms. Variability in individual metabolism has been related to the enzymatic polymorphisms involved in activation and detoxification of chemical carcinogens. This paper is a contemporary literature review on genetic polymorphisms involved in the metabolism of endocrine disruptors potentially related to cancer development.

  15. Genetic polymorphisms and metabolism of endocrine disruptors in cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Ana Hatagima

    2002-04-01

    Full Text Available Epidemiological studies have estimated that approximately 80% of all cancers are related to environmental factors. Individual cancer susceptibility can be the result of several host factors, including differences in metabolism, DNA repair, altered expression of tumor suppressor genes and proto-oncogenes, and nutritional status. Xenobiotic metabolism is the principal mechanism for maintaining homeostasis during the body's exposure to xenobiotics. The balance of xenobiotic absorption and elimination rates in metabolism can be important in the prevention of DNA damage by chemical carcinogens. Thus the ability to metabolize and eliminate xenobiotics can be considered one of the body's first protective mechanisms. Variability in individual metabolism has been related to the enzymatic polymorphisms involved in activation and detoxification of chemical carcinogens. This paper is a contemporary literature review on genetic polymorphisms involved in the metabolism of endocrine disruptors potentially related to cancer development.

  16. A Functional Variant at the miR-214 Binding Site in the Methylenetetrahydrofolatereductase Gene Alters Susceptibility to Gastric Cancer in a Chinese Han Population

    Directory of Open Access Journals (Sweden)

    Qiaoyun Chen

    2015-05-01

    Full Text Available Background and Aims: Single nucleotide polymorphisms in miRNA binding sites, which are located in mRNA 3' untranslated regions (3'-UTRs, were recently found to influence microRNA-target interactions. Specifically, such polymorphisms can modulatebinding affinity or create or destroy miRNA-binding sites; such variants have also been found to be associated with cancer risk. In this study, we explored the effect of a functional variant at the miR-214 binding site in the methylenetetrahydrofolate reductase gene (rs114673809 on gastric cancer (GC risk in a hospital-based case-control study in a Chinese Han population. Methods and Results: We genotyped the rs114673809 polymorphism in 345 gastric cancer patients and 376 cancer-free controls using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP technique. The functions of rs114673809 were investigated using a luciferase activity assay and validated by immunoblotting. We found that participants carrying the rs114673809 AA genotype or A allele had a significantly increased risk of gastric cancer (OR = 1.667, 95% CI = 1.044-2.660, P = 0.034; OR = 1.261, 95% CI = 1.017-1.563, P = 0.037, respectively compared to those carrying the GG genotype and G allele. In addition, rs114673809 modified the binding of hsa-miR-214 to MTHFR as well as MTHFR protein levels in gastric cancer patients. Conclusion: Our data suggested that rs114673809, which is located at the miR-214 binding site in the 3'-UTR of MTHFR, may play an important role in the development of gastric cancer in a Chinese Han population.

  17. Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer susceptibility%雌激素合成及代谢基因的多态性与乳腺癌易感性

    Institute of Scientific and Technical Information of China (English)

    姜永冬; 刘晶; 庞达

    2009-01-01

    Estrogens,the major risk factors for breast cancer,are speculated to affect breast cancer risk through estrogens receptor(ER), thus, genetic polymorphisms of the genes involved in the estrogens biosynthesis and metabolism are expected as the main risk factors for breast cancer. Polymorphisms of the genes involved in estrogens biosynthesis (CYP11A1, CYP17, CYP19) and metabolism (CYP1A1, CYP1B1, CYP1A2) in modulating the susceptibility of breast cancer is important.%雌激素是乳腺癌的主要危险因素,推测是通过雌激素受体影响乳腺癌的发病风险.因此,与雌激素合成和代谢相关的基因多态性被认为是乳腺癌的主要危险因子.与雌激素合成基因(CYP11A1、CYP17、CYP19)和代谢基因(CYP1A1、CYP1B1、CYP1A2)相关的基因多态性在调节乳腺癌易感性中具有一定意义.

  18. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Tyrer, Jonathan

    2009-01-01

    Epithelial ovarian cancer has a major heritable component, but the known susceptibility genes explain less than half the excess familial risk. We performed a genome-wide association study (GWAS) to identify common ovarian cancer susceptibility alleles. We evaluated 507,094 SNPs genotyped in 1,817...

  19. 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...

  20. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

    Directory of Open Access Journals (Sweden)

    Anne M L Jansen

    Full Text Available Lynch Syndrome (LS is caused by pathogenic germline variants in one of the mismatch repair (MMR genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG. Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29% cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32% with one pathogenic somatic variant (n = 8 or one VUS predicted to be pathogenic (n = 1.This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%. In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  1. Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer.

    Science.gov (United States)

    Mondal, Pinaki; Datta, Sayantan; Maiti, Guru Prasad; Baral, Aradhita; Jha, Ganga Nath; Panda, Chinmay Kumar; Chowdhury, Shantanu; Ghosh, Saurabh; Roy, Bidyut; Roychoudhury, Susanta

    2013-01-01

    Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E-05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia.

  2. Gene Therapy of Cancerous Diseases

    OpenAIRE

    Valenčáková, A.; Dziaková, A.; Hatalová, E.

    2015-01-01

    Gene therapy of cancerous diseases provides new means of curing patients with oncologic illnesses. There are several approaches in treating cancer by gene therapy. Most commonly used methods are: cancer immunogene therapy, suicide gene therapy, application of tumor-suppressor genes, antiangiogenic therapy, mesenchymal stem cells used as vectors, gene directed enzyme/prodrug therapy and bacteria used as anti-cancer agents. Cancer gene immunotherapy uses several immunologic agents for the purp...

  3. 前列腺癌易感基因及遗传流行病学研究进展%Research progress of susceptible genes and genetic epidemiology of prostate cancer

    Institute of Scientific and Technical Information of China (English)

    吴琪俊; 徐剑锋; 施榕

    2011-01-01

    遗传学研究证实遗传因素在前列腺癌的发展过程中具有一定的作用.同时,一些病例对照研究与基于人群的队列研究也提示前列腺癌具有复杂的遗传流行病学的特征.文章分析了流行病学暴露因素及易感基因与前列腺癌的关系,并就国内外前列腺癌遗传流行病学方面的研究现状以及今后研究的发展方向作一综述.%Many genetic researches have suggested that genetic factor plays an important role in the development of prostate cancer.Meanwhile, some case-control studies and population-based cohort studies have also revealed the complex genetic epidemiology characters of prostate cancer.This paper not only analyses the relationship between epidemic exposure factors,susceptible genes and prostate cancer, but also points out the present status of genetic epidemiology of prostate cancer and the prospects of research in this aspect.

  4. Mapping and localization of susceptible genes in asthma

    Institute of Scientific and Technical Information of China (English)

    GU Ming-liang; ZHAO Jing

    2011-01-01

    Objective To elucidate the development of mapping and localization of susceptible genes on chromosomes to asthma related phenotypes.Data sources Published articles about susceptibility genes for asthma related phenotypes were selected using PubMed.Study selection Using methods of candidate gene positional clone and genome-wide scan with linkage and association analysis to determine the location in the genome of susceptibility genes to asthma and asthma related phenotypes.Results There are multiple regions in the genome harboring susceptibility genes to asthma and asthma relatedphenotypes, including chromosomes 5, 11, 12, 6, 2, 3, 13, 7, 14, 9, 19 and 17. Many of these regions contain candidate genes involved in asthma development and progression. Some susceptible genes may affect the phenotype expression or response to therapy. In addition, the interaction of multiple genes with the environment may contribute to the susceptibility to asthma.Conclusions As an essential step toward cloning the susceptible genes to asthma, fine mapping and localization onchromosomes are definitely needed. Novel powerful tools for gene discovery and the integration of genetics, biology and bioinformatics should be pursued.

  5. Breast cancer susceptibility variants alter risk in familial ovarian cancer.

    Science.gov (United States)

    Latif, A; McBurney, H J; Roberts, S A; Lalloo, F; Howell, A; Evans, D G; Newman, W G

    2010-12-01

    Recent candidate gene and genome wide association studies have revealed novel loci associated with an increased risk of breast cancer. We evaluated the effect of these breast cancer associated variants on ovarian cancer risk in individuals with familial ovarian cancer both with and without BRCA1 or BRCA2 mutations. A total of 158 unrelated white British women (54 BRCA1/2 mutation positive and 104 BRCA1/2 mutation negative) with familial ovarian cancer were genotyped for FGFR2, TNRC9/TOX3 and CASP8 variants. The p.Asp302His CASP8 variant was associated with reduced ovarian cancer risk in the familial BRCA1/2 mutation negative ovarian cancer cases (P = 0.016). The synonymous TNRC9/TOX3 (Ser51) variant was present at a significantly lower frequency than in patients with familial BRCA1/2 positive breast cancer (P = 0.0002). Our results indicate that variants in CASP8 and TNRC9/TOX3 alter the risk of disease in individuals affected with familial ovarian cancer.

  6. Promoter polymorphisms in trefoil factor 2 and trefoil factor 3 genes and susceptibility to gastric cancer and atrophic gastritis among Chinese population.

    Science.gov (United States)

    Xu, Qian; Chen, Mo-Ye; He, Cai-Yun; Sun, Li-Ping; Yuan, Yuan

    2013-10-15

    The polymorphisms in trefoil factor (TFF) gene family that protect gastrointestinal epithelium might influence individual vulnerability to gastric cancer (GC) and atrophic gastritis. We used the Sequenom MassARRAY platform to identify the genotypes of TFF2 rs3814896 and TFF3 rs9981660 polymorphisms in 478 GC patients, 652 atrophic gastritis patients, and 724 controls. For the TFF2 rs3814896 polymorphism, in the subgroup aged ≤ 50 years, we found that AG+GG genotypes were associated with a 0.746-fold decreased risk of atrophic gastritis [p=0.023, 95% confidence interval (CI)=0.580-0.960], a 0.626-fold decreased risk of GC (p=0.005, 95% CI=0.451-0.868), and a 0.663-fold decreased risk of diffuse-type GC (p=0.034, 95% CI=0.452-0.970) compared with the common AA genotype. For the TFF3 rs9981660 polymorphism, in the male subgroup, individuals with variant AG+AA genotype were associated with a 0.761-fold decreased risk of diffuse-type GC compared with the common GG genotype (p=0.043, 95% CI=0.584-0.992). Additionally, we found that in subjects aged ≤ 50 years compared with common AA genotype, TFF2 rs3814896 AG+GG genotypes were associated with increased TFF2 mRNA levels in the total gastric cancer specimens and in the diffuse-type gastric cancer specimens; and in males aged ≤ 50 years compared with common GG genotype, TFF3 rs9981660 AA+AG genotypes were associated with TFF3 mRNA levels in diffuse-type gastric cancer tissues and their corresponding non-cancerous tissues. To our knowledge, this is the first report of an association between the TFF2 rs3814896 AG+GG genotypes and decreased risks of GC, diffuse-type GC, and atrophic gastritis in younger people aged ≤ 50 years, and an association between TFF3 rs9981660 AG+AA genotype and decreased risk of diffuse-type GC in men. Moreover, we found that TFF2 rs3814896 AG+GG genotypes in people aged ≤ 50 years and TFF3 rs9981660 AG+AA genotypes in younger males with diffuse-type GC were associated with higher levels of

  7. Prioritization of Disease Susceptibility Genes Using LSM/SVD.

    Science.gov (United States)

    Gong, Lejun; Yang, Ronggen; Yan, Qin; Sun, Xiao

    2013-12-01

    Understanding the role of genetics in diseases is one of the most important tasks in the postgenome era. It is generally too expensive and time consuming to perform experimental validation for all candidate genes related to disease. Computational methods play important roles for prioritizing these candidates. Herein, we propose an approach to prioritize disease genes using latent semantic mapping based on singular value decomposition. Our hypothesis is that similar functional genes are likely to cause similar diseases. Measuring the functional similarity between known disease susceptibility genes and unknown genes is to predict new disease susceptibility genes. Taking autism as an instance, the analysis results of the top ten genes prioritized demonstrate they might be autism susceptibility genes, which also indicates our approach could discover new disease susceptibility genes. The novel approach of disease gene prioritization could discover new disease susceptibility genes, and latent disease-gene relations. The prioritized results could also support the interpretive diversity and experimental views as computational evidence for disease researchers.

  8. 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

  9. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

    DEFF Research Database (Denmark)

    Kabisch, Maria; Lorenzo Bermejo, Justo; Dünnebier, Thomas

    2015-01-01

    The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encodi...

  10. 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

    3803662 (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......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...... 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...

  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

    3803662 (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......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...... 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...

  12. Identification of Srp9 as a febrile seizure susceptibility gene

    NARCIS (Netherlands)

    Hessel, Ellen V S; de Wit, Marina; Wolterink-Donselaar, Inge G; Karst, Henk; de Graaff, Esther; van Lith, Hein A; de Bruijn, Ewart; de Sonnaville, Sophietje; Verbeek, Nienke E; Lindhout, Dick; de Kovel, Carolien G F; Koeleman, Bobby P C; van Kempen, Marjan; Brilstra, Eva; Cuppen, Edwin; Loos, Maarten; Spijker, Sabine S; Kan, Anne A; Baars, Susanne E; van Rijen, Peter C; Gosselaar, Peter H; Groot Koerkamp, Marian J A; Holstege, Frank C P; van Duijn, Cornelia; Vergeer, Jeanette; Moll, Henriette A; Taubøll, Erik; Heuser, Kjell; Ramakers, Geert M J; Pasterkamp, R Jeroen; van Nieuwenhuizen, Onno; Hoogenraad, Casper C; Kas, Martien J H; de Graan, Pierre N E

    2014-01-01

    OBJECTIVE: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. METHODS:

  13. CTLA-4 polymorphisms associate with breast cancer susceptibility in Asians: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhiming Dai

    2017-01-01

    Full Text Available Previous studies have investigated the association between cytotoxic T-lymphocyte antigen-4 (CTLA-4 polymorphisms and breast cancer susceptibility, but the results remained inconsistent. Therefore, we evaluated the relationship between four common CTLA-4 polymorphisms and breast cancer risk by a meta-analysis, aiming to derive a comprehensive and precise conclusion. We searched EMBASE, Pubmed, Web of Science, CNKI, and Wanfang databases until July 18th, 2016. Finally, ten eligible studies involving 4,544 breast cancer patients and 4,515 cancer-free controls were included; all these studies were from Asia. Odds ratio (OR and 95% confidence interval (CI were used to evaluate the breast cancer risk in five genetic models. The results indicated that the CTLA-4 +49A>G (rs231775 polymorphism had a significant association with decreased breast cancer risk in allelic, homozygous, dominant and recessive models. Also, the +6230G>A (rs3087243 polymorphism reduced breast cancer risk especially in the Chinese population under homozygous and recessive models. In contrast, the −1661A>G (rs4553808 polymorphism increased breast cancer risk in allelic, heterozygous and dominant models, whereas −1722 T>C (rs733618 did not relate to breast cancer risk. In conclusion, CTLA-4 polymorphisms significantly associate with breast cancer susceptibility in Asian populations, and different gene loci may have different effects on breast cancer development. Further large-scale studies including multi-racial populations are required to confirm our findings.

  14. CTLA-4 polymorphisms associate with breast cancer susceptibility in Asians: a meta-analysis

    Science.gov (United States)

    Liu, Xinghan; Lin, Shuai; Yang, Pengtao; Liu, Kang; Zheng, Yi; Xu, Peng; Liu, Meng; Yang, Xuewen

    2017-01-01

    Previous studies have investigated the association between cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms and breast cancer susceptibility, but the results remained inconsistent. Therefore, we evaluated the relationship between four common CTLA-4 polymorphisms and breast cancer risk by a meta-analysis, aiming to derive a comprehensive and precise conclusion. We searched EMBASE, Pubmed, Web of Science, CNKI, and Wanfang databases until July 18th, 2016. Finally, ten eligible studies involving 4,544 breast cancer patients and 4,515 cancer-free controls were included; all these studies were from Asia. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the breast cancer risk in five genetic models. The results indicated that the CTLA-4 +49A>G (rs231775) polymorphism had a significant association with decreased breast cancer risk in allelic, homozygous, dominant and recessive models. Also, the +6230G>A (rs3087243) polymorphism reduced breast cancer risk especially in the Chinese population under homozygous and recessive models. In contrast, the −1661A>G (rs4553808) polymorphism increased breast cancer risk in allelic, heterozygous and dominant models, whereas −1722 T>C (rs733618) did not relate to breast cancer risk. In conclusion, CTLA-4 polymorphisms significantly associate with breast cancer susceptibility in Asian populations, and different gene loci may have different effects on breast cancer development. Further large-scale studies including multi-racial populations are required to confirm our findings. PMID:28097051

  15. Caspase 9 promoter polymorphisms confer increased susceptibility to breast cancer.

    Science.gov (United States)

    Theodoropoulos, George E; Michalopoulos, Nikolaos V; Pantou, Malena P; Kontogianni, Panagiota; Gazouli, Maria; Karantanos, Theodoros; Lymperi, Maria; Zografos, George C

    2012-10-01

    Caspases (CASPs), play a crucial role in the development and progression of cancer. We evaluated the association between two polymorphisms (rs4645978 and rs4645981) of the CASP9 gene and the risk of breast cancer (BC). Genotypes and allelic frequencies for the two polymorphisms were determined in 261 patients with breast cancer and 480 healthy controls. Polymerase chain reaction-restriction fragment length polymorphisms were used, and statistical significance was determined by the χ(2) test. Carriers of the rs4645978G allele (AG and GG genotypes) were at higher risk for BC than individuals with other genotypes (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.07-2.37, P = 0.022). The rs4645978GG genotype, in particular, was associated with the highest risk for BC development (OR 2.25, 95% CI 1.45-3.49, P = 0.0003). Similarly, individuals with at least one rs4645981T allele were at a significantly increased risk of developing BC compared with those harboring the CC genotype (OR 2.75, 95% CI 1.99-3.78, P < 0.0001), and the risk of BC increased with increasing numbers of rs4645981T alleles (OR 2.66, 95% CI 1.91-3.69, P < 0.0001 for the CT genotype; OR 3.95, 95% CI 1.58-9.88, P = 0.004 for the TT genotype). The CASP9 promoter polymorphisms rs4645978 and rs4645981 are associated with BC susceptibility and suggest that CASP9 transcriptional regulation is an important factor during BC development.

  16. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

    NARCIS (Netherlands)

    M. Kabisch (Maria); J.L. Bermejo (Justo Lorenzo); T. Dun̈nebier (Thomas); S. Ying (Shibo); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet); Q. Wang (Qing); J. Dennis (Joe); M. Shah (Mitul); B. Perkins (Barbara); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); D. Lambrechts (Diether); P. Neven (Patrick); S.T.H. Peeters (Stephanie); C. Weltens (Caroline); F.J. Couch (Fergus); J.E. Olson (Janet); X. Wang (Xianshu); K. Purrington (Kristen); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); J. Peto (Julian); I. dos Santos Silva (Isabel); N. Johnson (Nichola); O. Fletcher (Olivia); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); F.B.L. Hogervorst (Frans); J. Li (Jingmei); J.S. Brand (Judith S.); M.K. Humphreys (Manjeet); P. Guénel (Pascal); T. Truong (Thérèse); F. Menegaux (Florence); M. Sanchez (Marie); B. Burwinkel (Barbara); F. Marme (Federick); R. Yang (Rongxi); P. Bugert (Peter); A. González-Neira (Anna); J. Benítez (Javier); M.P. Zamora (Pilar); J.I. Arias Pérez (José Ignacio); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); C.A. Haiman (Christopher); F.R. Schumacher (Fredrick); B.E. Henderson (Brian); L. Le Marchand (Loic); A. Lindblom (Annika); S. Margolin (Sara); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); M. Kriege (Mieke); L.B. Koppert (Linetta); J. Hopper (John); M.C. Southey (Melissa); H. Tsimiklis (Helen); C. Apicella (Carmel); S. Slettedahl (Seth); A.E. Toland (Amanda); C. Vachon (Celine); D. Yannoukakos (Drakoulis); G.G. Giles (Graham); R.L. Milne (Roger); C.A. McLean (Catriona Ann); P.A. Fasching (Peter); M. Ruebner (Matthias); A.B. Ekici (Arif); M.W. Beckmann (Matthias); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); A.J. Swerdlow (Anthony ); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); H. Brauch (Hiltrud); T. Brüning (Thomas); Y-D. Ko (Yon-Dschun); P. Radice (Paolo); P. Peterlongo (Paolo); G. Scuvera (Giulietta); S. Fortuzzi (S.); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Devilee (Peter); R.A.M. Tollenaar (Robert A.M.); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); W. Zheng (Wei); M. Shrubsole (Martha); Q. Cai (Qiuyin); D. Torres (Diana); H. Anton-Culver (Hoda); V. Kristensen (Vessela); F. Bacot (Francois); D.C. Tessier (Daniel C.); D. Vincent (Daniel); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); J. Simard (Jacques); G. Chenevix-Trench (Georgia); P. Hall (Per); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); D.F. Easton (Douglas); U. Hamann (Ute)

    2014-01-01

    textabstractThe chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in gen

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

    Directory of Open Access Journals (Sweden)

    Bo Shen

    2013-01-01

    Full Text Available 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 A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals.

  18. Genome-wide association study identifies novel breast cancer susceptibility loci

    Science.gov (United States)

    Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Marchand, Loic Le; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.; Luccarini, Craig; Conroy, Don; Shah, Mitul; Munday, Hannah; Jordan, Clare; Perkins, Barbara; West, Judy; Redman, Karen; Driver, Kristy; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armes, Jane; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Begley, Glenn; Beilby, John; Bennett, Ian; Bennett, Barbara; Berry, Geoffrey; Blackburn, Anneke; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chenevix-Trench, Georgia; Clarke, Christine; Colley, Alison; Cotton, Dick; Cui, Jisheng; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Field, Michael; Firgaira, Frank; Fleming, Jean; Forbes, John; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Harris, Marion; Hart, Stewart; Hayward, Nick; Hopper, John; Humphrey, Evelyn; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kirk, Judy; Kollias, James; Kovalenko, Sergey; Lakhani, Sunil; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Maclurcan, Mariette; Mann, Graham; Marsh, Deborah; McCredie, Margaret; McKay, Michael; McLachlan, Sue Anne; Meiser, Bettina; Milne, Roger; Mitchell, Gillian; Newman, Beth; O'Loughlin, Imelda; Osborne, Richard; Peters, Lester; Phillips, Kelly; Price, Melanie; Reeve, Jeanne; Reeve, Tony; Richards, Robert; Rinehart, Gina; Robinson, Bridget; Rudzki, Barney; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Scott, Clare; Scott, Elizabeth; Scott, Rodney; Seshadri, Ram; Shelling, Andrew; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Taylor, Donna; Tennant, Christopher; Thorne, Heather; Townshend, Sharron; Tucker, Kathy; Tyler, Janet; Venter, Deon; Visvader, Jane; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Watson, Elizabeth; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Young, Mary Ann; Bowtell, David; Green, Adele; deFazio, Anna; Chenevix-Trench, Georgia; Gertig, Dorota; Webb, Penny

    2009-01-01

    Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. PMID:17529967

  19. Selenoprotein S (SEPS1 gene -105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population

    Directory of Open Access Journals (Sweden)

    Nagasaka Mitsuo

    2009-01-01

    Full Text Available Abstract Background Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPS1 is involved in the control of the inflammatory response in the endoplasmic reticulum (ER. Recently the -105G>A polymorphism in the promoter of SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined the association between this polymorphism and the risk of gastric cancer. Methods We took stomach biopsies during endoscopies of 268 Japanese gastric cancer patients (193 males and 75 females, average age 65.3, and 306 control patients (184 males and 122 females, average age 62.7 and extracted the DNA from the biopsy specimens. All subjects provided written informed consent. For the genotyping of the SEPS1 promoter polymorphism at position -105G>A, PCR-RFLP methods were used and the PCR products were digested with PspGI. Logistic-regression analysis was used to estimate odds ratios (OR and 95% confidence intervals (CI, adjusting for age, sex, and H. pylori infection status. Results Among cases, the distribution of genotypes was as follows: 88.4% were GG, 11.2% were GA, and 0.4% were AA. Among controls, the distribution was as follows: 92.5% were GG, 7.2% were GA, and 0.3% were AA. Among males, carrying the A allele was associated with an increased odds of gastric cancer, compared with the GG genotype (OR: 2.0, 95% CI 1.0–4.1, p = 0.07. Compared with the GG genotype, carrying the A allele was significantly associated with increased risks of intestinal type gastric cancer (OR: 2.0, 95%CI 1.0–3.9, p Conclusion The -105G>A promoter polymorphism of SEPS1 was associated with the intestinal type of gastric cancer. This polymorphism may influence the inflammatory conditions of gastric mucosa. Larger population-based studies are needed for clarifying the relation between inflammatory responses and SEPS1 polymorphism.

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

    OpenAIRE

    Chang eShen; Jing eGao; Yu Jun Sheng; Jinfa eDou; Fusheng eZhou; Xiaodong eZheng; Randy eKo; Xianfa eTang; Caihong Hong Zhu; Xianyong Yong Yin; Liangdan Dan Sun; Yong eCui; Xue Jun Zhang

    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 and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association stud...

  2. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes.

    Science.gov (United States)

    Dozmorov, Mikhail G; Wren, Jonathan D; Alarcón-Riquelme, Marta E

    2014-02-01

    Genome-wide association studies have identified a number of autoimmune disease-susceptibility genes. Whether or not these loci share any regulatory or functional elements, however, is an open question. Finding such common regulators is of considerable research interest in order to define systemic therapeutic targets. The growing amount of experimental genomic annotations, particularly those from the ENCODE project, provide a wealth of opportunities to search for such commonalities. We hypothesized that regulatory commonalities might not only delineate a regulatory landscape predisposing to autoimmune diseases, but also define functional elements distinguishing specific diseases. We further investigated if, and how, disease-specific epigenomic elements can identify novel genes yet to be associated with the diseases. We evaluated transcription factors, histone modifications, and chromatin state data obtained from the ENCODE project for statistically significant over- or under-representation in the promoters of genes associated with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Systemic Sclerosis (SSc). We identified BATF, BCL11A, IRF4, NFkB, PAX5, and PU.1 as transcription factors over-represented in SLE- and RA-susceptibility gene promoters. H3K4me1 and H3K4me2 epigenomic marks were associated with SLE susceptibility genes, and H3K9me3 was common to both SLE and RA. In contrast to a transcriptionally active signature in SLE and RA, SSc-susceptibility genes were depleted in activating epigenomic elements. Using epigenomic elements enriched in SLE and RA, we identified additional immune and B cell signaling-related genes with the same elements in their promoters. Our analysis suggests common and disease-specific epigenomic elements that may define novel therapeutic targets for controlling aberrant activation of autoimmune susceptibility genes.

  3. Gene therapy of liver cancer

    Institute of Scientific and Technical Information of China (English)

    Ruben Hernandez-Alcoceba; Bruno Sangro; Jesus Prieto

    2006-01-01

    The application of gene transfer technologies to the treatment of cancer has led to the development of new experimental approaches like gene directed enzyme/prodrug therapy (GDEPT), inhibition of oncogenes and restoration of tumor-suppressor genes. In addition,gene therapy has a big impact on other fields like cancer immunotherapy, anti-angiogenic therapy and virotherapy.These strategies are being evaluated for the treatment of primary and metastatic liver cancer and some of them have reached clinical phases. We present a review on the basis and the actual status of gene therapy approaches applied to liver cancer.

  4. Rheumatoid arthritis susceptibility genes: An overview.

    Science.gov (United States)

    Korczowska, Izabela

    2014-09-18

    Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease sustained by genetic factors. Various aspects of the genetic contribution to the pathogenetics and outcome of RA are still unknown. Several genes have been indicated so far in the pathogenesis of RA. Apart from human leukocyte antigen, large genome wide association studies have identified many loci involved in RA pathogenesis. These genes include protein tyrosine phosphatase, nonreceptor type 22, Peptidyl Arginine Deiminase type IV, signal transducer and activator of transcription 4, cytotoxic T-lymphocyte-associated protein 4, tumor necrosis factor-receptor associated factor 1/complement component 5, tumor necrosis factor and others. It is important to determine whether a combination of RA risk alleles are able to identify patients who will develop certain clinical outcomes, such myocardium infarction, severe infection or lymphoma, as well as to identify patients who will respond to biological medication therapy.

  5. Common non-synonymous SNPs associated with breast cancer susceptibility

    DEFF Research Database (Denmark)

    Milne, Roger L; Burwinkel, Barbara; Michailidou, Kyriaki

    2014-01-01

    Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsS...

  6. Identifying cancer genes from cancer mutation profiles by cancer functions

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    It is of great importance to identify new cancer genes from the data of large scale genome screenings of gene mutations in cancers. Considering the alternations of some essential functions are indispensable for oncogenesis, we define them as cancer functions and select, as their approximations, a group of detailed functions in GO (Gene Ontology) highly enriched with known cancer genes. To evaluate the efficiency of using cancer functions as features to identify cancer genes, we define, in the screened genes, the known protein kinase cancer genes as gold standard positives and the other kinase genes as gold standard negatives. The results show that cancer associated functions are more efficient in identifying cancer genes than the selection pressure feature. Furthermore, combining cancer functions with the number of non-silent mutations can generate more reliable positive predictions. Finally, with precision 0.42, we suggest a list of 46 kinase genes as candidate cancer genes which are annotated to cancer functions and carry at least 3 non-silent mutations.

  7. [Susceptibility gene in multiple system atrophy (MSA)].

    Science.gov (United States)

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress.

  8. Replication of breast cancer susceptibility loci in whites and African Americans using a Bayesian approach.

    Science.gov (United States)

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

    2014-02-01

    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 single nucleotide polymorphisms (SNPs) and breast cancer among Carolina Breast Cancer Study (1993-2001) participants using maximum likelihood, Bayesian, and hierarchical methods. The selected SNPs were previous GWAS hits (n = 22), near-hits (n = 19), otherwise well-established risk loci (n = 5), or located in the same genes as selected variants (n = 37). We successfully replicated 18 GWAS-identified SNPs in whites (n = 2,352) and 10 in African Americans (n = 1,447). SNPs in the fibroblast growth factor receptor 2 gene (FGFR2) and the TOC high mobility group box family member 3 gene (TOX3) were strongly associated with breast cancer in both races. SNPs in the mitochondrial ribosomal protein S30 gene (MRPS30), mitogen-activated protein kinase kinase kinase 1 gene (MAP3K1), zinc finger, MIZ-type containing 1 gene (ZMIZ1), and H19, imprinted maternally expressed transcript gene (H19) were associated with breast cancer in whites, and SNPs in the estrogen receptor 1 gene (ESR1) and H19 gene were associated with breast cancer in African Americans. We provide precise and well-informed race-stratified odds ratios for key breast cancer-related SNPs. Our results demonstrate the utility of Bayesian methods in genetic epidemiology and provide support for their application in small, etiologically driven investigations.

  9. Polymorphisms in autophagy genes and susceptibility to tuberculosis.

    NARCIS (Netherlands)

    Songane, M.; Kleinnijenhuis, J.; Alisjahbana, B.; Sahiratmadja, E.; Parwati, I.; Oosting, M.; Plantinga, T.S.; Joosten, L.A.B.; Netea, M.G.; Ottenhoff, T.H.; Vosse, E. van de; Crevel, R. van

    2012-01-01

    Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB) among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana

  10. Identification of targetable FGFR gene fusions in diverse cancers.

    Science.gov (United States)

    Wu, Yi-Mi; Su, Fengyun; Kalyana-Sundaram, Shanker; Khazanov, Nickolay; Ateeq, Bushra; Cao, Xuhong; Lonigro, Robert J; Vats, Pankaj; Wang, Rui; Lin, Su-Fang; Cheng, Ann-Joy; Kunju, Lakshmi P; Siddiqui, Javed; Tomlins, Scott A; Wyngaard, Peter; Sadis, Seth; Roychowdhury, Sameek; Hussain, Maha H; Feng, Felix Y; Zalupski, Mark M; Talpaz, Moshe; Pienta, Kenneth J; Rhodes, Daniel R; Robinson, Dan R; Chinnaiyan, Arul M

    2013-06-01

    Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer. After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid cancer, oral cancer, glioblastoma, and head and neck squamous cell cancer. All FGFR fusion partners tested exhibit oligomerization capability, suggesting a shared mode of kinase activation. Overexpression of FGFR fusion proteins induced cell proliferation. Two bladder cancer cell lines that harbor FGFR3 fusion proteins exhibited enhanced susceptibility to pharmacologic inhibition in vitro and in vivo. Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised to identify rare, targetable FGFR fusions across diverse cancer types.

  11. 福建地区口腔癌患者p53基因72密码子多态性与口腔癌易感性的研究%Study on p53 Gene Condon 72 Polymorphisms and Susceptibility of Oral Cancer of Fuji an Oral Cancer Pati ents

    Institute of Scientific and Technical Information of China (English)

    何保昌; 陈法; 刘芳萍; 柳迪萌; 陈珍; 蔡琳

    2014-01-01

    目的:研究p53基因多态性与口腔癌的关联。方法对149例口腔癌病例和303例对照病例采集5 mL血液样本,提取基因组DNA ,采用PCR‐RFLP法检测p53基因的多态性,利用Stata12.1软件分析p53基因的多态性与口腔癌的关联,并进行基因‐环境交互作用分析。结果 p53基因Pro/Pro基因型携带者较Arg/Arg基因型携带者口腔癌的发病风险增加1.837倍(95% CI:1.016,3.325)。p53基因Pro/Pro基因型与饮酒有相乘交互作用(OR相乘:4.375,95% CI:1.646,11.627)。结论 p53基因Pro/Pro基因型可能是福建地区口腔癌的易感基因,Pro/Pro基因型与饮酒具有相乘交互作用。%Objective To discover the association between p53 gene polymorphism and oral cancer in Fujian area . Methods 5 mL blood sample of 149 oral cancer patients and 303 controls w ere collected and their DNAs were extracted . p53 gene polymorphism was detected by polymerase chain reaction‐re‐striction fragment length . The association between p53 gene polymorphism and oral cancer ,and the in‐teraction effects of p53 gene polymorphism and environmental factors were analyzed by using Stata12 .1 . ResuIts Compared with Arg/Arg genotype ,p53 gene with Pro/Pro genotype was associated with higher risk of oral cancer(OR:1 .837 ,95% CI:1 .016 ,3 .325) . A multiplicative interaction between p53 gene with Pro/Pro genotype and alcohol drinking was found for oral cancer (ORmultiplicative :4 .375 ,95% CI:1 .646 , 11 .627) . ConcIusions There is multiplication interaction between p53 gene with Pro/Pro genotype and alcohol drinking ,w hich may be related to susceptibility of oral cancer in Fujian area .

  12. Candidate Genes for Inherited Autism Susceptibility in the Lebanese Population

    Science.gov (United States)

    Kourtian, Silva; Soueid, Jihane; Makhoul, Nadine J.; Guisso, Dikran Richard; Chahrour, Maria; Boustany, Rose-Mary N.

    2017-01-01

    Autism spectrum disorder (ASD) is characterized by ritualistic-repetitive behaviors and impaired verbal/non-verbal communication. Many ASD susceptibility genes implicated in neuronal pathways/brain development have been identified. The Lebanese population is ideal for uncovering recessive genes because of shared ancestry and a high rate of consanguineous marriages. Aims here are to analyze for published ASD genes and uncover novel inherited ASD susceptibility genes specific to the Lebanese. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33) and 100 unaffected Lebanese controls. Cytogenetics 2.7 M Microarrays/CytoScan™ HD arrays allowed mapping of homozygous regions of the genome. The CNTNAP2 gene was screened by Sanger sequencing. Homozygosity mapping uncovered DPP4, TRHR, and MLF1 as novel candidate susceptibility genes for ASD in the Lebanese. Sequencing of hot spot exons in CNTNAP2 led to discovery of a 5 bp insertion in 23/37 ASD patients. This mutation was present in unaffected family members and unaffected Lebanese controls. Although a slight increase in number was observed in ASD patients and family members compared to controls, there were no significant differences in allele frequencies between affecteds and controls (C/TTCTG: γ2 value = 0.014; p = 0.904). The CNTNAP2 polymorphism identified in this population, hence, is not linked to the ASD phenotype. PMID:28358038

  13. 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.

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

    Directory of Open Access Journals (Sweden)

    Chang eShen

    2016-02-01

    Full Text Available 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 and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association studies (GWASs. More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWASs. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo, such as immunoregulatory function, melanocyte regulation and so on. A number of 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 vitiligo development.

  15. The power of DNA double-strand break (DSB) repair testing to predict breast cancer susceptibility.

    Science.gov (United States)

    Keimling, Marlen; Deniz, Miriam; Varga, Dominic; Stahl, Andreea; Schrezenmeier, Hubert; Kreienberg, Rolf; Hoffmann, Isabell; König, Jochem; Wiesmüller, Lisa

    2012-05-01

    Most presently known breast cancer susceptibility genes have been linked to DSB repair. To identify novel markers that may serve as indicators for breast cancer risk, we performed DSB repair analyses using a case-control design. Thus, we examined 35 women with defined familial history of breast and/or ovarian cancer (first case group), 175 patients with breast cancer (second case group), and 245 healthy women without previous cancer or family history of breast cancer (control group). We analyzed DSB repair in peripheral blood lymphocytes (PBLs) by a GFP-based test system using 3 pathway-specific substrates. We found increases of microhomology-mediated nonhomologous end joining (mmNHEJ) and nonconservative single-strand annealing (SSA) in women with familial risk vs. controls (P=0.0001-0.0022) and patients with breast cancer vs. controls (P=0.0004-0.0042). Young age (DSB repair activities in PBLs as method to estimate breast cancer susceptibility beyond limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair-dysfunctional tumors.

  16. Gene therapy in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Xu Chang-tai; Guo Xue-gang; Pan Bo-rong

    2003-01-01

    @@ 1 Introduction We have reviewed the gene therapy in gastrointestinal diseases[1]. Gastric cancer is common in China[2~20] ,and its early diagnosis andtreatment are still difficult up to now[13~36]. The expression of anexogenous gene introduced by gene therapy into patients with gliomascan be monitored non- invasively by positron- emission tomography[4]. In recent years, gene study in cancer is a hotspot, and great progress hasbeen achieved[33~41].

  17. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections.

    Directory of Open Access Journals (Sweden)

    Ettie M Lipner

    Full Text Available Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects.

  18. Identification of candidate genes for dyslexia susceptibility on chromosome 18.

    Directory of Open Access Journals (Sweden)

    Thomas S Scerri

    Full Text Available Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s conferring susceptibility by a two stage strategy of linkage and association analysis.Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R, dymeclin (DYM and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L.Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

  19. 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.

  20. 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.

  1. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility

    OpenAIRE

    Simmons, J.; Mullighan, C; Welsh, K; JEWELL, D

    2000-01-01

    BACKGROUND—The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome screening techniques. It is the cellular receptor for 1,25(OH)2 vitamin D3 (calcitriol) which has a wide range of different regulatory effects on the immune system. IBD is characterised by activation of the mucosal immune system.
AIM—To determine if polymo...

  2. Cyclooxygenase 2 genotypes influence prostate cancer susceptibility in Japanese Men.

    Science.gov (United States)

    Sugie, Satoru; Tsukino, Hiromasa; Mukai, Shoichiro; Akioka, Takahiro; Shibata, Norihiko; Nagano, Masafumi; Kamoto, Toshiyuki

    2014-03-01

    This study aims to evaluate the relationship between the cyclooxygenase 2 (COX2) G1195A (rs689465) polymorphism and the risk of prostate cancer in a Japanese population and the associations between COX2 polymorphisms and clinicopathological characteristics, including Gleason grade and prostate-specific antigen (PSA) grade. We recruited 134 patients with prostate cancer and 86 healthy controls matched for age and smoking status. The COX2 G1195A polymorphism status was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Genotype distributions (p = 0.028) and allelic frequencies (p = 0.014) differed significantly between prostate cancer and control groups in terms of the COX2 G1195A polymorphism (Pearson's χ (2) test). Logistic regression analysis of case and control outcomes showed an odds ratio between the GG and AA genotypes of 3.15 (95% confidence interval = 1.27-8.08, p = 0.014), indicating an increased risk of prostate cancer associated with the AA genotype. Subset analysis revealed no significant associations between this polymorphism and clinicopathological characteristics of prostate cancer. This study demonstrated a relationship between the COX2 G1195A variant and prostate cancer risk. This polymorphism may merit further investigation as a potential genomic marker for the early detection of prostate cancer. Our results support the hypothesis that rs689465 influences susceptibility to prostate cancer; however, prostate cancer progression was not associated with rs689465 in a Japanese population.

  3. Molecular epidemiology of and genetic susceptibility to esophageal cancer.

    Science.gov (United States)

    Bajpai, Manisha; Das, Kiron M; Lefferts, Joel; Lisovsky, Mikhail; Mashimo, Hiroshi; Phillips, Wayne A; Srivastava, Amitabh; To, Henry

    2014-09-01

    The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on clonal evolution in Barrett's carcinogenesis; biomarkers for early detection of esophageal cancer; the role of the methylguanine methyl transferase biomarker in the management of adenocarcinoma; and the discovery of high-risk genes in families.

  4. Prioritisation and network analysis of Crohn's disease susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Daniele Muraro

    Full Text Available Recent Genome-Wide Association Studies (GWAS have revealed numerous Crohn's disease susceptibility genes and a key challenge now is in understanding how risk polymorphisms in associated genes might contribute to development of this disease. For a gene to contribute to disease phenotype, its risk variant will likely adversely communicate with a variety of other gene products to result in dysregulation of common signaling pathways. A vital challenge is to elucidate pathways of potentially greatest influence on pathological behaviour, in a manner recognizing how multiple relevant genes may yield integrative effect. In this work we apply mathematical analysis of networks involving the list of recently described Crohn's susceptibility genes, to prioritise pathways in relation to their potential development of this disease. Prioritisation was performed by applying a text mining and a diffusion based method (GRAIL, GPEC. Prospective biological significance of the resulting prioritised list of proteins is highlighted by changes in their gene expression levels in Crohn's patients intestinal tissue in comparison with healthy donors.

  5. 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...

  6. 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.

  7. 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.

  8. CYP1B1 gene polymorphism and susceptibility to breast cancer with abnormal Hilit%CYP1B1基因多态性与异常体液型乳腺癌易感性

    Institute of Scientific and Technical Information of China (English)

    吐尔逊·买买提; 哈木拉提·吾甫尔; 伊力哈木·乃扎木; 彭晓梅; 多力坤·买买提玉素甫; 卡依尔·玉素甫

    2011-01-01

    Objective To explore the association between gene polymorphism of cytochrome P4501 Bl in exon 3 codon 432 Leu-Val and breast cancer( BC) and its clinical subgroups( breast cancer with abnormal Hilit[ BCAH]. Methods The BC patients were divided into four groups with different body fluid type according to Uighur medicine theory. The polymerase chain reaction-restriction fragment length polymorphism( PCR-RFLP) technique was used to detect the polymorphism in exon 3 Leu432Val of CYP1B1 in 84 BC patients and 131 normal control subjects. Results The frequency of genotype and allele of CYP1B1 of BC,BCAH and the control group was not significantly different(P>0.05). Compared with wild type(Leu/Leu) ,the susceptibility to BC for subjects with the Leu/Val + Val/Val was increased by 2.137(odds ratio [OR] =2. 137,95% confidence interval [CY] :0.969 -4.717,P =0.056),and by 3.636( OR =3.636,95% C7:0.996 -13.157;/>=0.062) in BCAH patients. Conclusion Mutation of genotype (Leu/Val + Val/Val) of CYP1B1 may be correlated to the susceptibility to BC and BCABH in Chinese Han population of Xinjiang.%目的 探讨细胞色素氧化酶p450(cytochrome,CYP)1B1基因外显子3密码子432亮氨酸(Leu)-缬氨酸(Val)位点多态性与乳腺癌(BC)及其异常体液型乳腺癌(BCAH)的相关性.方法 按维吾尔医学将乳腺癌病例组分为4种体液型,应用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)技术检测84例BC患者和131例对照组的CYP1B1基因Leu432Val位点多态性的分布频率.结果 CYP1 B1各基因型及等位基因分布频率在BC、BCAH与对照组之间差异均无统计学意义(P>0.05);在BC病例组中Leu/Val和Val/Val合并后其发生BC的风险是野生型Leu/Leu个体的2.137倍(95%CI=0.969 ~4.717,P=0.056),在BCABH病例组中其发生BC的风险是野生型Leu/Leu个体的3.636倍(95% CI =0.996~13.157,P=0.062).结论 CYP1B1突变基因型(Leu/Val+ Val/Val)可能与新疆汉族人群BC和BCABH易感性有关.

  9. [CZECANCA: CZEch CAncer paNel for Clinical Application-- Design and Optimization of the Targeted Sequencing Panel for the Identification of Cancer Susceptibility in High-risk Individuals from the Czech Republic].

    Science.gov (United States)

    Soukupová, J; Zemánková, P; Kleiblová, P; Janatová, M; Kleibl, Z

    2016-01-01

    Individuals with hereditary cancer syndromes form a minor but clinically important subgroup of oncology patients, comprising several thousand cases in the Czech Republic annually. In these patients, the identification of pathogenic mutations in cancer susceptibility genes has an important predictive and, in some cases, prognostic value. It also enables rational preventive strategies in asymptomatic carriers from affected families. More than 150 cancer susceptibility genes have been described so far; however, mutations in most of them are very rare, occurring with substantial population variability, and hence their clinical interpretation is very complicated. Diagnostics of mutations in cancer susceptibility genes have benefited from the broad availability of next-generation sequencing analyses using targeted gene panels. In order to rationalize the diagnostics of hereditary cancer syndromes in the Czech Republic, we have prepared the sequence capture panel "CZECANCA", targeting 219 cancer susceptibility genes. Besides more than 50 clinically important high- and moderate-penetrance susceptibility genes, the panel also targets less common candidate genes with uncertain clinical relevance. Alongside the panel design, we have optimized the analytical and bioinformatics pipeline, which will facilitate establishing a collective nationwide database of genotypes and clinical data from the analyzed individuals. The key objective of this project is to provide diagnostic laboratories in the Czech Republic with a reliable procedure and collective database improving the clinical utility of next-generation sequencing analyses in high-risk patients, which would help improve the interpretation of rare or population-specific variants in cancer susceptibility genes.

  10. Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

    Directory of Open Access Journals (Sweden)

    Angela Toss

    2015-01-01

    Full Text Available More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

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

    Science.gov (United States)

    Bolognesi, Claudia; Bruzzi, Paolo; Gismondi, Viviana; Volpi, Samantha; Viassolo, Valeria; Pedemonte, Simona; Varesco, Liliana

    2014-01-01

    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.

  12. Relationship between measles HI titers and an MS susceptibility gene.

    Science.gov (United States)

    Haile, R W; Visscher, B R; Detels, R; Valdiviezo, N L; Sever, J L; Madden, D L

    1981-01-01

    Recently published studies of formal linkage analyses strongly suggest that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA region of the sixth chromosome. The objective of this analysis was to investigate whether or not the gene has any demonstrable relationship to the immune status with regard to measles within members of multiple-case MS families. Family members were HLA-typed, and levels of antibodies to measles were determined using the hemagglutination inhibition assay. Since a specific, HLA-defined haplotype within each family is presumably a marker for the MSS gene, family members were characterized as either carrying [(+) controls] or not carrying [(-) controls] the MSS gene by the presence of this specific haplotype. Twenty families were entered into the analyses. Results revealed that the mean titer to measles was not different between (+) and (-) controls, and that MS cases had significantly higher titers than both control groups combined.

  13. MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis

    Directory of Open Access Journals (Sweden)

    Wu Wei

    2011-05-01

    Full Text Available Abstract Background The tumor suppressor gene p53 is involved in multiple cellular pathways including apoptosis, transcriptional control, and cell cycle regulation. In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory. Methods To investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls. Results The data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR = 1.25, 95% confidence interval (CI = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17. We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively. In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively. However, no association was seen between MDM2 SNP309 and tumor susceptibility

  14. 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...

  15. 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

  16. The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study

    DEFF Research Database (Denmark)

    Andersen, V.; Agerstjerne, L.; Jensen, D.;

    2009-01-01

    Background: Smoking, dietary factors, and alcohol consumption are known life style factors contributing to gastrointestinal carcinogenesis. Genetic variations in carcinogen handling may affect cancer risk. The multidrug resistance 1(MDR1/ABCB1) gene encodes the transport protein P-glycoprotein (a...

  17. GSTT1 Null Genotype Significantly Increases the Susceptibility to Urinary System Cancer: Evidences from 63,876 Subjects.

    Science.gov (United States)

    Wang, Ying; He, Jing; Ma, Tian-Jiao; Lei, Wei; Li, Feng; Shen, Han; Shen, Zhen-Ya

    2016-01-01

    GSTT1 gene plays an important role in detoxification and clearance of reactive oxygen species(ROS). A null variant in this gene has been demonstrated to confer cancer susceptibility. Although many studies have demonstrated the association between GSTT1 null polymorphism and urinary system cancer susceptibility, several publications reported opposite conclusions. For better understanding the effects of this polymorphism on the risk of urinary system cancer, a updated meta-analysis was performed with a total of 26,666 cases and 37,210 controls extracted from 117 studies, by following the latest meta-analysis guidelines (PRISMA). The results suggested that the GSTT1 null genotype was significantly associated with an increased risk of urinary system cancer (OR=1.13, 95%CI=1.05-1.22). Furthermore, stratified analyses by the type of cancer, ethnicity, source of control and quality score presented a significantly increased risk associated with GSTT1 null genotype in bladder and prostate cancer subgroup, Caucasians and Indians subgroup, population-based(PB) subgroup, medium quality and low quality subgroup. Overall, our meta-analysis suggested that GSTT1 null genotype is a potential cancer susceptibility variant. Well-designed and large-cohort studies are needed to confirm the association between GSTT1 null genotype and urinary system cancer risk.

  18. GSTT1 Null Genotype Significantly Increases the Susceptibility to Urinary System Cancer: Evidences from 63,876 Subjects

    Science.gov (United States)

    Wang, Ying; He, Jing; Ma, Tian-Jiao; Lei, Wei; Li, Feng; Shen, Han; Shen, Zhen-Ya

    2016-01-01

    GSTT1 gene plays an important role in detoxification and clearance of reactive oxygen species(ROS). A null variant in this gene has been demonstrated to confer cancer susceptibility. Although many studies have demonstrated the association between GSTT1 null polymorphism and urinary system cancer susceptibility, several publications reported opposite conclusions. For better understanding the effects of this polymorphism on the risk of urinary system cancer, a updated meta-analysis was performed with a total of 26,666 cases and 37,210 controls extracted from 117 studies, by following the latest meta-analysis guidelines (PRISMA). The results suggested that the GSTT1 null genotype was significantly associated with an increased risk of urinary system cancer (OR=1.13, 95%CI=1.05-1.22). Furthermore, stratified analyses by the type of cancer, ethnicity, source of control and quality score presented a significantly increased risk associated with GSTT1 null genotype in bladder and prostate cancer subgroup, Caucasians and Indians subgroup, population-based(PB) subgroup, medium quality and low quality subgroup. Overall, our meta-analysis suggested that GSTT1 null genotype is a potential cancer susceptibility variant. Well-designed and large-cohort studies are needed to confirm the association between GSTT1 null genotype and urinary system cancer risk.

  19. Identification of Pseudomonas aeruginosa genes associated with antibiotic susceptibility

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Pseudomonas aeruginosa causes acute and chronic infections in humans and these infections are difficult to treat due to the bacteria’s high-level of intrinsic and acquired resistance to antibiotics. To address this problem, it is crucial to investigate the molecular mechanisms of antibiotic resistance in this organism. In this study, a P. aeruginosa transposon insertion library of 17000 clones was constructed and screened for altered susceptibility to seven antibiotics. Colonies grown on agar plates con- taining antibiotics at minimum inhibitory concentrations (MICs) and those unable to grow at ? MIC were collected. The transposon-disrupted genes in 43 confirmed mutants that showed at least a three-fold increase or a two-fold decrease in suscep- tibility to at least one antibiotic were determined by semi-random PCR and subsequent sequencing analysis. In addition to nine genes known to be associated with antibiotic resistance, including mexI, mexB and mexR, 24 new antibiotic resis- tance-associated genes were identified, including a fimbrial biogenesis gene pilY1 whose disruption resulted in a 128-fold in- crease in the MIC of carbenicillin. Twelve of the 43 genes identified were of unknown function. These genes could serve as targets to control or reverse antibiotic resistance in this important human pathogen.

  20. Introduction: Cancer Gene Networks.

    Science.gov (United States)

    Clarke, Robert

    2017-01-01

    Constructing, evaluating, and interpreting gene networks generally sits within the broader field of systems biology, which continues to emerge rapidly, particular with respect to its application to understanding the complexity of signaling in the context of cancer biology. For the purposes of this volume, we take a broad definition of systems biology. Considering an organism or disease within an organism as a system, systems biology is the study of the integrated and coordinated interactions of the network(s) of genes, their variants both natural and mutated (e.g., polymorphisms, rearrangements, alternate splicing, mutations), their proteins and isoforms, and the organic and inorganic molecules with which they interact, to execute the biochemical reactions (e.g., as enzymes, substrates, products) that reflect the function of that system. Central to systems biology, and perhaps the only approach that can effectively manage the complexity of such systems, is the building of quantitative multiscale predictive models. The predictions of the models can vary substantially depending on the nature of the model and its inputoutput relationships. For example, a model may predict the outcome of a specific molecular reaction(s), a cellular phenotype (e.g., alive, dead, growth arrest, proliferation, and motility), a change in the respective prevalence of cell or subpopulations, a patient or patient subgroup outcome(s). Such models necessarily require computers. Computational modeling can be thought of as using machine learning and related tools to integrate the very high dimensional data generated from modern, high throughput omics technologies including genomics (next generation sequencing), transcriptomics (gene expression microarrays; RNAseq), metabolomics and proteomics (ultra high performance liquid chromatography, mass spectrometry), and "subomic" technologies to study the kinome, methylome, and others. Mathematical modeling can be thought of as the use of ordinary

  1. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

    Directory of Open Access Journals (Sweden)

    C. J. Carter

    2013-01-01

    Full Text Available Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (multiple sclerosis, and autism (, but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD to 33% (MS of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as to the disease itself.

  2. 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.

  3. Association of TP53 gene polymorphisms with genetic susceptibility to liver metastases of colorectal cancer%TP53基因多态与结直肠癌肝转移遗传易感性的相关性

    Institute of Scientific and Technical Information of China (English)

    王爱忠; 朱忠政; 丛文铭; 贾杭若; 金夏祥; 何向蕾; 朱冠山

    2008-01-01

    Objective To investigate the possible association between the single nucleotide polymorphisms (SNPs)(C-8343G,C-1863T and R72P)in TP53 gene and susceptibility to liver metastases of coloreetal cancer(CRC)in a Chinese popuation.Methods The genotypes of each SNP in TP53 gene were determined by either TaqMan assays or PCR-based restriction fragment length polymorphism(RFLP)method in 121 colorectal cancer patients with liver metastases and sex-,age-matched 280 cases with nonmetastatic CRC as a control.Immunohistochemical stainirig for P=53 was performed on paraffin-embedded sections.Odds ratios(ORs)for colorectal liver metastases and 95%coatidence intervals(CIs)from unconditional logistic regression models were used to evaluate relative risks.Results No significant association of C-8343G or C-1863T with colorectal liver metastases risk was observed.However,the R allele of the TP53 R72P polymorphism was more frequenfly found in metastatic cases than in nonmetastatic cases(P=0.037).When compared with PP homozygotes,the ORs of metastases for RP heterozygotes was 2.21(95%CI:1.13-4.33),for RR homozygotes was 2.26(95%CI:1.03-4.94),and for carriers of the 72R allele(RP or RR genotype)was 2.22(95%CI:1.16-4.26).Stratified analysis indicated that carrying the 72R allele had a more pronounced inerease in colorectal liver metastases risk among patients with positive P53 expression tumors(OR=3.28,95%CI:1.21-8.88),whereas no significantly increased metastases risk was found in patienm with negative P53 expression tumors(OR=1.37,95%CI:0.52-3.62).Conclusion The R allele of the TP53 R72P polymorphism may contribute to the etiology of liver metastases in CRC patients,particularly among those with positive P53 expression tumors.BothTP53 C-8343G and C-1863T may be not associated with colorectal liver metastases risk.%目的 探讨TP53基因C-8343G、C-1863T及第72密码子(R72P)单核苷酸多态性与结直肠癌(colorectal cancer,CRC)肝转移风险的关系.方法 采用TaqMan和聚

  4. DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis.

    Science.gov (United States)

    Yu, Zhaojin; Xiao, Qinghuan; Zhao, Lin; Ren, Jie; Bai, Xuefeng; Sun, Mingli; Wu, Huizhe; Liu, Xiaojian; Song, Zhiguo; Yan, Yuanyuan; Mi, Xiaoyi; Wang, Enhua; Jin, Feng; Wei, Minjie

    2015-09-01

    DNA methyltransferases (DNMTs), including DNMT1, 3a, and 3b, play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of DNMTs is associated with the development of breast cancer. This study aimed to explore the clinical significance of DNMT proteins in sporadic breast cancer. We investigated the expression of DNMT1, 3a, and 3b in 256 breast cancer and 36 breast fibroadenoma, using immunohistochemistry. The expression of DNMT1 and 3a was significantly higher in breast cancer than in fibroadenoma. In breast cancer, the expression of DNMT1 was significantly correlated with lymph node metastasis (P = 0.020), and the expression of DNMT3a and 3b was significantly correlated with advanced clinical stages (P = 0.046 and 0.012, respectively). Overexpression of DNMT1/3a was correlated with promoter hypermethylation and reduced expression of ERα and BRCA1. The expression levels of DNMT1 or DNMT3a were associated with a significantly shorter DFS or OS in a subgroup of breast cancer patients (patients with the age ≤50 years old, ERα-negative status, or HER2-postive status). The expression of DNMT1 or a combined expression of DNMT1 and 3a was associated with poor prognosis in patients who received chemotherapy and endocrine therapy, but not in patients who received chemotherapy alone. These findings suggest that DNMT1 and 3a may be involved in the progression and prognosis of sporadic breast cancer.

  5. Th17-Related Genes and Celiac Disease Susceptibility

    Science.gov (United States)

    Medrano, Luz María; García-Magariños, Manuel; Dema, Bárbara; Espino, Laura; Maluenda, Carlos; Polanco, Isabel; Figueredo, M. Ángeles; Fernández-Arquero, Miguel; Núñez, Concepción

    2012-01-01

    Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD), recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs), mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA), were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk. PMID:22359581

  6. Th17-related genes and celiac disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Luz María Medrano

    Full Text Available Th17 cells are known to be involved in several autoimmune or inflammatory diseases. In celiac disease (CD, recent studies suggest an implication of those cells in disease pathogenesis. We aimed at studying the role of genes relevant for the Th17 immune response in CD susceptibility. A total of 101 single nucleotide polymorphisms (SNPs, mainly selected to cover most of the variability present in 16 Th17-related genes (IL23R, RORC, IL6R, IL17A, IL17F, CCR6, IL6, JAK2, TNFSF15, IL23A, IL22, STAT3, TBX21, SOCS3, IL12RB1 and IL17RA, were genotyped in 735 CD patients and 549 ethnically matched healthy controls. Case-control comparisons for each SNP and for the haplotypes resulting from the SNPs studied in each gene were performed using chi-square tests. Gene-gene interactions were also evaluated following different methodological approaches. No significant results emerged after performing the appropriate statistical corrections. Our results seem to discard a relevant role of Th17 cells on CD risk.

  7. Genetic susceptibility for specific cancers. Medical liability of the clinician.

    Science.gov (United States)

    Severin, M J

    1999-12-01

    The use of genetic profiling techniques to detect individuals with an increased susceptibility to heritable cancers has provoked recent legal interest in the duties of the attending physician and in the rights of patients and their families. In the current study specific prima facie and recently litigated cases are presented and explored to delineate the issues facing physicians and to illustrate the prerogatives of patients who are caught up in a heritable cancer enigma. Various courts have attempted to answer questions involving lawsuits in which incidents of breast/ovarian carcinoma and colon carcinoma have provoked claims of negligence against health care providers. Health care workers involved in the care of these patients have specific duties to these individuals. It would appear that physicians are being forced to assume the additional duty of delving into a patient's family history of cancer through multiple generations. This duty is followed by a responsibility to provide detailed counseling to those patients in whom such activity impacts the diagnosis and management of familial cancer.

  8. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility

    DEFF Research Database (Denmark)

    Permuth, Jennifer B; Reid, Brett; Earp, Madalene

    2016-01-01

    RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleo......, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.......RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single...... nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1...

  9. Seeking genetic susceptibility variants for colorectal cancer: the EPICOLON consortium experience.

    Science.gov (United States)

    Castellví-Bel, Sergi; Ruiz-Ponte, Clara; Fernández-Rozadilla, Ceres; Abulí, Anna; Muñoz, Jenifer; Bessa, Xavier; Brea-Fernández, Alejandro; Ferro, Marta; Giráldez, María Dolores; Xicola, Rosa M; Llor, Xavier; Jover, Rodrigo; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Carracedo, Angel

    2012-03-01

    The EPICOLON consortium was initiated in 1999 by the Gastrointestinal Oncology Group of the Spanish Gastroenterology Association. It recruited consecutive, unselected, population-based colorectal cancer (CRC) cases and control subjects matched by age and gender without personal or familial history of cancer all over Spain with the main goal of gaining knowledge in Lynch syndrome and familial CRC. This epidemiological, prospective and multicentre study collected extensive clinical data and biological samples from ∼2000 CRC cases and 2000 controls in Phases 1 and 2 involving 25 and 14 participating hospitals, respectively. Genetic susceptibility projects in EPICOLON have included candidate-gene approaches evaluating single-nucleotide polymorphisms/genes from the historical category (linked to CRC risk by previous studies), from human syntenic CRC susceptibility regions identified in mouse, from the CRC carcinogenesis-related pathways Wnt and BMP, from regions 9q22 and 3q22 with positive linkage in CRC families, and from the mucin gene family. This consortium has also participated actively in the identification 5 of the 16 common, low-penetrance CRC genetic variants identified so far by genome-wide association studies. Finishing their own pangenomic study and performing whole-exome sequencing in selected CRC samples are among EPICOLON future research prospects.

  10. Association of the Three Common SNPs of Cyclooxygenase-2 Gene (rs20417, rs689466, and rs5275 with the Susceptibility of Breast Cancer: An Updated Meta-Analysis Involving 34,590 Subjects

    Directory of Open Access Journals (Sweden)

    Zhi-Jun Dai

    2014-01-01

    Full Text Available Several single nucleotide polymorphisms have been identified in cyclooxygenase-2 (COX-2 genes (e.g., −765 G>C (rs20417, −1195G>A (rs689466, and 8473 C>T (rs5275. The association of these SNPs with the risk of different cancer types is still controversial. This study aims to evaluate the correlation between these SNPs and breast cancer risk in different ethnic groups. We have searched PubMed, Web of Knowledge, and Embase for relevant studies. Odds ratios (ORs with 95% confidence intervals (CIs were used to estimate the strength of the associations. A total of 13 studies (15,330 cases and 19,260 controls were eligible for meta-analysis. This meta-analysis showed that COX-2 rs20417 polymorphism was correlated with an increased risk of breast cancer in Caucasians, while rs689466 was associated with a decreased risk of breast cancer in Caucasians. The rs5275 polymorphism had no association with breast cancer risk.

  11. 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.

  12. Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology.

    Science.gov (United States)

    O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Waddington, John L

    2012-01-01

    Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models.

  13. Polymorphisms in autophagy genes and susceptibility to tuberculosis.

    Directory of Open Access Journals (Sweden)

    Mario Songane

    Full Text Available Recent data suggest that autophagy is important for intracellular killing of Mycobacterium tuberculosis, and polymorphisms in the autophagy gene IRGM have been linked with susceptibility to tuberculosis (TB among African-Americans, and with TB caused by particular M. tuberculosis genotypes in Ghana. We compared 22 polymorphisms of 14 autophagy genes between 1022 Indonesian TB patients and 952 matched controls, and between patients infected with different M. tuberculosis genotypes, as determined by spoligotyping. The same autophagy polymorphisms were studied in correlation with ex-vivo production of TNF, IL-1β, IL-6, IL-8, IFN-γ and IL-17 in healthy volunteers. No association was found between TB and polymorphisms in the genes ATG10, ATG16L2, ATG2B, ATG5, ATG9B, IRGM, LAMP1, LAMP3, P2RX7, WIPI1, MTOR and ATG4C. Associations were found between polymorphisms in LAMP1 (p = 0.02 and MTOR (p = 0.02 and infection with the successful M. tuberculosis Beijing genotype. The polymorphisms examined were not associated with M. tuberculosis induced cytokines, except for a polymorphism in ATG10, which was linked with IL-8 production (p = 0.04. All associations found lost statistical significance after correction for multiple testing. This first examination of a broad set of polymorphisms in autophagy genes fails to show a clear association with TB, with M. tuberculosis Beijing genotype infection or with ex-vivo pro-inflammatory cytokine production.

  14. Gene therapy for prostate cancer.

    LENUS (Irish Health Repository)

    Tangney, Mark

    2012-01-31

    Cancer remains a leading cause of morbidity and mortality. Despite advances in understanding, detection, and treatment, it accounts for almost one-fourth of all deaths per year in Western countries. Prostate cancer is currently the most commonly diagnosed noncutaneous cancer in men in Europe and the United States, accounting for 15% of all cancers in men. As life expectancy of individuals increases, it is expected that there will also be an increase in the incidence and mortality of prostate cancer. Prostate cancer may be inoperable at initial presentation, unresponsive to chemotherapy and radiotherapy, or recur following appropriate treatment. At the time of presentation, patients may already have metastases in their tissues. Preventing tumor recurrence requires systemic therapy; however, current modalities are limited by toxicity or lack of efficacy. For patients with such metastatic cancers, the development of alternative therapies is essential. Gene therapy is a realistic prospect for the treatment of prostate and other cancers, and involves the delivery of genetic information to the patient to facilitate the production of therapeutic proteins. Therapeutics can act directly (eg, by inducing tumor cells to produce cytotoxic agents) or indirectly by upregulating the immune system to efficiently target tumor cells or by destroying the tumor\\'s vasculature. However, technological difficulties must be addressed before an efficient and safe gene medicine is achieved (primarily by developing a means of delivering genes to the target cells or tissue safely and efficiently). A wealth of research has been carried out over the past 20 years, involving various strategies for the treatment of prostate cancer at preclinical and clinical trial levels. The therapeutic efficacy observed with many of these approaches in patients indicates that these treatment modalities will serve as an important component of urological malignancy treatment in the clinic, either in isolation or

  15. The MTAP-CDKN2A Locus Confers Susceptibility to a Naturally Occurring Canine Cancer

    Science.gov (United States)

    Shearin, Abigail L.; Hedan, Benoit; Cadieu, Edouard; Erich, Suzanne A.; Schmidt, Emmett V.; Faden, Daniel L.; Cullen, John; Abadie, Jerome; Kwon, Erika M.; Gröne, Andrea; Devauchelle, Patrick; Rimbault, Maud; Karyadi, Danielle M.; Lynch, Mary; Galibert, Francis; Breen, Matthew; Rutteman, Gerard R.; André, Catherine; Parker, Heidi G.; Ostrander, Elaine A.

    2012-01-01

    Background Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15–25% of Bernese Mountain Dogs (BMD). Methods Genomic DNA was collected from affected and unaffected BMD in North America (NA) and Europe. Both independent and combined genome wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. Results Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. Conclusions We present the first GWAS for HS in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data demonstrate the power of studying distinctive malignancies in highly predisposed dog breeds. Impact Here, we establish a naturally-occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight regarding this cancer-associated, complex, and poorly understood genomic region. PMID:22623710

  16. Treating psoriasis by targeting its susceptibility gene Rel.

    Science.gov (United States)

    Fan, Tingting; Wang, Shaowen; Yu, Linjiang; Yi, Huqiang; Liu, Ruiling; Geng, Wenwen; Wan, Xiaochun; Ma, Yifan; Cai, Lintao; Chen, Youhai H; Ruan, Qingguo

    2016-04-01

    Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis.

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

    Science.gov (United States)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K; Broeks, Annegien; Van't Veer, Laura J; Hogervorst, Frans B; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Slettedahl, Seth; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Van Asperen, Christi J; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J; Hollestelle, Antoinette; van Deurzen, Carolien H M; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Pharoah, Paul D P; Dunning, Alison M; Shah, Mitul; Perkins, Barbara J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J; Meindl, Alfons; Schmutzler, Rita K; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Hunter, David J; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Easton, Douglas F; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian

    2015-05-15

    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 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

  18. HLA genes and other candidate genes involved in susceptibility for (pre)neoplastic cervical disease

    NARCIS (Netherlands)

    Zoodsma, M; Nolte, IM; Meerman, GJT; De Vries, EGE; Van Der Zee, AGJ

    2005-01-01

    This review focuses on common and genetic risk factors such as HLA and other genes that may be involved in susceptibility for (pre)neoplastic cervical disease. The goal of this review is the evaluation of polymorphisms that are either associated with cervical intraepithelial neoplasia (CIN) and/or c

  19. Genetic susceptibility variants associated with colorectal cancer prognosis.

    Science.gov (United States)

    Abulí, Anna; Lozano, Juan José; Rodríguez-Soler, María; Jover, Rodrigo; Bessa, Xavier; Muñoz, Jenifer; Esteban-Jurado, Clara; Fernández-Rozadilla, Ceres; Carracedo, Angel; Ruiz-Ponte, Clara; Cubiella, Joaquín; Balaguer, Francesc; Bujanda, Luis; Reñé, Josep M; Clofent, Juan; Morillas, Juan Diego; Nicolás-Pérez, David; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Andreu, Montserrat; Castells, Antoni; Castellví-Bel, Sergi

    2013-10-01

    Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

  20. 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...

  1. 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...

  2. Prioritization of Susceptibility Genes for Ectopic Pregnancy by Gene Network Analysis.

    Science.gov (United States)

    Liu, Ji-Long; Zhao, Miao

    2016-02-01

    Ectopic pregnancy is a very dangerous complication of pregnancy, affecting 1%-2% of all reported pregnancies. Due to ethical constraints on human biopsies and the lack of suitable animal models, there has been little success in identifying functionally important genes in the pathogenesis of ectopic pregnancy. In the present study, we developed a random walk-based computational method named TM-rank to prioritize ectopic pregnancy-related genes based on text mining data and gene network information. Using a defined threshold value, we identified five top-ranked genes: VEGFA (vascular endothelial growth factor A), IL8 (interleukin 8), IL6 (interleukin 6), ESR1 (estrogen receptor 1) and EGFR (epidermal growth factor receptor). These genes are promising candidate genes that can serve as useful diagnostic biomarkers and therapeutic targets. Our approach represents a novel strategy for prioritizing disease susceptibility genes.

  3. Asthma susceptible genes in Chinese population: A meta-analysis

    Directory of Open Access Journals (Sweden)

    He Chao

    2010-09-01

    Full Text Available Abstract Background Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population. Methods The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications. Results Seven polymorphisms were found being associated with risk of asthma, namely: A Disintegrin and Metalloprotease 33 (ADAM33 T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73, Angiotensin-Converting Enzyme (ACE D/I (OR = 3.85, 95%CI: 2.49-5.94, High-affinity IgE receptor β chain (FcεRIβ -6843G/A (OR = 1.49, 95%CI: 1.01-2.22, Interleukin 13(IL-13 -1923C/T (OR = 2.99, 95%CI: 2.12-4.24, IL-13 -2044A/G (OR = 1.49, 95%CI: 1.07-2.08, Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES -28C/G (OR = 1.64, 95%CI: 1.09-2.46, Tumor Necrosis Factor-α (TNF-α -308G/A(OR = 1.42, 95%CI: 1.09, 1.85. After subgroup analysis by age, the ACE D/I, β2-Adrenergic Receptor (β2-AR -79G/C, TNF-α -308G/A, Interleukin 4 receptor(IL-4R -1902G/A and IL-13 -1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the ACE D/I, FcεRIβ -6843G/A, TNF-α -308G/A, IL-13 -1923C/T and IL-13 -2044A/G polymorphisms were associated with asthma risk in Chinese adults. Conclusion ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R and IL-13 genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.

  4. Significant association among the Fas -670 A/G (rs1800682) polymorphism and esophageal cancer, hepatocellular carcinoma, and prostate cancer susceptibility: a meta-analysis.

    Science.gov (United States)

    Liu, Tao; Zuo, Li; Li, Lin; Yin, Lei; Liang, Kai; Yu, Hongyuan; Ren, Hui; Zhou, Wen; Jing, Hongwei; Liu, Yang; Kong, Chuize

    2014-11-01

    The Fas gene plays a key role in regulation of apoptotic cell death, and corruption of this signaling pathway has been shown to participate in immune escape and tumorgenesis. Single-nucleotide polymorphism in the promoter of Fas gene at position -670 A/G may affect its expression and play an important role in the pathology of many kinds of cancer. The association between Fas -670 A/G polymorphism and cancer risk is still controversial and ambiguous. Therefore, we conducted a meta-analysis of the currently literature to clarify this relationship. We conducted a search in the PubMed, EMbase, CNKI, and WanFang databases, covering all papers published by May 5, 2014. Overall, 59 case-control studies with 17,035 cases and 23,155 controls were retrieved based on the search criteria for cancer susceptibility related to -670 A/G polymorphism in Fas gene. Odds ratios (OR) and 95% confidence intervals (CI) revealed association strengths. Although no significant relationship was detected between Fas -670 A/G polymorphism and whole cancer risk, in the ethnicity subgroup, significant associations were found in three types of cancer: prostate cancer (OR = 1.06, 95% CI = 1.01-1.11 for A-allele vs. G-allele); hepatocellular carcinoma (OR = 0.89, 95% CI = 0.80-0.99 for AG vs. GG); esophageal cancer (OR = 0.95, 95% CI = 0.92-0.99 for AA + AG vs. GG). Moreover, lower cancer risk was found in smokers carried A-allele, when compared to smokers carried the GG genotype. The Fas -670 A/G polymorphism may be associated with esophageal cancer, hepatocellular carcinoma, and prostate cancer susceptibility from our meta-analysis. Studies with larger samples and gene-environment interactions are warranted to understand the role of Fas -670 A/G polymorphism for cancer risk.

  5. Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

    Science.gov (United States)

    Rapley, E A; Barfoot, R; Bonaïti-Pellié, C; Chompret, A; Foulkes, W; Perusinghe, N; Reeve, A; Royer-Pokora, B; Schumacher, V; Shelling, A; Skeen, J; Tourreil, S de; Weirich, A; Pritchard-Jones, K; Stratton, M R; Rahman, N

    2000-01-01

    Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found. © 2000 Cancer Research Campaign PMID:10901367

  6. Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer.

    Directory of Open Access Journals (Sweden)

    Jirong Long

    Full Text Available Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls. SNP rs9485372, near the TGF-β activated kinase (TAB2 gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals were 0.89 (0.85-0.94 and 0.80 (0.75-0.86 for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6 from the combined analysis of all samples, located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7, located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1, and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.

  7. Susceptibility genetic variants associated with early-onset colorectal cancer.

    Science.gov (United States)

    Giráldez, María Dolores; López-Dóriga, Adriana; Bujanda, Luis; Abulí, Anna; Bessa, Xavier; Fernández-Rozadilla, Ceres; Muñoz, Jenifer; Cuatrecasas, Miriam; Jover, Rodrigo; Xicola, Rosa M; Llor, Xavier; Piqué, Josep M; Carracedo, Angel; Ruiz-Ponte, Clara; Cosme, Angel; Enríquez-Navascués, José María; Moreno, Victor; Andreu, Montserrat; Castells, Antoni; Balaguer, Francesc; Castellví-Bel, Sergi

    2012-03-01

    Colorectal cancer (CRC) is the second most common cancer in Western countries. Hereditary forms only correspond to 5% of CRC burden. Recently, genome-wide association studies have identified common low-penetrant CRC genetic susceptibility loci. Early-onset CRC (CRC65 years old) (n = 1264). CRC susceptibility variants at 8q23.3 (rs16892766), 8q24.21 (rs6983267), 10p14 (rs10795668), 11q23.1 (rs3802842), 15q13.3 (rs4779584), 18q21 (rs4939827), 14q22.2 (rs4444235), 16q22.1 (rs9929218), 19q13.1 (rs10411210) and 20p12.3 (rs961253) were genotyped in all DNA samples. A genotype-phenotype correlation with clinical and pathological characteristics in both groups was performed. Risk allele carriers for rs3802842 [Odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.05, P = 0.0096, dominant model) and rs4779584 (OR = 1.39, 95% CI 1.02-1.9, P = 0.0396, dominant model) were more frequent in the CRC<50 group, whereas homozygotes for rs10795668 risk allele were also more frequent in the early-onset CRC (P = 0.02, codominant model). Regarding early-onset cases, 14q22 (rs4444235), 11q23 (rs3802842) and 20p12 (rs961253) variants were more associated with family history of CRC or tumors of the Lynch syndrome spectrum excluding CRC. In our entire cohort, sum of risk alleles was significantly higher in patients with a CRC family history (OR = 1.40, 95% CI 1.06-1.85, P = 0.01). In conclusion, variants at 10p14 (rs10795668), 11q23.1 (rs3802842) and 15q13.3 (rs4779584) may have a predominant role in predisposition to early-onset CRC. Association of CRC susceptibility variants with some patient's familiar and personal features could be relevant for screening and surveillance strategies in this high-risk group and it should be explored in further studies.

  8. The relationship between polymorphisms of xenobiotic metabolizing enzymes and susceptibility to cancer.

    Science.gov (United States)

    Vineis, Paolo

    2002-12-27

    Although it is well established that highly penetrant genes explain less than 5% of all cancers, it is much less clear what proportion is attributable to low penetrant genes and their interactions with environmental exposures. It was possible to estimate indirectly the fraction of lung and bladder cancers attributable to known genetic polymorphisms, on the basis of an extensive review of the literature, and of the pooled analyses of approximately 15000 healthy subjects in three continents. The emerging picture is one of considerable homogeneity within ethnic group, and heterogeneity among ethnic groups. By combining relative risks and genotype frequencies we have computed theoretical attributable risks for lung and bladder cancers and the CYP1A1 Msp1, CYP1A1 Exon 7, GSTM1 and NAT2*5 genotypes, among Caucasians and among Asians. Such attributable risks are probably overestimated, since: (a) they include the interaction with carcinogenic exposures, in the absence of which genetic polymorphisms per se are not effective; (b) they do not reflect the combination of different genotypes. However, our calculations suggest that attributable risks due to genetic susceptibility are much lower than those related to smoking or other environmental risk factors, and that Asians seem to carry higher risks than Caucasians. In addition, a theoretical approach to the problem of gene-environment interactions at low levels of exposure is offered.

  9. Gene therapy for gastric cancer: A review

    Institute of Scientific and Technical Information of China (English)

    Chao Zhang; Zhan-Kui Liu

    2003-01-01

    Gastric cancer is common in China, and its early diagnosis and treatment are difficult. In recent years great progress has been achieved in gene therapy, and a wide array of gene therapy systems for gastric cancer has been investigated. The present article deals with the general principles of gene therapy and then focuses on how these principles may be applied to gastric cancer.

  10. Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes.

    Science.gov (United States)

    Thier, Ricarda; Brüning, Thomas; Roos, Peter H; Rihs, Hans-Peter; Golka, Klaus; Ko, Yon; Bolt, Hermann M

    2003-06-01

    Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of

  11. Relationship between hOGG1 and XPD gene polymorphism and genetic susceptibility of gastric cancer%人类8-羟基鸟嘌呤DNA糖苷酶1及着色性干皮病基因D基因多态性与胃癌遗传易感性的关系研究

    Institute of Scientific and Technical Information of China (English)

    郭燕

    2014-01-01

    Objective To investigate the relationship between hOGG1 and XPD gene polymorphism and genetic susceptibility of gastric cancer.Methods This study was carried out in Dongying Shengli Petroleum Administration Bureau Hospital.Under the narrow band imaging(NBI) mode,the blood samples of a total of 98 gastric cancers and 80 controls without cancers were collected.Genetic polymorphisms of DNA repair genes were identified by polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP),then its relationship with cancers was analyzed.Results Carrying 326Cys allele with the wine increased the risk of gastric cancer; Lys 751Gln genotype increased the susceptibility of the gastric cancers (OR =1.486,0.73 ~ 3.025).Conclusion Lys751 Gln genotype increases the risk of gastric cancer.%目的 探讨人类8-羟基鸟嘌呤DNA糖苷酶1(hOGG 1)基因和人类着色性干皮病基因D(XPD)基因多态性与胃癌遗传易感性的关系.方法 收集胜利石油管理局胜利医院98例胃癌患者和80例非肿瘤对照组志愿者,内镜窄带成像(NBI)模式下取出病理组织,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)检测法检测胃癌人群的外周血中DNA损伤修复酶基因多态性,分析其与肿瘤遗传易感性的关系.结果 Lys751 Gln基因型使胃癌的发病风险增加1.5倍(OR值=1.486,0.730 ~3.025).两基因的交互作用使胃癌的发病风险降低(S<1,API =0.24).结论 Lys751 Gln基因型与个体患胃癌疾病的易感性可能有相关性.

  12. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Valentina Escott-Price

    Full Text Available Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6 and 14 (IGHV1-67 p = 7.9×10-8 which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  13. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

    Science.gov (United States)

    Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; 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; Hernández, Isabel; 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.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; 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; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Van Broeckhoven, Christine; Farrer, Lindsay A.; van Duijn, Cornelia M.; Ramirez, Alfredo

    2014-01-01

    Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. PMID:24922517

  14. Identification of susceptibility genes and genetic modifiers of human diseases

    Science.gov (United States)

    Abel, Kenneth; Kammerer, Stefan; Hoyal, Carolyn; Reneland, Rikard; Marnellos, George; Nelson, Matthew R.; Braun, Andreas

    2005-03-01

    The completion of the human genome sequence enables the discovery of genes involved in common human disorders. The successful identification of these genes is dependent on the availability of informative sample sets, validated marker panels, a high-throughput scoring technology, and a strategy for combining these resources. We have developed a universal platform technology based on mass spectrometry (MassARRAY) for analyzing nucleic acids with high precision and accuracy. To fuel this technology, we generated more than 100,000 validated assays for single nucleotide polymorphisms (SNPs) covering virtually all known and predicted human genes. We also established a large DNA sample bank comprised of more than 50,000 consented healthy and diseased individuals. This combination of reagents and technology allows the execution of large-scale genome-wide association studies. Taking advantage of MassARRAY"s capability for quantitative analysis of nucleic acids, allele frequencies are estimated in sample pools containing large numbers of individual DNAs. To compare pools as a first-pass "filtering" step is a tremendous advantage in throughput and cost over individual genotyping. We employed this approach in numerous genome-wide, hypothesis-free searches to identify genes associated with common complex diseases, such as breast cancer, osteoporosis, and osteoarthritis, and genes involved in quantitative traits like high density lipoproteins cholesterol (HDL-c) levels and central fat. Access to additional well-characterized patient samples through collaborations allows us to conduct replication studies that validate true disease genes. These discoveries will expand our understanding of genetic disease predisposition, and our ability for early diagnosis and determination of specific disease subtype or progression stage.

  15. Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

    Science.gov (United States)

    Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

    2016-01-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. PMID:27432226

  16. IL18 Gene Variants Influence the Susceptibility to Chagas Disease

    Science.gov (United States)

    Leon Rodriguez, Daniel A; Carmona, F. David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-01-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  17. Gene-network analysis identifies susceptibility genes related to glycobiology in autism.

    Directory of Open Access Journals (Sweden)

    Bert van der Zwaag

    Full Text Available The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD, and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.

  18. Evaluation of breast cancer susceptibility using improved genetic algorithms to generate genotype SNP barcodes.

    Science.gov (United States)

    Yang, Cheng-Hong; Lin, Yu-Da; Chuang, Li-Yeh; Chang, Hsueh-Wei

    2013-01-01

    Genetic association is a challenging task for the identification and characterization of genes that increase the susceptibility to common complex multifactorial diseases. To fully execute genetic studies of complex diseases, modern geneticists face the challenge of detecting interactions between loci. A genetic algorithm (GA) is developed to detect the association of genotype frequencies of cancer cases and noncancer cases based on statistical analysis. An improved genetic algorithm (IGA) is proposed to improve the reliability of the GA method for high-dimensional SNP-SNP interactions. The strategy offers the top five results to the random population process, in which they guide the GA toward a significant search course. The IGA increases the likelihood of quickly detecting the maximum ratio difference between cancer cases and noncancer cases. The study systematically evaluates the joint effect of 23 SNP combinations of six steroid hormone metabolisms, and signaling-related genes involved in breast carcinogenesis pathways were systematically evaluated, with IGA successfully detecting significant ratio differences between breast cancer cases and noncancer cases. The possible breast cancer risks were subsequently analyzed by odds-ratio (OR) and risk-ratio analysis. The estimated OR of the best SNP barcode is significantly higher than 1 (between 1.15 and 7.01) for specific combinations of two to 13 SNPs. Analysis results support that the IGA provides higher ratio difference values than the GA between breast cancer cases and noncancer cases over 3-SNP to 13-SNP interactions. A more specific SNP-SNP interaction profile for the risk of breast cancer is also provided.

  19. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each p...... with a high frequency of loss of heterozygosity. The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of CRC.......Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226...

  20. Polymorphism of exon G435T in RASSF1A gene associated with the susceptibility of breast cancer%RASSF1A基因G435T多态性与乳腺癌易感性的相关性研究

    Institute of Scientific and Technical Information of China (English)

    李建国; 焦玮; 王宇; 柳晓义

    2011-01-01

    Objective: To explore the relationship between the polymorphism of the third exon G435T in Ras association domain family 1A (RASSF1A) gene and the susceptibility of breast cancer. Methods: The polymorphism of G435T in RASSF1A gene was determined in 212 female patients with breast cancer, 218 female patients with breast benign disease and 220 female healthy controls by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, and the correlation of RASSF1A polymorphism with the susceptibility of breast cancer was evaluated. Results: The frequencies of GT+TT and T allele at G435T site in RASSF1A gene were significantly higher in patients with breast cancer than those with benign breast disease and healthy controls. Conclusion: The polymorphism of the third exon G435T in RASSF1A gene may be associated with the susceptibility of breast cancer. RASSF1A 435T allele can be a potential predictive factor for the risk of breast cancer.%目的:探讨肿瘤抑制基因Ras相关区域家族1A基因(Ras association domain family 1A gene,RASSF1A)第3外显子G435T多态性与乳腺癌发病的相关性.方法:采用聚合酶链反应-单链构象多态性分析(PCR-single strand conformation polymorphism analysis,PCR-SSCP)法检测212例乳腺癌患者、218例乳腺良性病变患者,及220例健康对照人群RASSF1A基因G435T的多态性,并分析RASSFIA基因多态性与乳腺癌易感性的相关性.结果:RASSF1A基因G435T位点的TG+TT基因型及T等位基因的频率乳腺癌组明显高于乳腺良性病变组和健康对照人群组2个对照组.而乳腺良性病变组与健康对照人群组之间,则差异无统计学意义;结论:RASSF1A基因第3外显子G435T位点G/T多态性可能为乳腺癌发病的易感基因位点,T等位基因可能乳腺癌发病的易感基因位点.

  1. Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma.

    Science.gov (United States)

    Jannot, Anne-Sophie; Meziani, Roubila; Bertrand, Guylene; Gérard, Benedicte; Descamps, Vincent; Archimbaud, Alain; Picard, Catherine; Ollivaud, Laurence; Basset-Seguin, Nicole; Kerob, Delphine; Lanternier, Guy; Lebbe, Celeste; Saiag, P; Crickx, Beatrice; Clerget-Darpoux, Françoise; Grandchamp, Bernard; Soufir, Nadem; Melan-Cohort

    2005-08-01

    The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.

  2. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.

    Science.gov (United States)

    Hamdi, Yosr; Soucy, Penny; Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G; Goldberg, Mark S; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J; Hopper, John L; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Le Marchand, Loic; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J; Schmidt, Marjanka K; Shu, Xiao-Ou; Southey, Melissa C; Swerdlow, Anthony; Tollenaar, Rob A E M; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M W; Wang, Qin; Winqvist, Robert; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M; Pharoah, Paul D P; Kristensen, Vessela; Hall, Per; Easton, Douglas F; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-12-06

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.

  3. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

    Science.gov (United States)

    Adoue, Véronique; Michailidou, Kyriaki; Canisius, Sander; Lemaçon, Audrey; Droit, Arnaud; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broeks, Annegien; Burwinkel, Barbara; Chang-Claude, Jenny; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Eriksson, Mikael; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Grenaker-Alnæs, Grethe; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hallberg, Emily; Hooning, Maartje J.; Hopper, John L.; Jakubowska, Anna; Jones, Michael; Kabisch, Maria; Kataja, Vesa; Lambrechts, Diether; Marchand, Loic Le; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Maranian, Mel; Margolin, Sara; Marme, Frederik; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Neven, Patrick; Olswold, Curtis; Peto, Julian; Plaseska-Karanfilska, Dijana; Pylkäs, Katri; Radice, Paolo; Rudolph, Anja; Sawyer, Elinor J.; Schmidt, Marjanka K.; Shu, Xiao-Ou; Southey, Melissa C.; Swerdlow, Anthony; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Vachon, Celine; Van Den Ouweland, Ans M. W.; Wang, Qin; Winqvist, Robert; Investigators, kConFab/AOCS; Zheng, Wei; Benitez, Javier; Chenevix-Trench, Georgia; Dunning, Alison M.; Pharoah, Paul D. P.; Kristensen, Vessela; Hall, Per; Easton, Douglas F.; Pastinen, Tomi; Nord, Silje; Simard, Jacques

    2016-01-01

    There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas. PMID:27792995

  4. Impacts of CA9 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan.

    Directory of Open Access Journals (Sweden)

    Shian-Shiang Wang

    Full Text Available BACKGROUND: 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 effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC and the clinicopathological status. METHODOLOGY AND PRINCIPAL FINDINGS: A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05 than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638 had a 4.75-fold (95% CI = 1.204-18.746 increased risk of invasive cancer. CONCLUSION: The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan.

  5. Schizophrenia susceptibility gene locus at Xp22.3.

    Science.gov (United States)

    Milunsky, J; Huang, X L; Wyandt, H E; Milunsky, A

    1999-06-01

    Multiple genetic loci have been implicated in the search for schizophrenia susceptibility genes, none having been proven as causal. Genetic heterogeneity is probable in the polygenic etiology of schizophrenia. We report on two unrelated Caucasian women with paranoid schizophrenia (meeting Diagnostic and Statistical Manual of Mental Disorders (DSM IV) criteria) who have an Xp22.3 overlapping deletion characterized by fluorescence in situ hybridization (FISH). Patient 1 was previously reported by us (Wyandt HE, Bugeau-Michaud L, Skare JC, Milunsky A. Partial duplication of Xp: a case report and review of previously reported cases. Amer J Med Genet 1991: 40: 280-283) to have a de novo partial duplication of Xp. At that time, she was a 24-year-old woman with short stature, irregular menses, other abnormalities suggestive of Turner syndrome, and paranoid schizophrenia. Recently, FISH analysis demonstrated that she has an inverted duplication (X)(p22.1p11.2) and a microscopic deletion (X)(p22.2p22.3) between DXS1233 and DXS7108 spanning approximately 16-18 cM. Patient 2 is a 14-year-old girl with short stature, learning disabilities, and paranoid schizophrenia. High-resolution chromosome analysis revealed a de novo deletion involving Xp22. FISH analysis showed that the deletion (X)(p22.2p22.3) spanned 10-12 cM between AFMB290XG5 and DXS1060. Given that deletions of Xp22 are not common events, the occurrence of two unrelated schizophrenia patients with an overlapping deletion of this region would be extraordinarily rare. Hence, the deletion within Xp22.3 almost certainly contains a gene involved in the pathogenesis of paranoid schizophrenia.

  6. 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.

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

    NARCIS (Netherlands)

    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, w

  8. 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 ...

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

    DEFF Research Database (Denmark)

    Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki

    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...

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

    NARCIS (Netherlands)

    Ghoussaini, M.; Fletcher, O.; Michailidou, K.; Turnbull, C.; Schmidt, M.K.; Dicks, E.; Dennis, J.; Wang, Q.; Humphreys, M.K.; Luccarini, C.; Baynes, C.; Conroy, D.; Maranian, M.; Ahmed, S.; Driver, K.; Johnson, N.; Orr, N.; dos Santos Silva, I.; Waisfisz, Q.; Meijers-Heijboer, H.; Uitterlinden, A.G.; Rivadeneira, F.; Hall, P.; Czene, K.; Irwanto, A.; Liu, J.; Nevanlinna, H.; Aittomaki, K.; Blomqvist, C.; Meindl, A.; Schmutzler, R.K.; Muller-Myhsok, B.; Lichtner, P.; Chang-Claude, J.; Hein, R.; Nickels, S.; Flesch-Janys, D.; Tsimiklis, H.; Makalic, E.; Schmidt, D.; Bui, M.; Hopper, J.L.; Apicella, C.; Park, D.J.; Southey, M.; Hunter, D.J.; Chanock, S.J.; Broeks, A.; Verhoef, S.; Hogervorst, F.B.; Fasching, P.A.; Lux, M.P.; Beckmann, M.W.; Ekici, A.B.; Sawyer, E.; Tomlinson, I.; Kerin, M.; Marme, F.; Schneeweiss, A.; Sohn, C.; Burwinkel, B.; Guenel, P.; Truong, T.; Cordina-Duverger, E.; Menegaux, F.; Bojesen, S.E.; Nordestgaard, B.G.; Nielsen, S.F.; Flyger, H.; Milne, R.L.; Alonso, M.R.; Gonzalez-Neira, A.; Benitez, J.; Anton-Culver, H.; Ziogas, A.; Bernstein, L.; Dur, C.C.; Brenner, H.; Muller, H.; Arndt, V.; Stegmaier, C.; Justenhoven, C.; Brauch, H.; Bruning, T.; Wang-Gohrke, S.; Eilber, U.; Dork, T.; Schurmann, P.; Bremer, M.; Hillemanns, P.; Bogdanova, N.V.; Antonenkova, N.N.; Rogov, Y.I.; Karstens, J.H.; Bermisheva, M.; Prokofieva, D.; Ligtenberg, M.J.

    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 approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies

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

    NARCIS (Netherlands)

    M. Riaz (Muhammad); F. Elstrodt (Fons); A. Hollestelle (Antoinette); A. Dehghan (Abbas); J.G.M. Klijn (Jan); M. Schutte (Mieke)

    2009-01-01

    textabstractBackground: Low-risk breast cancer susceptibility alleles or SNPs confer only modest breast cancer risks ranging from just over 1.0 to 1.3 fold. Yet, they are common among most populations and therefore are involved in the development of essentially all breast cancers. The mechanism by w

  12. 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.

  13. 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.

  14. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  15. Genetic susceptibility and environmental factors of esophageal cancer in Xi'an

    Institute of Scientific and Technical Information of China (English)

    An-Hui Wang; Chang-Sheng Sun; Liang-Shou Li; Jiu-Yi Huang; Qing-Shu Chen; De-Zhong Xu

    2004-01-01

    AIM: To analyse the role of genetic susceptibility and environmental factors in the process of esophageal cancer (EC) formation in Xi'an, China.METHODS: A hospital based case-control study, combined with molecular epidemiological method, was carried out. A total of 127 EC cases and 101 controls were interviewed with questionnaires containing demographic items, habit of tobacco smoking, alcohol drinking, and family history of EC.Polymorphism of CYP1A1 and GSTM1 of 127 EC cases and 101 controls were detected by PCR method. The interactions between genetic susceptibility and environmental factors were also discussed.RESULTS: Tobacco smoking, alcohol drinking and a family history of EC were risk factors for EC with an OR of 2.04(95% CI 1.15-3.60), 3.45(95% CI 1.74-6.91), 3.14 (95%CI 1.28-7.94), respectively. Individuals carrying CYP1A1 Val/Valgenotype compared to those with CYP1A1 Ile/Ile genotype had an increased risk for EC (OR 3.35, 95% CI 1.49-7.61). GSTM1 deletion genotype was a risk factor for EC (OR1.81, 95% CI 1.03-3.18). Gene-environment interaction analysis showed that CYP1A1 Val/Valgenotype, GSTM1 deletion genotype had synergetic interactions with tobacco smoking, alcohol drinking and family history of EC.CONCLUSION: Tobacco smoking, alcohol drinking and a family history of EC are risk factors for EC. CYP1A1 Val/'Va/and GSTM1 deletion genotypes are genetic susceptibility biomarkers for EC. There are synergic interactions between genetic susceptibility and environmental factors.

  16. Gene Therapy In Oral Cancer : An Overview

    OpenAIRE

    2010-01-01

    The treatment and prevention of oral cancer is one of the major hurdles in the field ofcancer. Gene therapy is one of the recent advances in this field to tackle this hurdle with promisingprospects. This overview introduces the reader into the basic idea of gene therapy, types of genetherapy and the various modes of introduction of therapeutic gene into the cancer affected cell.

  17. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour

    NARCIS (Netherlands)

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-01-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive en

  18. Application of fuzzy consensus for oral pre-cancer and cancer susceptibility assessment

    Directory of Open Access Journals (Sweden)

    Satarupa Banerjee

    2016-11-01

    Full Text Available Health questionnaire data assessment conventionally relies upon statistical analysis in understanding disease susceptibility using discrete numbers and fails to reflect physician’s perspectives and missing narratives in data, which play subtle roles in disease prediction. In addressing such limitations, the present study applies fuzzy consensus in oral health and habit questionnaire data for a selected Indian population in the context of assessing susceptibility to oral pre-cancer and cancer. Methodically collected data were initially divided into age based small subgroups and fuzzy membership function was assigned to each. The methodology further proposed the susceptibility to oral precancers (viz. leukoplakia, oral submucous fibrosis and squamous cell carcinoma in patients considering a fuzzy rulebase through If-Then rules with certain conditions. Incorporation of similarity measures using the Jaccard index was used during conversion into the linguistic output of fuzzy set to predict the disease outcome in a more accurate manner and associated condition of the relevant features. It is also expected that this analytical approach will be effective in devising strategies for policy making through real-life questionnaire data handling.

  19. Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions.

    Directory of Open Access Journals (Sweden)

    Ho-Chang Kuo

    Full Text Available Kawasaki disease (KD is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL formation. We examined 384 single-nucleotide polymorphisms (SNPs for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73, KD patients without CAL (n = 153, and cohort controls (n = 575. Individual SNPs were first assessed by univariate analysis (UVA and multivariate analysis (MVA. We used multifactor dimensionality reduction (MDR to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10, while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05. Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05. In logistic regression, combined possession of PDE2A (rs341058 and CYFIP2 (rs767007 significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7, while combinations of LOC100133214 (rs2517892 and IL2RA (rs3118470 significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5. Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

  20. 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...

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

    NARCIS (Netherlands)

    N. Orr (Nick); F. Dudbridge (Frank); N. Dryden (Nicola); S. Maguire (Sarah); D. Novo (Daniela); E. Perrakis (Eleni); N. Johnson (Nichola); M. Ghoussaini (Maya); J. Hopper (John); M.C. Southey (Melissa); C. Apicella (Carmel); J. Stone (Jennifer); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); F.B.L. Hogervorst (Frans); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias W.); L.J. Gibson (Lorna); A. Aitken; H. Warren (Helen); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Chistof); P. Guénel (Pascal); T. Truong (Thérèse); E. Cordina-Duverger (Emilie); M. Sanchez (Marie); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); U. Hamann (Ute); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); Y.-D. Ko (Yon-Dschun); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Khan (Sofia); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); D. Lambrechts (Diether); M. Moisse (Matthieu); O.A.M. Floris; B. Beuselinck (B.); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); P. Radice (Paolo); P. Peterlongo (Paolo); B. Peissel (Bernard); V. Pensotti (Valeria); F.J. Couch (Fergus); J.E. Olson (Janet); S. Slettedahl (Seth); C. Vachon (Celine); G.G. Giles (Graham G.); R.L. Milne (Roger L.); C.A. McLean (Catriona Ann); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); J. Simard (Jacques); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); V. Kristensen (Vessela); G.G. Alnæs (Grethe Grenaker); S. Nord (Silje); A.-L. Borresen-Dale (Anne-Lise); W. Zheng (Wei); S.L. Deming-Halverson (Sandra); M. Shrubsole (Martha); J. Long (Jirong); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); P. Devilee (Peter); R.A.E.M. Tollenaar (Robertus A. E. M.); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); D. Klevebring (Daniel); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); C.H.M. van Deurzen (Carolien); M. Kriege (Mieke); P. Hall (Per); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); M. Shah (Mitul); B. Perkins (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Michael); M. Schoemaker (Minouk); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Olswold (Curtis); S. Slager (Susan); A.E. Toland (Amanda); D. Yannoukakos (Drakoulis); K.R. Muir (K.); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); K. Matsuo (Keitaro); H. Ito (Hidema); H. Iwata (Hisato); J. Ishiguro (Junko); A.H. Wu (Anna H.); C.-C. Tseng (Chiu-chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); S.-H. Teo; C.H. Yip (Cheng Har); P. Kang (Peter); M.K. Ikram (Kamran); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; H. Cai (Hui); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); D-Y. Noh (Dong-Young); J.M. Hartman (Joost); X. Miao; W.-Y. Lim (Wei-Yen); S.C. Lee (Soo Chin); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); J-C. Yu (Jyh-Cherng); C-Y. Shen (Chen-Yang); W.J. Blot (William); Q. Cai (Qiuyin); L.B. Signorello (Lisa B.); C. Luccarini (Craig); C. Bayes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); A. González-Neira (Anna); G. Pita (G.); M. Rosario Alonso; N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); D. Hunter (David); S. Lindstrom (Stephen); J. Dennis (Joe); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet); D.F. Easton (Douglas); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); J. Peto (Julian)

    2015-01-01

    textabstractWe 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

  2. Relationship Between LAPTM4B Gene Polymorphism and Susceptibility of Malignant Melanoma in Chinese Patients

    Directory of Open Access Journals (Sweden)

    Meng Zhang

    2014-10-01

    Full Text Available Lysosomal-associated protein transmembrane 4 beta (LAPTM4B is known as an oncogene associated with many human malignant tumors. There are two alleles of the gene, LAPTM4B*1 and LAPTM4B*2. Previous studies have shown that LAPTM4B polymorphism contributes to the risk of many cancers. This case-control study was to investigate the relationship between LAPTM4B gene polymorphism and susceptibility of malignant melanoma. The genotypes of LAPTM4B were determined in 617 control subjects and 220 patients with malignant melanoma by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B and Hardy–Weinberg equilibrium were analyzed by χ2 test. Odds ratio and 95% confidence interval was calculated by unconditional logistic regression. The distributions of LAPTM4B genotypes were significantly different between melanoma patients (45.9% for *1/1, 46.4% for *1/2 and 7.7 for *2/2 and controls (54.5% for *1/1, 39.9% for *1/2 and 5.7 for *2/2. LAPTM4B *1/2 and LAPTM4B *2/2 had a 1.396-fold and 1.619-fold higher risk for melanoma occurrence than *1/1, and subjects with LAPTM4B*2 have a 1.308-fold higher risk than LAPTM4B*1 carriers. No association between LAPTM4B genotypes and gender, age, subtype, Clark level of invasion, Breslow thickness, ulceration, clinical stage, and C-KIT, BRAF gene mutation status was observed. LAPTM4B*2 is associated with the high risk of malignant melanoma and carrying LAPTM4B *2 may be a susceptible factor to Chinese melanoma patients.

  3. Interaction of collagen-related genes and susceptibility to betel quid-induced oral submucous fibrosis.

    Science.gov (United States)

    Chiu, Chung-Jung; Chang, Min-Lee; Chiang, Chun-Pin; Hahn, Liang-Jiunn; Hsieh, Ling-Ling; Chen, Chien-Jen

    2002-07-01

    Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity. It is a collagen-related disorder induced by betel quid chewing, a habit that is common in Taiwan. However, the cumulative exposure to betel quids varies in OSF patients. It seems that there is individual susceptibility to betel quid-induced OSF. This study compared the association of OSF and polymorphisms of six collagen-related genes, collagen 1A1 and 1A2 (COL1A1 and COL1A2), collagenase-1 (COLase), transforming growth factor beta1 (TGF-beta1), lysyl oxidase (LYOXase), and cystatin C (CST3), between patients with low and high exposure to betel quids. A total of 166 patients with OSF from a medical center and 284 betel quid chewers who were free of OSF and oral cancer, from the same hospital and five townships, were recruited. PCR-based restriction fragment length polymorphism assays were used to determine the genotypes of the six collagen-related genes situated on different chromosomes. We found that the genotypes associated with the highest OSF risk for collagen 1A1, collagen 1A2, collagenase-1, transforming growth factor beta1, lysyl oxidase, and cystatin C were CC, AA, TT, CC, AA, and AA, respectively, for the low-exposure group, and TT, BB, AA, CC, GG, and AA, respectively, for the high-exposure group. A trend was noted for an increased risk of OSF with increasing number of high-risk alleles for those with both high and low exposures for betel quid. The cell selection mechanism of oral fibroblasts is proposed to explain the effect of the modification of cumulative betel quid exposure on the risk profiles of collagen-related genes. These results imply that susceptibility to OSF could involve multigenic mechanisms modified by the betel quid-exposure dose.

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

    Science.gov (United States)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.; Hogervorst, Frans B.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J.; Olson, Janet E.; Slettedahl, Seth; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A. E. M.; Seynaeve, Caroline M.; Van Asperen, Christi J.; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J.; Hollestelle, Antoinette; van Deurzen, Carolien H. M.; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Pharoah, Paul D. P.; Dunning, Alison M.; Shah, Mitul; Perkins, Barbara J.; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J.; Meindl, Alfons; Schmutzler, Rita K.; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B.; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S.; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Hunter, David J.; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K.; Easton, Douglas F.; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian

    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 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. PMID:25652398

  5. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

    Science.gov (United States)

    Milne, Roger L; Burwinkel, Barbara; Michailidou, Kyriaki; Arias-Perez, Jose-Ignacio; Zamora, M Pilar; Menéndez-Rodríguez, Primitiva; Hardisson, David; Mendiola, Marta; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Dennis, Joe; Wang, Qin; Bolla, Manjeet K; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk; Ko, Yon-Dschun; Brauch, Hiltrud; Hamann, Ute; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Li, Jingmei; Brand, Judith S; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Lambrechts, Diether; Peuteman, Gilian; Christiaens, Marie-Rose; Smeets, Ann; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katazyna; Hartman, Mikael; Hui, Miao; Yen Lim, Wei; Wan Chan, Ching; Marme, Federick; Yang, Rongxi; Bugert, Peter; Lindblom, Annika; Margolin, Sara; García-Closas, Montserrat; Chanock, Stephen J; Lissowska, Jolanta; Figueroa, Jonine D; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Hooning, Maartje J; Kriege, Mieke; van den Ouweland, Ans M W; Koppert, Linetta B; Fletcher, Olivia; Johnson, Nichola; dos-Santos-Silva, Isabel; Peto, Julian; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha J; Long, Jirong; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Schmidt, Marjanka K; Broeks, Annegien; Cornelissen, Sten; Braaf, Linde; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Simard, Jacques; Dumont, Martine; Goldberg, Mark S; Labrèche, France; Fasching, Peter A; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Radice, Paolo; Peterlongo, Paolo; Azzollini, Jacopo; Barile, Monica; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Hopper, John L; Schmidt, Daniel F; Makalic, Enes; Southey, Melissa C; Hwang Teo, Soo; Har Yip, Cheng; Sivanandan, Kavitta; Tay, Wan-Ting; Shen, Chen-Yang; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Hou, Ming-Feng; Guénel, Pascal; Truong, Therese; Sanchez, Marie; Mulot, Claire; Blot, William; Cai, Qiuyin; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Bogdanova, Natalia; Dörk, Thilo; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Zhang, Ben; Couch, Fergus J; Toland, Amanda E; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; McKay, James; Wang, Xianshu; Olson, Janet E; Vachon, Celine; Purrington, Kristen; Severi, Gianluca; Baglietto, Laura; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Czene, Kamila; Eriksson, Mikael; Humphreys, Keith; Darabi, Hatef; Ahmed, Shahana; Shah, Mitul; Pharoah, Paul D P; Hall, Per; Giles, Graham G; Benítez, Javier; Dunning, Alison M; Chenevix-Trench, Georgia; Easton, Douglas F

    2014-11-15

    Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.

  6. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

    Science.gov (United States)

    Milne, Roger L.; Burwinkel, Barbara; Michailidou, Kyriaki; Arias-Perez, Jose-Ignacio; Zamora, M. Pilar; Menéndez-Rodríguez, Primitiva; Hardisson, David; Mendiola, Marta; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Dennis, Joe; Wang, Qin; Bolla, Manjeet K.; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk; Ko, Yon-Dschun; Brauch, Hiltrud; Hamann, Ute; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Li, Jingmei; Brand, Judith S.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Lambrechts, Diether; Peuteman, Gilian; Christiaens, Marie-Rose; Smeets, Ann; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katazyna; Hartman, Mikael; Hui, Miao; Yen Lim, Wei; Wan Chan, Ching; Marme, Federick; Yang, Rongxi; Bugert, Peter; Lindblom, Annika; Margolin, Sara; García-Closas, Montserrat; Chanock, Stephen J.; Lissowska, Jolanta; Figueroa, Jonine D.; Bojesen, Stig E.; Nordestgaard, Børge G.; Flyger, Henrik; Hooning, Maartje J.; Kriege, Mieke; van den Ouweland, Ans M.W.; Koppert, Linetta B.; Fletcher, Olivia; Johnson, Nichola; dos-Santos-Silva, Isabel; Peto, Julian; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha J.; Long, Jirong; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Schmidt, Marjanka K.; Broeks, Annegien; Cornelissen, Sten; Braaf, Linde; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Simard, Jacques; Dumont, Martine; Goldberg, Mark S.; Labrèche, France; Fasching, Peter A.; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Radice, Paolo; Peterlongo, Paolo; Azzollini, Jacopo; Barile, Monica; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Hopper, John L.; Schmidt, Daniel F.; Makalic, Enes; Southey, Melissa C.; Hwang Teo, Soo; Har Yip, Cheng; Sivanandan, Kavitta; Tay, Wan-Ting; Shen, Chen-Yang; Hsiung, Chia-Ni; Yu, Jyh-Cherng; Hou, Ming-Feng; Guénel, Pascal; Truong, Therese; Sanchez, Marie; Mulot, Claire; Blot, William; Cai, Qiuyin; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Wu, Anna H.; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O.; Bogdanova, Natalia; Dörk, Thilo; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Zhang, Ben; Couch, Fergus J.; Toland, Amanda E.; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; McKay, James; Wang, Xianshu; Olson, Janet E.; Vachon, Celine; Purrington, Kristen; Severi, Gianluca; Baglietto, Laura; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Czene, Kamila; Eriksson, Mikael; Humphreys, Keith; Darabi, Hatef; Ahmed, Shahana; Shah, Mitul; Pharoah, Paul D.P.; Hall, Per; Giles, Graham G.; Benítez, Javier; Dunning, Alison M.; Chenevix-Trench, Georgia; Easton, Douglas F.; Berchuck, Andrew; Eeles, Rosalind A.; Olama, Ali Amin Al; Kote-Jarai, Zsofia; Benlloch, Sara; Antoniou, Antonis; McGuffog, Lesley; Offit, Ken; Lee, Andrew; Dicks, Ed; Luccarini, Craig; Tessier, Daniel C.; Bacot, Francois; Vincent, Daniel; LaBoissière, Sylvie; Robidoux, Frederic; Nielsen, Sune F.; Cunningham, Julie M.; Windebank, Sharon A.; Hilker, Christopher A.; Meyer, Jeffrey; Angelakos, Maggie; Maskiell, Judi; van der Schoot, Ellen; Rutgers, Emiel; Verhoef, Senno; Hogervorst, Frans; Boonyawongviroj, Prat; Siriwanarungsan, Pornthep; Schrauder, Michael; Rübner, Matthias; Oeser, Sonja; Landrith, Silke; Williams, Eileen; Ryder-Mills, Elaine; Sargus, Kara; McInerney, Niall; Colleran, Gabrielle; Rowan, Andrew; Jones, Angela; Sohn, Christof; Schneeweiß, Andeas; Bugert, Peter; Álvarez, Núria; Lacey, James; Wang, Sophia; Ma, Huiyan; Lu, Yani; Deapen, Dennis; Pinder, Rich; Lee, Eunjung; Schumacher, Fred; Horn-Ross, Pam; Reynolds, Peggy; Nelson, David; Ziegler, Hartwig; Wolf, Sonja; Hermann, Volker; Lo, Wing-Yee; Justenhoven, Christina; Baisch, Christian; Fischer, Hans-Peter; Brüning, Thomas; Pesch, Beate; Rabstein, Sylvia; Lotz, Anne; Harth, Volker; Heikkinen, Tuomas; Erkkilä, Irja; Aaltonen, Kirsimari; von Smitten, Karl; Antonenkova, Natalia; Hillemanns, Peter; Christiansen, Hans; Myöhänen, Eija; Kemiläinen, Helena; Thorne, Heather; Niedermayr, Eveline; Bowtell, D; Chenevix-Trench, G; deFazio, A; Gertig, D; Green, A; Webb, P; Green, A.; Parsons, P.; Hayward, N.; Webb, P.; Whiteman, D.; Fung, Annie; Yashiki, June; Peuteman, Gilian; Smeets, Dominiek; Brussel, Thomas Van; Corthouts, Kathleen; Obi, Nadia; Heinz, Judith; Behrens, Sabine; Eilber, Ursula; Celik, Muhabbet; Olchers, Til; Manoukian, Siranoush; Peissel, Bernard; Scuvera, Giulietta; Zaffaroni, Daniela; Bonanni, Bernardo; Feroce, Irene; Maniscalco, Angela; Rossi, Alessandra; Bernard, Loris; Tranchant, Martine; Valois, Marie-France; Turgeon, Annie; Heguy, Lea; Sze Yee, Phuah; Kang, Peter; Nee, Kang In; Mariapun, Shivaani; Sook-Yee, Yoon; Lee, Daphne; Ching, Teh Yew; Taib, Nur Aishah Mohd; Otsukka, Meeri; Mononen, Kari; Selander, Teresa; Weerasooriya, Nayana; staff, OFBCR; Krol-Warmerdam, E.; Molenaar, J.; Blom, J.; Brinton, Louise; Szeszenia-Dabrowska, Neonila; Peplonska, Beata; Zatonski, Witold; Chao, Pei; Stagner, Michael; Bos, Petra; Blom, Jannet; Crepin, Ellen; Nieuwlaat, Anja; Heemskerk, Annette; Higham, Sue; Cross, Simon; Cramp, Helen; Connley, Dan; Balasubramanian, Sabapathy; Brock, Ian; Luccarini, Craig; Conroy, Don; Baynes, Caroline; Chua, Kimberley

    2014-01-01

    Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act

  7. Characterization of Ciprofloxacin-Resistant and Ciprofloxacin-Susceptible Uropathogenic Escherichia coli Obtained from Patients with Gynecological Cancer.

    Science.gov (United States)

    Capett, Muniqui S; Vollú-Silva, Patricia; Melchiades, Vanessa A; Bokehi, Luciana C; Araújo, Fernanda M; Martins, Ianick Souto; Neves, Felipe P G; Gonzalez, Alice G M; Oswald, Eric; de Paula, Geraldo R; Teixeira, Lenise A

    2016-11-01

    The objective of this work was to assess the genetic characteristics of uropathogenic Escherichia coli, ciprofloxacin resistance or susceptibility, obtained from patients with gynecological cancer and urinary tract infection (UTI). Seventy-seven E. coli ciprofloxacin-resistant isolates and 38 ciprofloxacin-susceptible were analyzed by polymerase chain reaction (PCR) to determine the phylogenetic groups, virulence factors as iucC, fyuA, hlyC, cnf1 genes, and pks pathogenicity island. The presence of genes related to ciprofloxacin resistance such as qnrA, qnrB, qnrS, aac(6')-Ib-cr, and qepA, and the sequencing of DNA gyrase genes and topoisomerase IV were determined. The genetic profile of the isolates was determined by pulsed-field gel electrophoresis (PFGE). Statistical analysis was performed using Fisher's exact test and Chi-square test. Phylogenetic group B2 was the most prevalent although a great genetic diversity was observed by PFGE. Only genes associated to siderophores were found in ciprofloxacin-resistant isolates; however, in ciprofloxacin-susceptible isolates, genes related to siderophores and toxin, were detected. Additionally qnrB was detected in both populations, ciprofloxacin resistant and susceptible. DNA mutations in gyrA were Ser-83-Leu and Asp-87-Asn and in parC were Ser-80-Ile and Glu-84-Val, Glu-84-Lys. In conclusion, it was observed a high prevalence of qnrB in the population studied; in addition, it was the first time the pks island was observed only in ciprofloxacin-susceptible isolates.

  8. 新疆维吾尔族和汉族早发性乳腺癌中乳腺癌易感基因1相互作用蛋白1基因外显子共有突变位点的分析%Analysis on common mutation locus of breast cancer susceptibility gene 1 associated C terminal helicase 1 gene in exon of the early onset breast cancer patients of Uygur and Han nationalities in Xinjiang

    Institute of Scientific and Technical Information of China (English)

    马斌; 杨乐; 吴军; 马斌林

    2015-01-01

    目的 检测新疆地区维吾尔族(简称维族)和汉族妇女早发性乳腺癌患者乳腺癌易感基因1相互作用蛋白1(BACH1)基因外显子突变情况,探讨维、汉族共有的突变位点与临床病理特征的相关性.方法 直接测序法检测新疆地区维吾尔族与汉族妇女早发性乳腺癌(年龄30 ~ 40岁,各80例)BACHI基因外显子区域的突变情况.结果 (1)维族、汉族共检测出4个共有的突变位点,包括2个错义突变、2个同义突变,分别位于外显子(EXON)6、EXON19和EXON20.Polyphen和SIFT软件预测蛋白质功能,结果表明维、汉早发性乳腺癌患者共有的突变位点rs4986764可能为有害突变,可能影响BACH1蛋白质的功能.(2)在汉族人群中,c.587A→G、rs4986765、rs49867654、rs4986763位点的野生型与突变型在三阴性、非三阴性乳腺癌中的差异均无统计学意义(P>0.05).但rs49867654、rs4986763位点的野生型与突变型在组织学分级Ⅰ+Ⅱ、Ⅲ级中的差异有统计学意义(P<0.05),与野生型基因型比较,突变型基因型可降低病理组织学分级[比值比(OR)=0.063、0.015].在维族人群中,上述3个位点的野生型与突变型在三阴性、非三阴性乳腺癌及组织学分级Ⅰ+Ⅱ、Ⅲ级中的差异均无统计学意义(P>0.05).结论 在汉族人群中,rs49867654、rs4986763位点的突变型基因型可降低病理组织学分级,但在维族人群中未见统计学差异.%Objective Detect the state of common mutation locus of breast cancer susceptibility gene 1 (BRCA1) associated C terminal helicase 1 (BACH1) gene in exon of the early onset breast cancer women patients of Uygur and Han nationalities in Xinjiang region and discuss the correlation between common mutation locus of Uygur and Han nationalities and clinicopathologic features.Methods Detect the state of mutation of BACH1 gene in exon of the early onset breast cancer women patients of Uygur and Han nationalities in Xinjiang region (aged 30

  9. Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

    Science.gov (United States)

    Favre, G; Banta Lavenex, P; Lavenex, P

    2012-10-23

    The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

  10. 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.

  11. 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...

  12. A risk evaluation model of cervical cancer based on etiology and human leukocyte antigen allele susceptibility

    Directory of Open Access Journals (Sweden)

    Bicheng Hu

    2014-11-01

    Conclusions: This model, based on etiology and HLA allele susceptibility, can estimate the risk of cervical cancer in chronic cervicitis patients after HPV infection. It combines genetic and environmental factors and significantly enhances the accuracy of risk evaluation for cervical cancer. This model could be used to select patients for intervention therapy and to guide patient classification management.

  13. Fine-mapping of the 1p11.2 breast cancer susceptibility locus

    NARCIS (Netherlands)

    Horne, H.N. (Hisani N.); Chung, C.C. (Charles C.); Zhang, H. (Han); Yu, K. (Kai); Prokunina-Olsson, L. (Ludmila); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet K.); Q. Wang (Qing); J. Dennis (Joe); J.L. Hopper (John); M.C. Southey (Melissa); M.K. Schmidt (Marjanka); A. Broeks (Annegien); K.R. Muir (K.); A. Lophatananon (Artitaya); P.A. Fasching (Peter); M.W. Beckmann (Matthias); O. Fletcher (Olivia); Johnson, N. (Nichola); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); Burwinkel, B. (Barbara); Marme, F. (Frederik); P. Guénel (Pascal); T. Truong (Thérèse); S.E. Bojesen (Stig); H. Flyger (Henrik); J. Benítez (Javier); A. González-Neira (Anna); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); Brenner, H. (Hermann); V. Arndt (Volker); A. Meindl (Alfons); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); U. Hamann (Ute); H. Nevanlinna (Heli); S. Khan (Sofia); K. Matsuo (Keitaro); H. Iwata (Hiroji); T. Dörk (Thilo); N.V. Bogdanova (Natalia); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); G. Chenevix-Trench (Georgia); A.H. Wu (Anna); Ven Den Berg, D. (David); A. Smeets (Ann); H. Zhao (Hui); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Radice (Paolo); M. Barile (Monica); F.J. Couch (Fergus); Vachon, C. (Celine); Giles, G.G. (Graham G.); R.L. Milne (Roger); C.A. Haiman (Christopher A.); L. Le Marchand (Loic); M.S. Goldberg (Mark); S.-H. Teo; N.A.M. Taib (Nur Aishah Mohd); V. Kristensen (Vessela); Borresen-Dale, A.-L. (Anne-Lise); W. Zheng (Wei); M. Shrubsole (Martha); R. Winqvist (Robert); A. Jukkola-Vuorinen (Arja); I.L. Andrulis (Irene); J.A. Knight (Julia); P. Devilee (Peter); C.M. Seynaeve (Caroline); M. García-Closas (Montserrat); K. Czene (Kamila); H. Darabi (Hatef); A. Hollestelle (Antoinette); J.W.M. Martens (John); J. Li (Jingmei); W. Lu (Wei); X.-O. Shu (Xiao-Ou); A. Cox (Angela); S.S. Cross (Simon); W.J. Blot (William); Q. Cai (Qiuyin); M. Shah (Mitul); C. Luccarini (Craig); Baynes, C. (Caroline); P. harrington (Patricia); D. Kang (Daehee); J.-Y. Choi (Ji-Yeob); J.M. Hartman (Joost); Chia, K.S. (Kee Seng); M. Kabisch (Maria); D. Torres (Diana); A. Jakubowska (Anna); J. Lubinski (Jan); S. Sangrajrang (Suleeporn); P. Brennan (Paul); S. Slager (Susan); D. Yannoukakos (Drakoulis); C.-Y. Shen (Chen-Yang); M.-F. Hou (Ming-Feng); A.J. Swerdlow (Anthony ); N. Orr (Nick); J. Simard (Jacques); P. Hall (Per); P.D.P. Pharoah (Paul); D.F. Easton (Douglas F.); Chanock, S.J. (Stephen J.); A.M. Dunning (Alison); J.D. Figueroa (Jonine)

    2016-01-01

    textabstractThe Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132)

  14. 肿瘤易感性与消化系统肿瘤易感基因%Tumor Susceptibility and Digestic System Tumor Susceptible Gene

    Institute of Scientific and Technical Information of China (English)

    吕有勇; 郭瑞芳

    1999-01-01

    The carcinogenesis and development is a progress of multi-gene alterations in the human gastric cancer (HGC).In order to determine the relation between the aberration of these genes and gastric cancer,we chose c-met (7q31)、hMLH1 (3p21)、E-cadherin (16q22.1) and HLA loci DQA1、DR2、DR3、DR4、DR7、DR9 and detected their changes in 32 tumor specimens of intestinal type HGC and 4 cell lines of gastric cancer by performing analysis of SSP/PCR、PCR/SSCP and MSI technigues.Our data show that none point mutation was detected in c-met gene.We examined two microsatellites loci D3S1298 and D3S1561 in hMLH1 gene and detected that 6 cases retain MSI (Microsatellite Instability) and 2 cases of LOH (Loss of Heterozygosity) at D3S1298 and 2 cases of MSI at D3S1561.We also examined E-cadherin gene at two microsatellites loci D16S3083 and D16S3095 close to the gene and detected that 5 cases retain MSI and 1 case of LOH at D16S3083 and no change at D16S3095.The point mutation incidence of HLA-DR4 loci is 9/20 (45%),higher than the other loci in HLA-Ⅱ.High frequent deletion,expression deregulation and methylation of mts1/p16 gene were detected in cell lines and solid tumors from human gastric cancer patients.   Our data showed that the point mutation of c-met gene is not the main pattern of alteration in intestinal type HGC that is consistent with the previous results.E-cadherin and hMLH1 are related to intestinal type HGC but whether they are susceptibility gene still need further study.The point mutation of the HLA-Ⅱ loci DR4 is closely related to intestinal type HGC.Methylation of mts1/p16 gene 5 CpG island might be plays an important role in the carcinogenesis in HGC.

  15. 肺癌遗传易感性研究进展%Research progress on genetic susceptibility to lung cancer

    Institute of Scientific and Technical Information of China (English)

    陆丽杰

    2016-01-01

    Lung cancer is currently one of the most common malignant tumors in the world, with an increasing trend of morbidity and mortality.The major causes of lung cancer are inhaled carcinogens, such as tobacco and environmental pollution, but a growing number of researches suggest that the incidence of lung cancer is closely related to genetic factors.In the past few years, great progress has been made in research on single nucleotide polymorphism of susceptibility gene in lung cancer, and the most studies that have aimed to ultimately provide scientific basis for preventing and controlling the lung cancer have focused on screening of lung cancer etiology and developing gene therapy.In this review, the new findings of genetic susceptibility in lung cancer have been summarized.%肺癌是目前全球范围内最常见的恶性肿瘤之一,发病率和病死率均呈上升趋势.烟草、环境污染物质等吸入性致癌物是引发肺癌的主要因素,但越来越多的研究表明肺癌发病与遗传因素关系密切.近年来,对肺癌易感基因单核苷酸多态性的研究取得了较大进展,全球学者致力于筛选肺癌病因、寻找基因治疗方法,最终为预防和控制肺癌提供科学依据.文章针对目前肺癌遗传易感性研究进展作一综述.

  16. 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.

  17. Rare variants in XRCC2 as breast cancer susceptibility alleles

    NARCIS (Netherlands)

    Hilbers, F.S.; Wijnen, J.T.; Hoogerbrugge-van der Linden, N.; Oosterwijk, J.C.; Collee, M.J.; Peterlongo, P.; Radice, P.; Manoukian, S.; Feroce, I.; Capra, F.; Couch, F.J.; Wang, X.; Guidugli, L.; Offit, K.; Shah, S.; Campbell, I.G.; Thompson, E.R.; James, P.A.; Trainer, A.H.; Gracia, J.; Benitez, J.; Asperen, C.J. van; Devilee, P.

    2012-01-01

    BACKGROUND: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. METHODS: The coding regions and exo

  18. The relationship between the polymorphism in CYP1B1 gene rs1056836 and the susceptibility to breast cancer in Xinjiang Uygur women%CYP1B1基因rs1056836位点多态性与新疆维吾尔族乳腺癌易感性的研究

    Institute of Scientific and Technical Information of China (English)

    杨亮; 李涌涛; 齐新; 杜露; 地力夏提·金斯汗; 朱丽萍

    2014-01-01

    目的:探讨CYP1B1基因rs1056836单核苷酸位点多态性与新疆维吾尔族乳腺癌易感性的关系。方法应用聚合酶链反应-限制片段长度多态性(PCR-RFLP)检测125例维吾尔族女性乳腺癌患者(乳腺癌组)和160例体检的健康维吾尔族女性(对照组) CYP1B1基因rs1056836位点多态性,分析该位点多态性在不同群体中的分布情况。采用问卷调查和病例查询的方法收集乳腺癌相关危险因素的资料,用Logistic回归模型分析rs1056836位点多态性与乳腺癌患病风险的相对危险度。结果 CYP1B1基因rs1056836位点中存在CC、CG、GG 3种基因型,其在乳腺癌组和健康女性对照组中的分布频率分别为43�2%、51�2%、5�6%和60�6%、34�4%、5�0%,两组基因型分布的差异有统计学意义( P<0�05);乳腺癌组C、G等位基因的分布频率分别为68�8%、31�2%,对照组分别为77�8%、22�2%,差异有统计学意义( P<0�05)。 Logistic回归模型分析显示携带CC基因型维吾尔族女性的乳腺癌发病风险降低。乳腺癌相关危险因素的分层分析显示初潮早、有肿瘤家族病史、未绝经妇女中携带CG、GG基因型者乳腺癌患病风险明显增加。结论 CYP1B1基因rs1056836位点多态性与维吾尔族乳腺癌的发生有关,其突变基因型增加了维吾尔族女性乳腺癌的患病风险。%Objective To investigate the association between the CYP1B1 gene rs1056836 polymorphism and the susceptibil-ity to breast cancer in Xinjiang Uygur women. Methods Polymerase chain reaction restriction fragment length polymorphism( PCR-RFLP) was performed to detect the polymorphism of the CYP1B1 gene rs1056836 between 125 cases of Uygur women with breast canc-er and 160 cases of healthy Uygur women and the relationship between polymorphic loci and the susceptibility to breast cancer was ana-lyzed. Results CYP1B1 gene in the rs1056836 site

  19. Fine mapping of the MLK-3 gene within 11q13 and its exclusion as the MEN1 susceptibility gene.

    Science.gov (United States)

    Lassam, N J; Lin, Z; Shennan, M G; Courseaux, A; Teh, B T; Gaudray, P; Larsson, C

    1997-06-01

    MLK-3 kinase is a widely expressed serine/ threonine kinase that bears multiple protein interaction domains and regulates signals mediated by the stress-responsive pathway. Thus, MLK-3 signaling affects numerous cellular processes, raising the possibility that MLK-3 might play a role in oncogenesis. In this report, we describe the fine mapping of the MLK-3 gene within the 11q13.1 chromosomal region. By integrating data from somatic cell hybrids and double color fluorescence in situ hybridization on metaphase chromosomes and DNA fibers. MLK-3 has been assigned approximately 1 Mb telomeric of PYGM, close to the D11S546 locus. Since the MEN1 susceptibility locus is also located within the 11q13.1 region, we have carried out Southern and Northern blot analyses, as well as protein truncation assays to establish whether abnormalities in MLK-3 lead to the development of this familial cancer syndrome. Our observations exclude MLK-3 as the MEN1 gene.

  20. Reevaluation of RINT1 as a breast cancer predisposition gene.

    Science.gov (United States)

    Li, Na; Thompson, Ella R; Rowley, Simone M; McInerny, Simone; Devereux, Lisa; Goode, David; Investigators, LifePool; Wong-Brown, Michelle W; Scott, Rodney J; Trainer, Alison H; Gorringe, Kylie L; James, Paul A; Campbell, Ian G

    2016-09-01

    Rad50 interactor 1 (RINT1) has recently been reported as an intermediate-penetrance (odds ratio 3.24) breast cancer susceptibility gene, as well as a risk factor for Lynch syndrome. The coding regions and exon-intron boundaries of RINT1 were sequenced in 2024 familial breast cancer cases previously tested negative for BRCA1, BRCA2, and PALB2 mutations and 1886 population-matched cancer-free controls using HaloPlex Targeted Enrichment Assays. Only one RINT1 protein-truncating variant was detected in a control. No excess was observed in the total number of rare variants (truncating and missense) (28, 1.38 %, vs. 27, 1.43 %. P > 0.999) or in the number of variants predicted to be pathogenic by various in silico tools (Condel, Polyphen2, SIFT, and CADD) in the cases compared to the controls. In addition, there was no difference in the incidence of classic Lynch syndrome cancers in RINT1 rare variant-carrying families compared to RINT1 wild-type families. This study had 90 % power to detect an odds ratio of at least 2.06, and the results do not provide any support for RINT1 being a moderate-penetrance breast cancer susceptibility gene, although larger studies will be required to exclude more modest effects. This study emphasizes the need for caution before designating a cancer predisposition role for any gene based on very rare truncating variants and in silico-predicted missense variants.

  1. Hormonal Involvement in Breast Cancer Gene Amplification

    Science.gov (United States)

    2010-10-01

    and s ubsequently amp lified at the Yale University sequenc ing facility for Illumina sequencing. However, it required a lot of effort to obtain this...and Polyak K. (2008). Genome-wide functi onal synergy between amp lified and mutated genes in human breast cancer. Cancer Res. 68: 9532-9540...east cancer patient samples. Other co-amp lified genes, within the HER2 amplicon and/or at other regions, could serve as additional novel target s for

  2. Identification of susceptibility genes for bipolar affective disorder and schizophrenia on chromosome 22q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob Eg

    2006-01-01

    Linkage analyses suggest that chromosome 22q12-13 may harbor one or more shared susceptibility loci for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of distantly related cases and control individuals from the Faeroe Islands our group has previously reported that chromosome 22......q13 may harbor two shared susceptibility loci for BPD and SZ. The aim of the Ph.D. project was to identify and characterize susceptibility genes for BPD and SZ located in these two loci on 22q13, primarily by association analyses of selected positional candidate genes in a number of population...... samples (total of 1,751 individuals), and by bioinformatic and expression analyses of a subset of disease associated genes and gene variants. In total 67 single nucleotide polymorphisms (SNPs) located in 18 positional candidate genes, and 4 microsattelite markers were investigated, using a Scottish case...

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

    Science.gov (United States)

    Cheng, Daye; Hao, Yiwen; Zhou, Wenling

    2014-01-01

    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-1α -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.

  4. 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

  5. Microsatellite Scan Identifies New Candidate Genes for Susceptibility to Alcoholic Chronic Pancreatitis in Japanese Patients

    Directory of Open Access Journals (Sweden)

    Kei Kitahara

    2008-01-01

    Full Text Available Alcohol abuse is one of the most common risk factor for chronic pancreatitis, but the underlying pathophysiological mechanisms remain unclear. The aim of this study was to identify genes that contribute to susceptibility or resistance for alcoholic chronic pancreatitis by screening the whole genome. Sixty-five patients with alcoholic chronic pancreatitis (63 men and 2 women, mean age 55.2 years and 99 healthy Japanese controls were enrolled in this study. This was an association study using 400 polymorphic microsatellite markers with an average spacing of 10.8 cM distributed throughout the whole genome. This search revealed 10 candidate susceptibility regions and 5 candidate resistant regions throughout the genome. No specific microsatellite markers were detected in association with previously reported susceptibility genes for chronic pancreatitis, such as PRSS1, PRSS2, CTRC, SPINK1, CFTR, ALDH2, and CYP2E1. Among the statistically significant markers, D15S1007 on chromosome 15q14 showed strong evidence for disease susceptibility (70.8% vs. 35.1%, Pc = 0.0001. Within 500 kb of D15S1007, several genes were candidate genes for susceptibility, including FMN1, DKFZP686C2281, LOC440268, RYR3, and AVEN, This study identified 10 candidate susceptibility and 5 candidate resistant regions that may contain genes involved in ACP pathogenesis.

  6. Impact of homeobox genes in gastrointestinal cancer

    Science.gov (United States)

    Joo, Moon Kyung; Park, Jong-Jae; Chun, Hoon Jai

    2016-01-01

    Homeobox genes, including HOX and non-HOX genes, have been identified to be expressed aberrantly in solid tumors. In gastrointestinal (GI) cancers, most studies have focused on the function of non-HOX genes including caudal-related homeobox transcription factor 1 (CDX1) and CDX2. CDX2 is a crucial factor in the development of pre-cancerous lesions such as Barrett’s esophagus or intestinal metaplasia in the stomach, and its tumor suppressive role has been investigated in colorectal cancers. Recently, several HOX genes were reported to have specific roles in GI cancers; for example, HOXA13 in esophageal squamous cell cancer and HOXB7 in stomach and colorectal cancers. HOXD10 is upregulated in colorectal cancer while it is silenced epigenetically in gastric cancer. Thus, it is essential to examine the differential expression pattern of various homeobox genes in specific tumor types or cell lineages, and understand their underlying mechanisms. In this review, we summarize the available research on homeobox genes and present their potential value for the prediction of prognosis in GI cancers. PMID:27729732

  7. Vitamin D receptor gene polymorphisms, dietary promotion of insulin resistance, and colon and rectal cancer.

    OpenAIRE

    Murtaugh, Maureen A.; Sweeney, Carol; Ma, Khe-ni; Potter, John D.; Caan, Bette J.; Wolff, Roger K.; Slattery, Martha L

    2006-01-01

    Biomarkers of individual susceptibility: field studies. Biomarker: vitamin D receptor (VDR) gene polymorphisms Effect studied: colon and rectal cancer risk. Tissue/biological material/sample size: colon, rectum. Method of analysis: genotyping of the VDR gene Study design: case-control studyStudy size: colon cancer (1,698 cases and 1,861 controls); rectal cancer (752 cases and 960 controls) Impact on outcome (including dose-response): The lowest colon cancer risk was observed with the Ff/ff Fo...

  8. Gene Therapy In Oral Cancer : An Overview

    Directory of Open Access Journals (Sweden)

    Kanaram Choudhary

    2010-07-01

    Full Text Available The treatment and prevention of oral cancer is one of the major hurdles in the field ofcancer. Gene therapy is one of the recent advances in this field to tackle this hurdle with promisingprospects. This overview introduces the reader into the basic idea of gene therapy, types of genetherapy and the various modes of introduction of therapeutic gene into the cancer affected cell.

  9. Combining Telomerase Reverse Transcriptase Genetic Variant rs2736100 with Epidemiologic Factors in the Prediction of Lung Cancer Susceptibility.

    Science.gov (United States)

    Wang, Xu; Ma, Kewei; Chi, Lumei; Cui, Jiuwei; Jin, Lina; Hu, Ji-Fan; Li, Wei

    2016-01-01

    Genetic variants from a considerable number of susceptibility loci have been identified in association with cancer risk, but their interaction with epidemiologic factors in lung cancer remains to be defined. We sought to establish a forecasting model for identifying individuals with high-risk of lung cancer by combing gene single-nucleotide polymorphisms with epidemiologic factors. Genotyping and clinical data from 500 lung cancer cases and 500 controls were used for developing the logistic regression model. We found that lung cancer was associated with telomerase reverse transcriptase (TERT) rs2736100 single-nucleotide polymorphism. The TERT rs2736100 model was still significantly associated with lung cancer risk when combined with environmental and lifestyle factors, including lower education, lower BMI, COPD history, heavy cigarettes smoking, heavy cooking emission, and dietary factors (over-consumption of meat and deficiency in fish/shrimp, vegetables, dairy products, and soybean products). These data suggest that combining TERT SNP and epidemiologic factors may be a useful approach to discriminate high and low-risk individuals for lung cancer.

  10. 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.

  11. Methylated genes as new cancer biomarkers.

    LENUS (Irish Health Repository)

    Duffy, M J

    2012-02-01

    Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2 for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene methylation need to be standardised, simplified and evaluated in external quality assurance programmes. It is concluded that methylated genes have the potential to provide a new generation of cancer biomarkers.

  12. Expression of polarity genes in human cancer.

    Science.gov (United States)

    Lin, Wan-Hsin; Asmann, Yan W; Anastasiadis, Panos Z

    2015-01-01

    Polarity protein complexes are crucial for epithelial apical-basal polarity and directed cell migration. Since alterations of these processes are common in cancer, polarity proteins have been proposed to function as tumor suppressors or oncogenic promoters. Here, we review the current understanding of polarity protein functions in epithelial homeostasis, as well as tumor formation and progression. As most previous studies focused on the function of single polarity proteins in simplified model systems, we used a genomics approach to systematically examine and identify the expression profiles of polarity genes in human cancer. The expression profiles of polarity genes were distinct in different human tissues and classified cancer types. Additionally, polarity expression profiles correlated with disease progression and aggressiveness, as well as with identified cancer types, where specific polarity genes were commonly altered. In the case of Scribble, gene expression analysis indicated its common amplification and upregulation in human cancer, suggesting a tumor promoting function.

  13. Differences in intestinal gene expression proflies in broiler lines varying in susceptibility to malabsorption syndrome

    NARCIS (Netherlands)

    Hemert, van S.; Hoekman, A.J.W.; Smits, M.A.; Rebel, J.M.J.

    2004-01-01

    Examination of the host gene expression response upon encounters with pathogens may provide insights into the cellular events following an infection. In addition, it may shed light on the basic mechanisms underlying differences in the susceptibility of the host. In this study gene expression in the

  14. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Okamoto, Koji; Iwasaki, Naoko; Nishimura, Chisa

    2010-01-01

    , member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the beta cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals...

  15. 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

    , three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend ....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...... cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function....

  16. Susceptibility to urinary bladder cancer: relevance of rs9642880[T], GSTM1 0/0 and occupational exposure.

    Science.gov (United States)

    Golka, Klaus; Hermes, Matthias; Selinski, Silvia; Blaszkewicz, Meinolf; Bolt, Hermann M; Roth, Gerhard; Dietrich, Holger; Prager, Hans-Martin; Ickstadt, Katja; Hengstler, Jan G

    2009-11-01

    Recently, a genome-wide single nucleotide polymorphism association study has identified a sequence variant 30 kb upstream of the c-Myc gene (allele T of rs9642880) that confers susceptibility to bladder cancer. However, the role of exposure to bladder carcinogens has not been considered. This prompted us to analyse the relevance of this polymorphism in 515 bladder cancer cases and 893 controls where the quality and quantity of occupational exposure to bladder carcinogens has been documented. When we analysed a hospital-based case-control series not selected for occupational exposure, rs9642880[T] was influential, in contrast to GSTM1 0/0. However, in a case-control series of patients that have been occupationally exposed to aromatic amines and polycyclic aromatic hydrocarbons, rs9642880[T] was not influential but GSTM1 0/0 was significantly associated with bladder cancer risk. Therefore, the degree to which rs9642880[T] and GSTM1 0/0 confer susceptibility to urinary bladder cancer seems to depend on the extent of exposure to urinary bladder carcinogens.

  17. Targeting tumor suppressor genes for cancer therapy.

    Science.gov (United States)

    Liu, Yunhua; Hu, Xiaoxiao; Han, Cecil; Wang, Liana; Zhang, Xinna; He, Xiaoming; Lu, Xiongbin

    2015-12-01

    Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.

  18. Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review

    Directory of Open Access Journals (Sweden)

    Cross SS

    2006-07-01

    Full Text Available Abstract Background Interleukins and cytokines play an important role in the pathogenesis of many solid cancers. Several single nucleotide polymorphisms (SNPs identified in cytokine genes are thought to influence the expression or function of these proteins and many have been evaluated for their role in inflammatory disease and cancer predisposition. The aim of this study was to evaluate any role of specific SNPs in the interleukin genes IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 in predisposition to breast cancer susceptibility and severity. Methods Candidate single nucleotide polymorphisms (SNPs in key cytokine genes were genotyped in breast cancer patients and in appropriate healthy volunteers who were similar in age, race and sex. Genotyping was performed using a high throughput allelic discrimination method. Data on clinico-pathological details and survival were collected. A systematic review of Medline English literature was done to retrieve previous studies of these polymorphisms in breast cancer. Results None of the polymorphisms studied showed any overall predisposition to breast cancer susceptibility, severity or to time to death or occurrence of distant metastases. The results of the systematic review are summarised. Conclusion Polymorphisms within key interleukin genes (IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 do not appear to play a significant overall role in breast cancer susceptibility or severity.

  19. Polymorphisms in DNA Repair Genes and Susceptibility to Glioma in a Chinese Population

    Directory of Open Access Journals (Sweden)

    Jun-Hong Guan

    2013-02-01

    Full Text Available The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1, and X-ray repair cross-complementing group 1 (XRCC1 genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ2 test and binary logistic regression were performed to determine the odds ratio (OR and a 95% confidence interval (95% CI for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43–4.45. Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02–1.64. The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86–9.06. Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54–4.04. XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population.

  20. NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population

    Directory of Open Access Journals (Sweden)

    Mercedes Fernández-Mestre

    2015-01-01

    Full Text Available Natural resistance-associated macrophage protein (Nramp1 and the vitamin D receptor (VDR are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3′UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST− controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3′UTR polymorphism with M. tuberculosis infection and disease progression.

  1. NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population

    Science.gov (United States)

    Fernández-Mestre, Mercedes; Villasmil, Ángel; Takiff, Howard; Fuentes Alcalá, Zhenia

    2015-01-01

    Natural resistance-associated macrophage protein (Nramp1) and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3′UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST− controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3′UTR polymorphism with M. tuberculosis infection and disease progression. PMID:26578819

  2. DNMT3B基因启动子单核苷酸多态性与结直肠癌易感性的关联研究%Correlation between polymorphism in the promoter of DNA methyltransferase-3B gene and susceptibility of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    徐峰; 于莹; 邹江

    2013-01-01

    目的 通过对天津地区汉族结直肠癌(CRC)患者和正常人群中DNA甲基转移酶3B(DNMT3B)基因单核苷酸多态性(SNP)位点rs1569686基因型的检测,探讨rs1569686位点基因型与CRC易感性的关系.方法 应用Sequenom MassArray飞行时间质谱系统检测89例CRC患者(观察组)及94例健康者(对照组)DNMT3B基因多态位点rs1569686的基因分型,判断其与CRC的相关性.结果 DNMT3B基因多态位点rs1569686的3种基因型TT、GT、GG在CRC患者中的频率分别为74.2%、24.7%、1.1%,与对照组(73.4%、23.4%、3.2%)相比,差异无统计学意义(P>0.05).结论 天津汉族人群CRC的遗传易感性可能与DNMT3B基因rs1569686位点的SNP无关.%Objective To observe and analyze the correlation between the DNA methyltransferase-3B (DNMT3B) gene single nucleotide polymorphisms (SNP) rs 1569686 and the susceptibility to colorectal cancer (CRC) in Tianjin Han population.Methods A case-control study was performed.89 CRC patients and 94 normal controls were examined,and Sequenom MassArray system was applied to detect the genotype of rs1569686 in DNMT3B gene polymorphisms.The association results were analyzed of the SNP and CRC.Results The frequencies of genotypes TT,GT and GG at SNP rs1569686 were 74.2%,24.7% and 1.1% in CRC patients respectively,which there were no significant differences from that in controls(73.4%,23.4% and 3.2%; P>0.05).Conclusion It suggests that the SNP rs1569686 of DNMT3B gene may not be related to susceptibility of CRC in Tianjin Han population.

  3. Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.

    Directory of Open Access Journals (Sweden)

    M Ann Kelly

    Full Text Available BACKGROUND: Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants. METHODOLOGY/PRINCIPAL FINDINGS: The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732 and without (N = 1780 type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium and white European cohorts (DIAGRAM+ using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5, while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003. Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively. CONCLUSIONS/SIGNIFICANCE: None of the selected circadian gene variants was associated with type

  4. Natural selection on genes that underlie human disease susceptibility

    Science.gov (United States)

    Blekhman, Ran; Man, Orna; Herrmann, Leslie; Boyko, Adam R.; Indap, Amit; Kosiol, Carolin; Bustamante, Carlos D.; Teshima, Kosuke M.; Przeworski, Molly

    2008-01-01

    What evolutionary forces shape genes that contribute to the risk of human disease? Do similar selective pressures act on alleles that underlie simple vs. complex disorders? [1-3]. Answers to these questions will shed light on the origin of human disorders (e.g., [4]), and help to predict the population frequencies of alleles that contribute to disease risk, with important implications for the efficient design of mapping studies [5-7]. As a first step towards addressing them, we created a hand-curated version of the Mendelian Inheritance in Man database (OMIM). We then examined selective pressures on Mendelian disease genes, genes that contribute to complex disease risk and genes known to be essential in mouse, by analyzing patterns of human polymorphism and of divergence between human and rhesus macaque. We find that Mendelian disease genes appear to be under widespread purifying selection, especially when the disease mutations are dominant (rather than recessive). In contrast, the class of genes that influence complex disease risk shows little signs of evolutionary conservation, possibly because this category includes both targets of purifying and positive selection. PMID:18571414

  5. ETS fusion genes in prostate cancer.

    Science.gov (United States)

    Gasi Tandefelt, Delila; Boormans, Joost; Hermans, Karin; Trapman, Jan

    2014-06-01

    Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostate-specific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

  6. Schizophrenia susceptibility genes on chromosome 13q32

    Institute of Scientific and Technical Information of China (English)

    胡颖; 许琪; 鞠桂芝; 刘树铮; 史杰萍; 于雅琴; 尉军

    2004-01-01

    @@Schizophrenia is a complex mental disorder affecting approximately 1% of the general population worldwide.1 It has a high incidence in the general population, a poor prognosis and a poor outcome, in that it has become a major social problem. Family, twin, and adoption studies have clearly shown that a genetic component is quite likely to play an important role in determining susceptibility to schizophrenia. The genome-wide scan indicates that several chromosomal regions are linked to schizophrenia, some of which have been replicated independently including 6p21-24, 8p21-22, 13q14-33 and 22q11-12.2,3 This study was designed to detect two single nucleotide polymorphisms (SNPs) located in the 13q14-33 region, rs188608 at the STK24 locus and rs2892679 at the GPC6 locus, among Chinese population.

  7. Identification of a T1D Susceptibility Gene

    Directory of Open Access Journals (Sweden)

    Grant Morahan

    2001-01-01

    Full Text Available It is not known what causes type 1 diabetes (T1D, which affects over 1 million people in the U.S. alone. Each year, 30,000 young people in the U.S. develop this disease and depend on insulin injections thereafter. Because of the huge cost to the individual, the family, and to society in increased health care costs, it is important to find what makes these people susceptible. The disease process itself is clear: the individual’s immune system — T lymphocytes in particular — attack and destroy the body’s insulin-producing cells. But how and why this autoimmune process starts or proceeds unregulated is still not known.

  8. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil

    OpenAIRE

    Castellucci, Léa; Jamieson, Sarra E; Almeida, Lucas; Oliveira, Joyce; Guimarães, Luiz Henrique; Lessa, Marcus; Fakiola, Michaela; Jesus, Amélia Ribeiro de; Miller, E. Nancy; Carvalho, Edgar M.; Blackwell, Jenefer M.

    2012-01-01

    Leishmania braziliensis causes cutaneous (CL) and mucosal (ML) leishmaniasis. In the mouse, Fli1 was identified as a gene influencing enhanced wound healing and resistance to CL caused by L. major. Polymorphism at FLI1 is associated with CL caused by L. braziliensis in humans, with an inverse association observed for ML disease. Here we extend the analysis to look at other wound healing genes, including CTGF, TGFB1, TGFBR1/2, SMADS 2/3/4/7 and FLII, all functionally linked along with FLI1 in ...

  9. 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)....

  10. Chromosomal Abnormalities and Putative Susceptibility Genes in Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    Nielsen, Mette Gilling

    Autism spectrum disorders (ASDs) is a heterogeneous group of neurodevelopmental disorders with a significant genetic component as shown by family and twin studies. However, only a few genes have repeatedly been shown to be involved in the development of ASDs. The aim of this study has been...

  11. Influence of doxorubicin on fluconazole susceptibility and efflux pump gene expression of Candida dubliniensis.

    LENUS (Irish Health Repository)

    Schulz, Bettina

    2012-05-01

    The effect of doxorubicin (DOX) on the fluconazole (FLU) susceptibility of C. dubliniensis was investigated. Isolates were exposed to DOX and FLU in a chequerboard assay and resistance gene expressions were analysed after DOX exposure. The susceptibility of the yeast to FLU was decreased in the presence of DOX in the chequerboard assay with FIC indices suggesting an antagonistic effect. Gene expression analyses showed an overexpression of CdCDR2. Hence, DOX was found to have an impact on resistance mechanisms in C. dubliniensis isolates.

  12. Genetic polymorphism of T6235C mutation in 3 non-coding region of CYP1A1 and GSTM1 genes and lung cancer susceptibility in the Mongolian population

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To estimate the relative risk for lung cancer associated with genetic polymorphism of T6235C mutation in 3' non-coding region(MspⅠ)of cytochrome P450 1A1(CYP1A1)and glutathione S-transferase M1(GSTM1)in the Mongolian population in Inner Mongolian Region of China.Methods Polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)and multiplex PCR methods were used to analyze blood samples obtained from 263 case subjects and 263 control subjects to determine their genotypes for CYP1...

  13. Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci.

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Jia, Peilin; Li, Ming; Su, Bing; Zhao, Zhongming; Gan, Lin

    2014-01-01

    Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.

  14. Combination of hearing screening and genetic screening for deafness-susceptibility genes in newborns.

    Science.gov (United States)

    Yao, Gen-Dong; Li, Shou-Xia; Chen, Ding-Li; Feng, Hai-Qin; Zhao, Su-Bin; Liu, Yong-Jie; Guo, Li-Li; Yang, Zhi-Ming; Zhang, Xiao-Fang; Sun, Cai-Xia; Wang, Ze-Hui; Zhang, Wei-Yong

    2014-01-01

    The aim of this study was to determine the clinical significance of the results of screening of newborn hearing and the incidence of deafness-susceptibility genes. One thousand newborn babies in the Handan Center Hospital (Handan, China) underwent screening of hearing and deafness-susceptibility genes. The first screening test was carried out using otoacoustic emissions (OAEs). Babies with hearing loss who failed to pass the initial screening were scheduled for rescreening at 42 days after birth. Cord blood was used for the screening of deafness-susceptibility genes, namely the GJB2, SLC26A4 and mitochondrial 12S rRNA (MTRNR1) genes. Among the 1,000 neonates that underwent the first hearing screening, 25 exhibited left-sided hearing loss, 21 exhibited right-sided hearing loss and 15 cases had binaural hearing loss. After rescreening 42 days later, only one of the initial 61 cases exhibited hearing loss under OAE testing. The neonatal deafness gene tests showed two cases with 1555A>G mutation and two cases with 1494C>T mutation of the MTRNR1 gene. In the SLC26A4 gene screening, four cases exhibited the heterozygous IVS7-2A>G mutation and one case exhibited heterozygous 1226G>A mutation. In the GJB2 gene screening, two cases exhibited the homozygous 427C>T mutation and 10 exhibited the heterozygous 235delC mutation. The genetic screening revealed 21 newborns with mutations in the three deafness-susceptibility genes. The overall carrier rate was 2.1% (21/1,000). The association of hearing and gene screening may be the promising screening strategy for the diagnosis of hearing loss.

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

    DEFF Research Database (Denmark)

    Ahmed, Shahana; Thomas, Gilles; Ghoussaini, Maya

    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...

  16. 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 ass...

  17. 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...

  18. 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…

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

    NARCIS (Netherlands)

    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.; Jonson, 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; Aittomaeki, Kristiina; Nevanlinna, Heli; Collee, 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; Lazaroso, Conxi; Angel Pujana, Miguel; 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.; Duerst, Matthias; Hillemanns, Peter; Doerk, 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

    2015-01-01

    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 associ

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

    NARCIS (Netherlands)

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

    2015-01-01

    textabstractGenome-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 ass

  1. The role of ERBB2 gene polymorphisms in leprosy susceptibility

    Directory of Open Access Journals (Sweden)

    Jamile Leão Rêgo

    2015-04-01

    Full Text Available Mycobacterium lepraeinfects skin and peripheral nerves causing deformities and disability. The M. lepraebacterium binds to ErbB2 on the Schwann cell surface causing demyelination and favoring spread of the bacilli and causing nerve injury. Polymorphisms at the ERBB2 gene were previously investigated as genetic risk factors for leprosy in two Brazilian populations but with inconsistent results. Herein we extend the analysis of ERBB2 variants to a third geographically distinct population in Brazil. Our results show that there is no association between the genotyped SNPs and the disease (p> 0.05 in this population. A gene set or pathway analysis under the genomic region of ERBB2 will be necessary to clarify its regulation under M. lepraestimulus.

  2. Cytokine gene polymorphisms and their association with cervical cancer: A North Indian study

    Directory of Open Access Journals (Sweden)

    Maneesh Kumar Gupta

    2016-04-01

    Conclusion: Therefore, the promoter polymorphisms in cytokine genes can be used as biomarkers to predict cervical cancer susceptibility in a north Indian population. However, such studies need to be carried out in different ethnic populations in order to discover the specific risk alleles, genotypes and combinations for disease prediction.

  3. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility

    Directory of Open Access Journals (Sweden)

    Pradhan V

    2010-01-01

    Full Text Available Systemic lupus erythematosus (SLE is a prototype autoimmune disease. SLE is a result of one or more immune mechanisms, like autoantibody production, complement activation, multiple inflammation and immune complex deposition leading to organ tissue damage. SLE affected patients are susceptible to common and opportunistic infections. There are several reports suggesting that Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas. Genetic factors and environmental factors also play an important role in the overall susceptibility to SLE pathophysiology. Recently, protein tyrosine phosphatase, non-receptor type 22 (PTPN22 gene, has been found to be associated with several autoimmune diseases like SLE, Grave′s disease and Hashimoto thyroiditis. The missense R620W polymorphism, rs 2476601, in PTPN22 gene at the nucleotide 1858 in codon 620 (620Arg > Trp has been associated with autoimmune diseases. The PTPN22 locus is also found to be responsible for development of pulmonary tuberculosis in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to tuberculosis in the Indian population. In this review, we focus on human PTPN22 gene structure and function as well as the association of PTPN22 gene polymorphisms with SLE susceptibility

  4. Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

    Institute of Scientific and Technical Information of China (English)

    SUN Xiangqing; JIA Yanbin; ZHANG Xuegong; XU Qi; SHEN Yan; LI Yanda

    2005-01-01

    Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMTand ALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

  5. BMP2/BMP4 colorectal cancer susceptibility loci in northern and southern European populations.

    Science.gov (United States)

    Fernandez-Rozadilla, Ceres; Palles, Claire; Carvajal-Carmona, Luis; Peterlongo, Paolo; Nici, Carmela; Veneroni, Silvia; Pinheiro, Manuela; Teixeira, Manuel R; Moreno, Victor; Lamas, Maria-Jesus; Baiget, Montserrat; Lopez-Fernandez, L A; Gonzalez, Dolors; Brea-Fernandez, Alejandro; Clofent, Juan; Bujanda, Luis; Bessa, Xavier; Andreu, Montserrat; Xicola, Rosa; Llor, Xavier; Jover, Rodrigo; Castells, Antoni; Castellvi-Bel, Sergi; Carracedo, Angel; Tomlinson, Ian; Ruiz-Ponte, Clara

    2013-02-01

    Genome-wide association studies have successfully identified 20 colorectal cancer susceptibility loci. Amongst these, four of the signals are defined by tagging single nucleotide polymorphisms (SNPs) on regions 14q22.2 (rs4444235 and rs1957636) and 20p12.3 (rs961253 and rs4813802). These markers are located close to two of the genes involved in bone morphogenetic protein (BMP) signaling (BMP4 and BMP2, respectively). By investigating these four SNPs in an initial cohort of Spanish origin, we found substantial evidence that minor allele frequencies (MAFs) may be different in northern and southern European populations. Therefore, we genotyped three additional southern European cohorts comprising a total of 2028 cases and 4273 controls. The meta-analysis results show that only one of the association signals (rs961253) is effectively replicated in the southern European populations, despite adequate power to detect all four. The other three SNPs (rs4444235, rs1957636 and rs4813802) presented discordant results in MAFs and linkage disequilibrium patterns between northern and southern European cohorts. We hypothesize that this lack of replication could be the result of differential tagging of the functional variant in both sets of populations. Were this true, it would have complex consequences in both our ability to understand the nature of the real causative variants, as well as for further study designs.

  6. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Gascoyne Randy D

    2009-11-01

    Full Text Available Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

  7. Joint effects of colorectal cancer susceptibility loci, circulating 25-hydroxyvitamin D and risk of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Linda T Hiraki

    Full Text Available Genome wide association studies (GWAS have identified several SNPs associated with colorectal cancer (CRC susceptibility. Vitamin D is also inversely associated with CRC risk.We examined main and joint effects of previously GWAS identified genetic markers of CRC and plasma 25-hydroxyvitamin D (25(OHD on CRC risk in three prospective cohorts: the Nurses' Health Study (NHS, the Health Professionals Follow-up Study (HPFS, and the Physicians' Health Study (PHS. We included 1895 CRC cases and 2806 controls with genomic DNA. We calculated odds ratios and 95% confidence intervals for CRC associated with additive genetic risk scores (GRSs comprised of all CRC SNPs and subsets of these SNPs based on proximity to regions of increased vitamin D receptor binding to vitamin D response elements (VDREs, based on published ChiP-seq data. Among a subset of subjects with additional prediagnostic 25(OHD we tested multiplicative interactions between plasma 25(OHD and GRS's. We used fixed effects models to meta-analyze the three cohorts.The per allele multivariate OR was 1.12 (95% CI, 1.06-1.19 for GRS-proximalVDRE; and 1.10 (95% CI, 1.06-1.14 for GRS-nonproxVDRE. The lowest quartile of plasma 25(OHD compared with the highest, had a multivariate OR of 0.63 (95% CI, 0.48-0.82 for CRC. We did not observe any significant interactions between any GRSs and plasma 25(OHD.We did not observe evidence for the modification of genetic susceptibility for CRC according to vitamin D status, or evidence that the effect of common CRC risk alleles differed according to their proximity to putative VDR binding sites.

  8. Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis.

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Liu, Hongqi; Fang, Chee-Mun; Erickson, Loren D; Pitha, Paula M; Choubey, Divaker

    2012-01-01

    Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for IFN regulatory factor 5 [IRF]5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the IFN-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5/Blimp-1 axis could regulate the expression of these genes. We found that an Irf5 deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2 deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone C57BL/6.Nba2, New Zealand Black, and C57BL/6.Sle123 female mice (as compared with age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Taken together, our observations demonstrate that the IRF5/Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and they suggest an important role for the IRF5/Blimp-1/p202 axis in murine lupus susceptibility.

  9. Distinct regulation of murine lupus susceptibility genes by the IRF5-Blimp-1 axis

    Science.gov (United States)

    Panchanathan, Ravichandran; Liu, Hongzhu; Liu, Hongqi; Fang, Chee-Mun; Erickson, Loren D.; Pitha, Paula M.; Choubey, Divaker

    2011-01-01

    Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for the IRF5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the interferon-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5-Blimp-1 axis could regulate the expression of these genes. We found that an Irf5-deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2-deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone B6.Nba2, NZB, and B6.Sle123 female mice (as compared to age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Together, our observations demonstrate that the IRF5-Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and suggest an important role for the IRF5-Blimp-1-p202 axis in murine lupus susceptibility. PMID:22116829

  10. An overview of gene therapy in head and neck cancer

    OpenAIRE

    2013-01-01

    Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction...

  11. Progress in understanding the association between interleukin-1B gene polymorphisms and susceptibility to gastric cancer%白介素-1B基因多态性与胃癌易感性关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    王乾; 琚坚

    2013-01-01

    胃癌(gastric cancer,GC)是严重危害人类健康的恶性肿瘤之一,除与幽门螺杆菌(Helicobacter pylori,H.pylori)感染有密切关系外,部分研究认为白介素-1B(interleukin-1B,IL-1B)基因多态性与GC易感性存在关联,从而增加GC的发生风险,然而,此观点尚存在争议.综述IL-1B基因多态性在不同地区、不同种族间与GC易感性之间关系的研究和进展,为进一步探讨二者关系提供参考.

  12. Genetic variants in epigenetic genes and breast cancer risk.

    Science.gov (United States)

    Cebrian, Arancha; Pharoah, Paul D; Ahmed, Shahana; Ropero, Santiago; Fraga, Mario F; Smith, Paula L; Conroy, Don; Luben, Robert; Perkins, Barbara; Easton, Douglas F; Dunning, Alison M; Esteller, Manel; Ponder, Bruce A J

    2006-08-01

    Epigenetic events, resulting changes in gene expression capacity, are important in tumour progression, and variation in genes involved in epigenetic mechanisms might therefore be important in cancer susceptibility. To evaluate this hypothesis, we examined common variants in 12 genes coding for DNA methyltransferases (DNMT), histone acetyltransferases, histone deacetyltransferases, histone methyltrasferases and methyl-CpG binding domain proteins, for association with breast cancer in a large case-control study (N cases = 4474 and N controls = 4580). We identified 63 single nucleotide polymorphisms (SNPs) that efficiently tag all the known common variants in these genes, and are also expected to tag any unknown SNP in each gene. We found some evidence for association for six SNPs: DNMT3b-c31721t [P (2 df) = 0.007], PRDM2-c99243 t [P (2 df) = 0.03] and t105413c [P-recessive = 0.05], EHMT1-g-9441a [P (2df) = 0.05] and g41451t (P-trend = 0.04), and EHMT2-S237S [P (2df) = 0.04]. The most significant result was for DNMT3b-c31721t (P-trend = 0.124 after adjusting for multiple testing). However, there were three other results with P variants in histone methyltransferases, and warrant the design of larger epidemiological and biochemical studies to establish the true meaning of these findings.

  13. What's New in Genetic Testing for Cancer Susceptibility?

    Science.gov (United States)

    Plichta, Jennifer K; Griffin, Molly; Thakuria, Joseph; Hughes, Kevin S

    2016-09-15

    The advent of next-generation sequencing, and its transition further into the clinic with the US Food and Drug Administration approval of a cystic fibrosis assay in 2013, have increased the speed and reduced the cost of DNA sequencing. Coupled with a historic ruling by the Supreme Court of the United States that human genes are not patentable, these events have caused a seismic shift in genetic testing in clinical medicine. More labs are offering genetic testing services; more multigene panels are available for gene testing; more genes and gene mutations are being identified; and more variants of uncertain significance, which may or may not be clinically actionable, have been found. All these factors, taken together, are increasing the complexity of clinical management. While these developments have led to a greater interest in genetic testing, risk assessment, and large-scale population screening, they also present unique challenges. The dilemma for clinicians is how best to understand and manage this rapidly growing body of information to improve patient care. With millions of genetic variants of potential clinical significance and thousands of genes associated with rare but well-established genetic conditions, the complexities of genetic data management clearly will require improved computerized clinical decision support tools, as opposed to continued reliance on traditional rote, memory-based medicine.

  14. Genetic Susceptibility to Estrogen-Induced Mammary Cancers

    Science.gov (United States)

    2000-11-01

    mammary glands were reflected in mammary histology. (A and E) Thin sections from Fig. 3. E2 induced pituitary growth and hyperprolactinemia similarly in...with E2 5 (33%) exhibited a normal DNA profile where the great for 12 wk induced pituitary growth and hyperprolactinemia in majority of cells displayed...etal. , " terone, or PRL. Hyperprolactinemia has been shown to be sufficient to induce mammary cancer in certain strains of mouse 1 , (29-31) and rat

  15. Ischemic stroke susceptibility gene in a Northern Han Chinese population

    Institute of Scientific and Technical Information of China (English)

    Haiping Wang; Shujuan Shi; Wenjing Yan; Yan Song; Jingjing Zhan; Chen Zhang; Haiji Wang

    2013-01-01

    Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the-607C al ele may increase ischemic stroke risk in the Han Chinese population. In the present study, we recruited 291 patients with ischemic cerebrovascular disease from the Affi-liated Hospital of Qingdao University Medical Col ege, China, and 226 healthy controls. Both pa-tients and controls were from the Han population in northern China. Immunoresonance scattering assays detected increased serum amyloid A protein, C-reactive protein, and interleukin-18 levels in ischemic cerebrovascular disease patients compared with healthy controls. Analysis of the-607C/A (rs1946518) polymorphism in the interleukin-18 gene promoter showed ischemic cerebrovascular disease patients exhibited increased frequencies of the CC genotype and C al eles than healthy controls. Genotype and al ele frequencies of the interleukin-18-137G/C (rs187238) polymorphism and the-13T/C (rs11024595) polymorphism in the 5'-flanking region of serum amyloid A, showed no significant difference between the two groups. Multivariate logistic regression analysis on the interleukin-18 promoter A/C genetic locus, for correction of age, gender, history of smoking, hyper-tension, diabetes mel itus, hypercholesteremia, and an ischemic stroke family history, showed ischemic cerebrovascular disease risk in individuals without the A al ele (C homozygotes) was 2.2-fold greater than in A al ele carriers. Overal , our findings suggest that the-13T/C (rs11024595) polymorphism in the 5′-flanking region of serum amyloid A has no correlation with ischemic cere-brovascular disease, but the C al ele of the-607C/A (rs1946518) polymorphism in the interleukin-18 promoter is a high-risk factor for ischemic cerebrovascular disease in the Han population of northern China. In addition, the A al ele is likely a protective gene for ischemic cerebrovascular disease.

  16. Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition: analyzing DNA methylation of transcriptional enhancers reveals missed regulatory links between cancer risk loci and genes.

    Science.gov (United States)

    Aran, Dvir; Hellman, Asaf

    2014-02-01

    Paradoxically, DNA sequence polymorphisms in cancer risk loci rarely correlate with the expression of cancer genes. Therefore, the molecular mechanism underlying an individual's susceptibility to cancer has remained largely unknown. However, recent evaluations of the correlations between DNA methylation and gene expression levels across healthy and cancerous genomes have revealed enrichment of disease-related DNA methylation variations within disease-associated risk loci. Moreover, it appears that transcriptional enhancers embedded in cancer risk loci often contain DNA methylation sites that closely define the expression of prominent cancer genes, despite the lack of significant correlations between gene expression levels and the surrounding disease-associated polymorphic sequences. We suggest that DNA methylation variations may obscure the effect of co-residing risk sequence alleles. Analysis of enhancer methylation data may help to reveal the regulatory circuits underlying predisposition to cancers and other common diseases.

  17. EFFECTS OF VITAMIN D RECEPTOR GENE POLYMORPHISMS ON SUSCEPTIBILITY TO TYPE 1 DIABETES MELLITUS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To investigate the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes mellitus (T1DM) in the Chinese Han population.Method One hundred and thirty-six Chinese Han people, including 54 T1DM patients and 82 unrelated healthy subjects as control were genotyped by polymerase chain reaction-restriction fragment length polymorphism for three restriction sites in the VDR gene, which were ApaI, TaqI, and BamI.Results The frequency of B allele of BsmI site in VDR gene was significantly higher in T1DM patients than in healthy subjects (P=0.033) while no difference was found between the two groups in the distribution of ApaI and TaqI polymorphisms.Conclusion The BsmI polymorphism of VDR gene may be associated with the susceptibility to T1DM in the Chinese Hah population of Beijing.

  18. Association of OGG1 Ser326Cys polymorphism and pancreatic cancer susceptibility: evidence from a meta-analysis.

    Science.gov (United States)

    Yan, Yulan; Chen, Xu; Li, Taijie; Li, Meng; Liang, Hongjie

    2014-03-01

    The 8-oxoguanine DNA glycosylase (OGG1) gene has been considered to be associated with cancer susceptibility. The OGG1 Ser326Cys polymorphism has been reported to be associated with pancreatic cancer (PC), but the published studies have yielded inconsistent results. For better understanding of the effect of OGG1 Ser326Cys polymorphism on PC susceptibility, a meta-analysis was performed. All eligible studies were identified through a search of PubMed, Excerpta Medica Database (Embase), Elsevier Science Direct, and Chinese Biomedical Literature Database before May 2013. The association between the OGG1 Ser326Cys polymorphism and PC risk was conducted by odds ratios (ORs) and 95% confidence intervals (CIs). A total of five case-control studies with 1,690 cases and 3,650 controls were eventually collected. Overall, we found that OGG1 Ser326Cys polymorphism was not associated with PC susceptibility (Cys/Cys vs. Ser/Ser: OR = 0.95, 95% CI = 0.80-1.14; Cys/Cys vs. Ser/Ser + Ser/Cys: OR = 0.95, 95% CI = 0.78-1.14; Cys/Cys + Ser/Cys vs. Ser/Ser (OR = 1.00, 95% CI = 0.89-1.12)). In the subgroup analysis based on ethnicity, source of control, sample size, and genotyping method, no significant association was found in any genetic models. This meta-analysis suggests that the OGG1 Ser326Cys polymorphism may not associated with PC susceptibility. Considering the limited sample size and ethnicity included in the meta-analysis, further larger scaled and well-designed studies are needed to confirm our results.

  19. 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

  20. Association between single nucleotide polymorphisms of BARD1 gene and susceptibility of early-onset breast cancer in Uygur women in Xinjiang%BARD1基因单核苷酸多态性与新疆维吾尔族妇女早发性乳腺癌的相关性研究

    Institute of Scientific and Technical Information of China (English)

    孙刚; 王江涛; 马斌林; 耿中利; 任光辉; 单美慧; 马斌; 马莉莉; 王岩

    2012-01-01

    目的 探讨BARD1基因Pro24Ser(C/T)、Arg378Ser(G/C)和Val507Met( G/A)单核苷酸多态性(SNPa)与新疆维吾尔族妇女早发性乳腺癌易感性的关系.方法 采用病例-对照研究,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测新疆地区144例维吾尔族妇女早发性乳腺癌(年龄≤40岁)和136例维吾尔族健康女性BARD1基因Pr024Ser (C/T)、Arg378 Ser( G/C)和Val507Met (G/A)位点基因型,比较各位点基因型分布与维吾尔族妇女早发性乳腺癌发病风险的关系.结果 初潮年龄早、初产年龄晚和肿瘤家族史可能是新疆地区维吾尔族早发性乳腺癌患者发病的高危因素.在维吾尔族早发性乳腺癌组和健康对照组中,BARD1基因Pro24Ser (C/T)、Arg378Ser(G/C)和Val507Met( G/A)位点的各基因型频率差异有统计学意义(P<0.05).Logistic同归分析表明,Pro24Ser(C/T)位点TT(OR =0.117,95% CI为0.058~0.236)及显性模型CT+ TT( OR=0.279,95%CI为0.157~0.494)、Arg378Ser( G/C)位点CC(OR=0.348,95%CI为0.145~0.834)和Val507 Met( G/A)位点AA(OR=0.359,95% CI为0.167~0.774)的改变,可以显著降低维吾尔族早发性乳腺癌发病风险,并且各位点之间存在协同作用;同时,显性模型CT+TT、GC +CC、GA +AA间的交互作用可以降低52.1%的乳腺癌发病风险(OR=0.479,95% CI为0.230~0.995).分层分析结果显示,Pro24Ser(C/T)和Arg378Ser( G/C)位点基因突变型的保护作用在初潮年龄早和肿瘤家族史阴性患者中更为明显.随着患者初潮年龄的增加,这种保护作用逐渐降低.结论 BARD1基因Pr24Ser(C/T)、Arg378Ser(G/C)和Val507Met( G/A)位点的SNPs变化,能够显著降低新疆地区维吾尔族妇女早发性乳腺癌的发病风险,初潮年龄早和无肿瘤家族史可以增加突变等位基因的保护作用.%Objective To investigate the association between single nucleotide polymorphisms (SNPs) of BARD1 gene and susceptibility of early-onset breast cancer in

  1. Targeting Gene-Virotherapy for Cancer

    Institute of Scientific and Technical Information of China (English)

    Xin-Yuan LIU; Jing-Fa GU; Wen-Fang SHI

    2005-01-01

    Gene therapy and viral therapy for cancer have therapeutic effects, but there has been no significant breakthrough in these two forms of therapy. Therefore, a new strategy called "targeting genevirotherapy", which combines the advantages of gene therapy and viral therapy, has been formulated. This new therapy has stronger antitumor effects than either gene therapy or viral therapy. A tumor-specific replicative adenovirus vector ZD55 (E1B55KD deleted Adv.) was constructed and various single therapeutic genes were inserted into ZD55 to form ZD55-gene. These are the targeting gene-virotherapy genes. But experiments showed that a single gene was not effective in eliminating the tumor mass, and therefore two genes were separately inserted into ZD55. This strategy is called "targeting dual gene-virotherapy" (with PCT patent). Better results were obtained with this strategy, and all the xenograft tumor masses were completely eliminated in all mice when two suitable genes producing a synergetic or compensative effect were chosen. Twenty-six papers on these strategies have been published by researchers in our laboratory.Furthermore, an adenoviral vector with two targeting promoters harboring two antitumor genes has been constructed for cancer therapy. Promising results have been obtained with this adenoviral vectorand another patent has been applied for. This antitumor strategy can be used to kill tumor cells completely with minimum damage to normal cells.

  2. Topological features in cancer gene expression data.

    Science.gov (United States)

    Lockwood, S; Krishnamoorthy, B

    2015-01-01

    We present a new method for exploring cancer gene expression data based on tools from algebraic topology. Our method selects a small relevant subset from tens of thousands of genes while simultaneously identifying nontrivial higher order topological features, i.e., holes, in the data. We first circumvent the problem of high dimensionality by dualizing the data, i.e., by studying genes as points in the sample space. Then we select a small subset of the genes as landmarks to construct topological structures that capture persistent, i.e., topologically significant, features of the data set in its first homology group. Furthermore, we demonstrate that many members of these loops have been implicated for cancer biogenesis in scientific literature. We illustrate our method on five different data sets belonging to brain, breast, leukemia, and ovarian cancers.

  3. 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.

  4. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

    NARCIS (Netherlands)

    Cenit, M.C.; Simeon, C.P.; Vonk, M.C.; Callejas-Rubio, J.L.; Espinosa, G.; Carreira, P.; Blanco, F.J.; Narvaez, J.; Tolosa, C.; Roman-Ivorra, J.A.; Gomez-Garcia, I.; Garcia-Hernandez, F.J.; Gallego, M.; Garcia-Portales, R.; Egurbide, M.V.; Fonollosa, V.; Garcia de la Pena, P.; Lopez-Longo, F.J.; Gonzalez-Gay, M.A.; The Spanish Scleroderma, G.; Hesselstrand, R.; Riemekasten, G.; Witte, T.; Voskuyl, A.E.; Schuerwegh, A.J.; Madhok, R.; Fonseca, C.; Denton, C.; Nordin, A.; Palm, O.; Laar, J.M. van; Hunzelmann, N.; Distler, J.H.; Kreuter, A.; Herrick, A.; Worthington, J.; Koeleman, B.P.; Radstake, T.R.D.J.; Martin, J.

    2012-01-01

    OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotyp

  5. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    NARCIS (Netherlands)

    Berube, Jean-Christophe; Gaudreault, Nathalie; Lavoie-Charland, Emilie; Sbarra, Laura; Henry, Cyndi; Madore, Anne-Marie; Pare, Peter D.; van den Berge, Maarten; Nickle, David; Laviolette, Michel; Laprise, Catherine; Boulet, Louis-Philippe; Bosse, Yohan

    2016-01-01

    Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs) associated with asthma in French Canadian adult women. A pooling-based genome-wide association study

  6. ALTERED HEPATIC GENE EXPRESSION IN MORBIDLY OBESE WOMEN AND ITS IMPLICATIONS FOR SUSCEPTIBILITY TO OTHER DISEASES

    Science.gov (United States)

    The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women un...

  7. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility

    DEFF Research Database (Denmark)

    Damotte, V; Guillot-Noel, L; Patsopoulos, N A;

    2014-01-01

    Genome-wide association studies (GWASs) perform per-SNP association tests to identify variants involved in disease or trait susceptibility. However, such an approach is not powerful enough to unravel genes that are not individually contributing to the disease/trait, but that may have a role in in...

  8. Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite

    Science.gov (United States)

    Grünewald, Thomas G. P.; Bernard, Virginie; Gilardi-Hebenstreit, Pascale; Raynal, Virginie; Surdez, Didier; Aynaud, Marie-Ming; Mirabeau, Olivier; Cidre-Aranaz, Florencia; Tirode, Franck; Zaidi, Sakina; Perot, Gaëlle; Jonker, Anneliene H.; Lucchesi, Carlo; Le Deley, Marie-Cécile; Oberlin, Odile; Marec-Bérard, Perrine; Véron, Amélie S.; Reynaud, Stephanie; Lapouble, Eve; Boeva, Valentina; Frio, Thomas Rio; Alonso, Javier; Bhatia, Smita; Pierron, Gaëlle; Cancel-Tassin, Geraldine; Cussenot, Olivier; Cox, David G.; Morton, Lindsay M.; Machiela, Mitchell J.; Chanock, Stephen J.; Charnay, Patrick; Delattre, Olivier

    2015-01-01

    Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs1–3. A recent genome-wide association study4 identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls revealed 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1–dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis. PMID:26214589

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

    Science.gov (United States)

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I; Conti, David V; Schumacher, Fredrick; Han, Ying; Benlloch, Sara; Hazelett, Dennis J; Wang, Zhaoming; Saunders, Ed; Leongamornlert, Daniel; Lindstrom, Sara; Jugurnauth-Little, Sara; Dadaev, Tokhir; Tymrakiewicz, Malgorzata; Stram, Daniel O; Rand, Kristin; Wan, Peggy; Stram, Alex; Sheng, Xin; Pooler, Loreall C; Park, Karen; Xia, Lucy; Tyrer, Jonathan; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Yeager, Merideth; Burdette, Laurie; Chung, Charles C; Hutchinson, Amy; Yu, Kai; Goh, Chee; Ahmed, Mahbubl; Govindasami, Koveela; Guy, Michelle; Tammela, Teuvo L J; Auvinen, Anssi; Wahlfors, Tiina; Schleutker, Johanna; Visakorpi, Tapio; Leinonen, Katri A; Xu, Jianfeng; Aly, Markus; Donovan, Jenny; Travis, Ruth C; Key, Tim J; Siddiq, Afshan; Canzian, Federico; Khaw, Kay-Tee; Takahashi, Atsushi; Kubo, Michiaki; Pharoah, Paul; Pashayan, Nora; Weischer, Maren; Nordestgaard, Borge G; Nielsen, Sune F; Klarskov, Peter; Røder, Martin Andreas; Iversen, Peter; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Stanford, Janet L; Kolb, Suzanne; Holt, Sarah; Knudsen, Beatrice; Coll, Antonio Hurtado; Gapstur, Susan M; Diver, W Ryan; Stevens, Victoria L; Maier, Christiane; Luedeke, Manuel; Herkommer, Kathleen; Rinckleb, Antje E; Strom, Sara S; Pettaway, Curtis; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; Cannon-Albright, Lisa; Cybulski, Cezary; Wokołorczyk, Dominika; Kluźniak, Wojciech; Park, Jong; Sellers, Thomas; Lin, Hui-Yi; Isaacs, William B; Partin, Alan W; Brenner, Hermann; Dieffenbach, Aida Karina; Stegmaier, Christa; Chen, Constance; Giovannucci, Edward L; Ma, Jing; Stampfer, Meir; Penney, Kathryn L; Mucci, Lorelei; John, Esther M; Ingles, Sue A; Kittles, Rick A; Murphy, Adam B; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej M; Blot, William; Signorello, Lisa B; Zheng, Wei; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Nemesure, Barbara; Carpten, John; Leske, Cristina; Wu, Suh-Yuh; Hennis, Anselm; Kibel, Adam S; Rybicki, Benjamin A; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Zheng, S Lilly; Batra, Jyotsna; Clements, Judith; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Witte, John S; Casey, Graham; Gillanders, Elizabeth M; Seminara, Daniella; Riboli, Elio; Hamdy, Freddie C; Coetzee, Gerhard A; Li, Qiyuan; Freedman, Matthew L; Hunter, David J; Muir, Kenneth; Gronberg, Henrik; Neal, David E; Southey, Melissa; Giles, Graham G; Severi, Gianluca; Cook, Michael B; Nakagawa, Hidewaki; Wiklund, Fredrik; Kraft, Peter; Chanock, Stephen J; Henderson, Brian E; Easton, Douglas F; Eeles, Rosalind A; Haiman, Christopher A

    2014-10-01

    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 cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P discover risk loci for disease.

  10. Employment of Salmonella in Cancer Gene Therapy.

    Science.gov (United States)

    Lee, Che-Hsin

    2016-01-01

    One of the primary limitations of cancer gene therapy is lack of selectivity of the therapeutic gene to tumor cells. Current efforts are focused on discovering and developing tumor-targeting vectors that selectively target only cancer cells but spare normal cells to improve the therapeutic index. The use of preferentially tumor-targeting bacteria as vectors is one of the innovative approaches for the treatment of cancer. This is based on the observation that some obligate or facultative-anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. In this study, we exploited attenuated Salmonella as a tumoricidal agent and a vector to deliver genes for tumor-targeted gene therapy. Attenuated Salmonella, carrying a eukaryotic expression plasmid encoding an anti-angiogenic gene, was used to evaluate its' ability for tumor targeting and gene delivery in murine tumor models. We also investigated the use of a polymer to modify or shield Salmonella from the pre-existing immune response in the host in order to improve gene delivery to the tumor. These results suggest that tumor-targeted gene therapy using Salmonella carrying a therapeutic gene, which exerts tumoricidal and anti-angiogenic activities, represents a promising strategy for the treatment of tumors.

  11. Detection of vanC 1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Directory of Open Access Journals (Sweden)

    Tiane Martin de Moura

    2013-06-01

    Full Text Available Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  12. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis.

    Science.gov (United States)

    Moura, Tiane Martin de; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-06-01

    Here we report the presence and expression levels of the vanC1 and vanC(2/3) genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC1 and vanC(2/3) genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis.

  13. Detection of vanC1 gene transcription in vancomycin-susceptible Enterococcus faecalis

    Science.gov (United States)

    de Moura, Tiane Martin; Cassenego, Ana Paula Vaz; Campos, Fabrício Souza; Ribeiro, Andrea Machado Leal; Franco, Ana Cláudia; d'Azevedo, Pedro Alves; Frazzon, Jeverson; Frazzon, Ana Paula Guedes

    2013-01-01

    Here we report the presence and expression levels of the vanC 1 and vanC 2/3 genes in vancomycin-susceptible strains of Enterococcus faecalis. The vanC 1 and vanC 2/3 genes were located in the plasmid DNA and on the chromosome, respectively. Specific mRNA of the vanC 1 gene was detected in one of these strains. Additionally, analysis of the vanC gene sequences showed that these genes are related to the vanC genes of Enterococcus gallinarum and Enterococcus casseliflavus. The presence of vanC genes is useful for the identification of E. gallinarum and E. casseliflavus. Moreover, this is the first report of vanC mRNA in E. faecalis. PMID:23828012

  14. ERCC2基因多态性与焦炉工DNA损伤及肺癌易感性的关联研究%Association of ERCC2 gene polymorphisms with DNA damage among coke oven workers and lung cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    王芳; 何越峰; 郭欢; 杨艳; 吴舟; 郑红艳

    2012-01-01

    Objective To investigate the relationship between ERCC2 gene polymorphisms and DNA damage and lung cancer susceptibility. Methods 821 workers, 1 152 primary lung cancer and 1 152 controls were enrolled in the study. Workers were divided into three groups including the exposure, recovery and control according to the working status and places. Urine 1-hydroxypyrene was determined by reversed phase high-performance liquid chromatography. Comet assay was used to evaluate DNA damage level and the level of DNA damage was measured by Olive Tail Moments (OTM). 5' nuclease allelic discrimination assay was used to genotype ERCC2 gene polymorphisms. Results The urine 1-hydroxypyrene level of workers in the exposure and recovery group (4. 41±1. 06 and 3. 79±1. 05) were significantly higher than that of the control (3. 33±1. 03), P<0.05. The OTM of workers in exposure group (-0. 86±0.70) was higher than that of the recovery and controls (-1. 18±0. 69 and -1. 14±0- 63, respectively), P<0.01. In the recovery group, the OTM of rs50871 GT carriers was significantly lower than that of the TT carriers (-1. 28 ± 0. 62 vs -1.11 ± 0. 71, P=0. 021). Similarly, carriers of rs50872 TC heterozygote had lower OTM than that of the CC homo-zygote (-1. 33±0. 69 vs -1.10±0. 67, P=0.003). No significant associations were found in other SNPs with DNA damage. No significance was found between rs50871 and rs50872 and lung cancer susceptibility. Conclusions The ERCC2 gene polymorphisms could modulate DNA damage of coke oven workers, but had no significant effects on lung cancer susceptibility.%目的 探讨ERCC2基因多态性与焦炉工DNA损伤及肺癌易感性的关联.方法 选取821例焦化工人、1 152例原发性肺癌患者为研究对象,1 152名健康体检者作为对照.焦化工人以工作状态和岗位分为暴露组、恢复组和对照组;使用反向高效液相色谱法测定尿1-羟基芘含量,采用彗星试验检测DNA损伤并以Olive尾矩(Olive Tail Moments

  15. Effects of Two Common Polymorphisms rs2910164 in miR-146a and rs11614913 in miR-196a2 on Gastric Cancer Susceptibility

    Directory of Open Access Journals (Sweden)

    Qing Ni

    2015-01-01

    Full Text Available Background. Single nucleotide polymorphisms (SNPs in genes encoding microRNAs may play important role in the development of gastric cancer. It has been reported that common SNPs rs2910164 in miR-146a and rs11614913 in miR-196a2 are associated with susceptibility to gastric cancer. The published results remain inconclusive or even controversial. A meta-analysis was conducted to quantitatively assess potential association between the two common SNPs and gastric cancer risk. Methods. A comprehensive literature search was performed in multiple internet-based electronic databases. Data from 12 eligible studies were extracted to estimate pooled odds ratios (ORs and 95% confidence intervals (95% CI. Results. C allele of rs2910164 is associated with reduced gastric cancer risk in heterozygote model and dominant model whereas rs11614913 indicates no significant association. Subgroup analysis demonstrates that C allele of rs2910164 and rs11614913 may decrease susceptibility to diffuse type gastric cancer in dominant model and recessive model, respectively, while rs11614913 increased intestinal type gastric cancer in dominant model. Conclusion. SNPs rs2910164 and rs11614913 might have effect on gastric cancer risk in certain genetic models and specific types of cancer. Further well-designed studies should be considered to validate the potential effect.

  16. Mutation Analysis in the BRCA1 Gene in Chinese Breast Cancer Families

    Institute of Scientific and Technical Information of China (English)

    WUZhengyan; ZHENLinlin; FANPing

    2003-01-01

    Objective: To study the mutation of BRCA1 gene in Chinese breast cancer families. Methods:Fifteen families were selected, involving 41 members, consisting of 23 breast cancer patients. Using poly-merase chain reaction and single stranded conformation polymorphism (PCR-SSCP), and subsequent DNA sequencing, the mutation of BRCA1 genes were analyzed. Results: Four mutations were found in all fam-ilies, and the proportion of mutation was 26.7% (4/15) in breast cancer families. One of the 4 mutations was 2228 insC, resulting in chain termination at codon 711. The remaining 3 mutations were 1884A→T and 3232A→G, resulting in single amino acid change respectively. Conclusion: BRCA1 is a breast cancer susceptibility gene. The relatively low proportion and frequency of BRCA1 mutations in our study hints additional BRCA genes existed.

  17. Gene Expression Analysis of Plum pox virus (Sharka Susceptibility/Resistance in Apricot (Prunus armeniaca L..

    Directory of Open Access Journals (Sweden)

    Manuel Rubio

    Full Text Available RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925, which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein PPVres region could also be involved in the resistance.

  18. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    Science.gov (United States)

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance.

  19. Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs?

    Science.gov (United States)

    Catchpole, Brian; Adams, Jamie P; Holder, Angela L; Short, Andrea D; Ollier, William E R; Kennedy, Lorna J

    2013-02-01

    Diabetes mellitus is a common endocrinopathy in companion animals, characterised by hyperglycaemia, glycosuria and weight loss, resulting from an absolute or relative deficiency in the pancreatic hormone insulin. There are breed differences in susceptibility to diabetes mellitus in dogs, with the Samoyed breed being overrepresented, while Boxers are relatively absent in the UK population of diabetic dogs, suggesting that genetic factors play an important role in determining susceptibility to the disease. A number of genes, linked with susceptibility to diabetes mellitus in humans, are associated with an increased risk of diabetes mellitus in dogs, some of which appear to be relatively breed-specific. Diabetes mellitus in dogs has been associated with major histocompatibility complex (MHC) class II genes (dog leucocyte antigen; DLA), with similar haplotypes and genotypes being identified in the most susceptible breeds. A region containing a variable number of tandem repeats (VNTR) and several polymorphisms have been identified in the canine insulin gene, with some alleles associated with susceptibility or resistance to diabetes mellitus in a breed-specific manner. Polymorphisms in the canine CTLA4 promoter and in other immune response genes are associated with susceptibility to diabetes mellitus in a number of pedigree breeds. Genome wide association studies are currently underway that should shed further light on the genetic factors responsible for the breed profile seen in the diabetic dog population.

  20. HE4 Gene Overexpression in Ovarian Cancer

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    A Shahi

    2016-03-01

    Full Text Available Introduction: Ovarian cancer is one of the common malignancies within women and the fifth cause of cancer death in women all over the world. Recent developments in Genomics and Proteomics technologies have led to the identification of unknown candidate markers for the diagnosis of ovarian cancer. Human epididymis protein 4 (HE4 has recently been supported to monitor the recurrence or the progression of epithelial ovarian cancer. Therefore, this study aimed to measure the expression of HE4 in women suffering from ovarian cancer. Methods: In this study, 20 paraffin-embedded tissue samples from women with ovarian cancer and 10 normal samples were collected from Imam Khomeini Hospital in Tehran. After removing paraffin, RNA extraction was performed with RNAPlus solution. cDNA was synthesized through reverse transcription by MMULV enzyme. Gene expression was measured by Relative Real time PCR method. Glyceraldehyde phosphate dehydrogenase gene (GAPDH was used as an internal control. Results: The HE4 was expressed in normal and cancerous tissues, though its expression was observed more in tumor tissues (4.083 than noncancerous tissues. The study results also revealed that the expression level of HE4 increased with the advancement of the disease. Conclusion: According to the results, it can be concluded that HE4 expression levels greatly increases in tumor samples. Therefore, HE4 gene expression measurements can serve as a valuable prognostic factor for early detection and treatment management of the disease.

  1. Modification of lung cancer susceptibility by green tea extract as measured by the comet assay.

    Science.gov (United States)

    Zhang, Huifeng; Spitz, Margaret R; Tomlinson, Gail E; Schabath, Matthew B; Minna, John D; Wu, Xifeng

    2002-01-01

    Green tea is widely consumed throughout the world and is known to possess various beneficial properties that may affect carcinogen metabolism, free radical scavenging, or formation of DNA adducts. Therefore, it is plausible that green tea extract may modify BPDE-induced DNA damage. In this report, we utilized the comet assay to (1) evaluate BPDE-induced DNA damage as a potential marker of cancer susceptibility and (2) assess the ability of green tea to modify BPDE-induced DNA damage. DNA damage in individual comet cells was quantified by (1) visually measuring the proportion of cells exhibiting migration versus those without and (2) the length of damaged DNA migration (comet tail). We detected a dose-response between BDPE concentration and mean comet tail length in EBV-immortalized lymphoblastiod (lymphoid) cell lines. As the concentration of BPDE increased from 0.5 to 3 microM, the length of the mean comet tail length increased proportionally in the 3590P (derived from a healthy subject) and 3640P (derived from a patient with head and neck cancer) cell lines. In separate experiments using lymphoid cells from 21 lung cancer cases and 12 healthy subjects, the mean comet tail length was significantly higher in the lung cancer cases (80.19 +/- 15.55) versus the healthy subjects (59.94 +/- 14.23) (P green tea extract was added in conjunction with BPDE, there was a notable reduction of the mean comet tail length (13.29 +/- 0.97) as compared to BPDE treatment alone (80.19 +/- 15.55) (P lung cancer cases. There were no statistical differences between the baseline (no treatments) (12.74 +/- 0.63) and the green tea extract treatment (13.06 +/- 0.97) (P = 0.21). These data suggest the modification of lung cancer susceptibility by the green tea extract. Similar results were observed for the percentage of induced comet cells and the statistical trends were similar for the 12 healthy subjects. This preliminary study demonstrated that the detection of BPDE-induced DNA damage via

  2. Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes.

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-11-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  3. The NCAN gene: schizophrenia susceptibility and cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Wang P

    2016-11-01

    Full Text Available Peirong Wang,1 Jun Cai,2 Jianliang Ni,1 Jiangtao Zhang,1 Wei Tang,3 Chen Zhang2 1Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 2Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 3Wenzhou Kangning Hospital, Wenzhou, Zhejiang, People’s Republic of China Background: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN, is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia.Methods: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS.Results: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction.Conclusion: Our findings indicate

  4. Gene and environment interaction: Is the differential susceptibility hypothesis relevant for obesity?

    Science.gov (United States)

    Dalle Molle, Roberta; Fatemi, Hajar; Dagher, Alain; Levitan, Robert D; Silveira, Patricia P; Dubé, Laurette

    2017-02-01

    The differential susceptibility model states that a given genetic variant is associated with an increased risk of pathology in negative environments but greater than average resilience in enriched ones. While this theory was first implemented in psychiatric-genetic research, it may also help us to unravel the complex ways that genes and environments interact to influence feeding behavior and obesity. We reviewed evidence on gene vs. environment interactions that influence obesity development, aiming to support the applicability of the differential susceptibility model for this condition, and propose that various environmental "layers" relevant for human development should be considered when bearing the differential susceptibility model in mind. Mother-child relationship, socioeconomic status and individual's response are important modifiers of BMI and food intake when interacting with gene variants, "for better and for worse". While only a few studies to date have investigated obesity outcomes using this approach, we propose that the differential susceptibility hypothesis is in fact highly applicable to the study of genetic and environmental influences on feeding behavior and obesity risk.

  5. Adenoviral gene therapy in gastric cancer: A review

    Institute of Scientific and Technical Information of China (English)

    Nima Khalighinejad; Hesammodin Hariri; Omid Behnamfar; Arash Yousefi; Amir Momeni

    2008-01-01

    Gastric cancer is one of the most common malignancies worldwide. With current therapeutic approaches the prognosis of gastric cancer is very poor, as gastric cancer accounts for the second most common cause of death in cancer related deaths. Gastric cancer like almost all other cancers has a molecular genetic basis which relies on disruption in normal cellular regulatory mechanisms regarding cell growth, apoptosis and cell division. Thus novel therapeutic approaches such as gene therapy promise to become the alternative choice of treatment in gastric cancer. In gene therapy, suicide genes, tumor suppressor genes and anti-angiogenesis genes among many others are introduced to cancer cells via vectors.Some of the vectors widely used in gene therapy are Adenoviral vectors. This review provides an update of the new developments in adenoviral cancer gene therapy including strategies for inducing apoptosis, inhibiting metastasis and targeting the cancer cells.

  6. An overview of gene therapy in head and neck cancer.

    Science.gov (United States)

    Bali, Amit; Bali, Deepika; Sharma, Ashutosh

    2013-07-01

    Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction and expression, mediation of apoptosis and clinical response including pathological complete responses. The objective of this article is to provide an overview of the current available gene therapies for head and neck cancer.

  7. Meta Analysis on DNA Repair Gene XRCC3 - 18067C > T Single Neucleotide Polymorphisms and Head and Neck Cancer Susceptibility%DNA修复基因XRCC3-18067C>T多态性与头颈部肿瘤易感性关系的系统评价

    Institute of Scientific and Technical Information of China (English)

    柯为洵; 李杰; 曹岐新; 嵇冰

    2011-01-01

    目的 采用系统评价的方法探讨DNA修复基因X线修复交叉互补因子3(x- ray cross - complementing group 3,XRCC3) 18067C>T位点单核苷酸多态性与头颈部肿瘤易感性的关系.方法 检索PubMed(1966~2010年)、EMBASE( 1974~2010年)、中国生物医学文献数据库CBM(1978~2010年)、中国期刊全文数据库CNKI(1994~2010年)公开发表的关于DNA修复基因XRCC3 - 18067C>T单核苷酸多态性与头颈部肿瘤易感性的研究.病例组及对照组XRCC3 - 18067C>T等位基因分布的比值比( odds ratio,OR)为效应指标,根据一致性检验的结果,选择固定效应模型或随机效应模型对OR进行合并,并进行偏倚评估.结果 共查到符合要求的文献9篇,病例组1872例,对照组3521例.分析结果显示:XRCC3 - 18067C >T位点突变纯合子(T/T)患头颈部肿瘤的风险与野生型纯合子(C/C)相比OR=L.16(95% CI:0.95 ~ 1.43,P=0.150);隐性模式下,18067C>T位点突变纯合子(T/T)患头颈部肿瘤的风险与野生型(纯合子+杂合子)(C/C)+(C/T)相比OR=1.16(95% CI:0.96~1.40,P=0.124);显性模式下,18067C>T位点突变个体(突变纯合子+突变杂合子)(T/T)+(C/T)患头颈部肿瘤的风险与野生型纯合子(C/C)相比OR=1.05(95% CI:0.93~1.19,P=0.426).结论 DNA修复基因XRCC3 18067C>T位点单核苷酸多态性与头颈部肿瘤易感性间存不在明显相关性.%Objective To evaluate the relationship between X - ray cross - complementing group 3 ( XRCC3 ) gene single neucleotide polymorphisms and head and neck cancer susceptibility. Methods By searching Medline, EMBSE, CBM and CNKI.et al, we collected studies about DNA X - ray cross - complementing group 3 ( XRCC3) gene polymorphisms and head and neck cancer susceptibility. The odds ratios (OR) of variant allele of XRCC3 - 18067C >T was calculated by using statistic software STATAU.O. Publication bias was also evaluated. Results Nine case -control studies were identified for the

  8. 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...

  9. 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

  10. The gene desert mammary carcinoma susceptibility locus Mcs1a regulates Nr2f1 modifying mammary epithelial cell differentiation and proliferation.

    Directory of Open Access Journals (Sweden)

    Bart M G Smits

    2013-06-01

    Full Text Available Genome-wide association studies have revealed that many low-penetrance breast cancer susceptibility loci are located in non-protein coding genomic regions; however, few have been characterized. In a comparative genetics approach to model such loci in a rat breast cancer model, we previously identified the mammary carcinoma susceptibility locus Mcs1a. We now localize Mcs1a to a critical interval (277 Kb within a gene desert. Mcs1a reduces mammary carcinoma multiplicity by 50% and acts in a mammary cell-autonomous manner. We developed a megadeletion mouse model, which lacks 535 Kb of sequence containing the Mcs1a ortholog. Global gene expression analysis by RNA-seq revealed that in the mouse mammary gland, the orphan nuclear receptor gene Nr2f1/Coup-tf1 is regulated by Mcs1a. In resistant Mcs1a congenic rats, as compared with susceptible congenic control rats, we found Nr2f1 transcript levels to be elevated in mammary gland, epithelial cells, and carcinoma samples. Chromatin looping over ∼820 Kb of sequence from the Nr2f1 promoter to a strongly conserved element within the Mcs1a critical interval was identified. This element contains a 14 bp indel polymorphism that affects a human-rat-mouse conserved COUP-TF binding motif and is a functional Mcs1a candidate. In both the rat and mouse models, higher Nr2f1 transcript levels are associated with higher abundance of luminal mammary epithelial cells. In both the mouse mammary gland and a human breast cancer global gene expression data set, we found Nr2f1 transcript levels to be strongly anti-correlated to a gene cluster enriched in cell cycle-related genes. We queried 12 large publicly available human breast cancer gene expression studies and found that the median NR2F1 transcript level is consistently lower in 'triple-negative' (ER-PR-HER2- breast cancers as compared with 'receptor-positive' breast cancers. Our data suggest that the non-protein coding locus Mcs1a regulates Nr2f1, which is a candidate

  11. Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease.

    Science.gov (United States)

    Hu, Yang; Zhang, Junli; Jia, Hongge; Sosso, Davide; Li, Ting; Frommer, Wolf B; Yang, Bing; White, Frank F; Wang, Nian; Jones, Jeffrey B

    2014-01-28

    Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations.

  12. Matrix metalloproteinase gene polymorphisms and oral cancer.

    Science.gov (United States)

    Pereira, Andresa C; Dias do Carmo, Elaine; Dias da Silva, Marco A; Blumer Rosa, Luiz E

    2012-12-01

    Since oral squamous cell carcinoma (OSCC) is the most prevalent malignant cancer in the oral cavity, several researches have been performed to study the role of important enzymes in this disease. Among them, the matrix metalloproteinases (MMPs) are highlighted, due to the fact that they are proteinases responsible to degrade many extra-cellular matrix components, making possible the invasion of neoplasic cells. Important tools in cancer prognosis have been utilized aiming to correlate high levels of MMPs and OSCC, such as immunohistochemical, zymographic and mRNA detection methods. However, these techniques are usually applied after cancer detection, characterizing a curative but not a preventive medicine. Trying to make interventions before the development of the disease and making possible the identification of people at high risk and, analysis of modifications in MMP genes has been a chance for modern medicine. Recently, polymorphisms in MMP genes have been related to different neoplasias, including OSCC. Despite investigation is beginning, MMP gene polymorphisms seems to have a promising future in oral cancer research and some of the present results have shown that there are MMP polymorphisms related to an increased risk for developing oral cancer. Key words:Oral cancer, polymorphism, matrix metalloproteinase.

  13. Methylated genes as new cancer biomarkers

    DEFF Research Database (Denmark)

    Brunner, Nils; Duffy, M.J; Napieralski, R.;

    2009-01-01

    Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested that meas......Aberrant hypermethylation of promoter regions in specific genes is a key event in the formation and progression of cancer. In at least some situations, these aberrant alterations occur early in the formation of malignancy and appear to be tumour specific. Multiple reports have suggested...... that measurement of the methylation status of the promoter regions of specific genes can aid early detection of cancer, determine prognosis and predict therapy responses. Promising DNA methylation biomarkers include the use of methylated GSTP1 for aiding the early diagnosis of prostate cancer, methylated PITX2...... for predicting outcome in lymph node-negative breast cancer patients and methylated MGMT in predicting benefit from alkylating agents in patients with glioblastomas. However, prior to clinical utilisation, these findings require validation in prospective clinical studies. Furthermore, assays for measuring gene...

  14. Lung Cancer Gene Signatures and Clinical Perspectives

    Directory of Open Access Journals (Sweden)

    Ruprecht Kuner

    2013-12-01

    Full Text Available Microarrays have been used for more than two decades in preclinical research. The tumor transcriptional profiles were analyzed to select cancer-associated genes for in-deep functional characterization, to stratify tumor subgroups according to the histopathology or diverse clinical courses, and to assess biological and cellular functions behind these gene sets. In lung cancer—the main type of cancer causing mortality worldwide—biomarker research focuses on different objectives: the early diagnosis of curable tumor diseases, the stratification of patients with prognostic unfavorable operable tumors to assess the need for further therapy regimens, or the selection of patients for the most efficient therapies at early and late stages. In non-small cell lung cancer, gene and miRNA signatures are valuable to differentiate between the two main subtypes’ squamous and non-squamous tumors, a discrimination which has further implications for therapeutic schemes. Further subclassification within adenocarcinoma and squamous cell carcinoma has been done to correlate histopathological phenotype with disease outcome. Those tumor subgroups were assigned by diverse transcriptional patterns including potential biomarkers and therapy targets for future diagnostic and clinical applications. In lung cancer, none of these signatures have entered clinical routine for testing so far. In this review, the status quo of lung cancer gene signatures in preclinical and clinical research will be presented in the context of future clinical perspectives.

  15. Radiosensitivity and cancer-related genes

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Akihisa; Ohnishi, Takeo [Nara Medical Univ., Kashihara (Japan)

    1997-03-01

    The influence of several cancer-related genes, myc, fos, jun, ras, raf mos, cot, src, erbB, bcl-2, RB and p53, on radiosensitivity has been shown by tranfection studies. This review focuses on the functions of growth arrest, DNA repair and apoptosis regulated by these cancer-related genes. Resistance to apoptosis has emerged as a major category of radiation sensitivity. In the near future, it might be clear which of the cancer-related genes acts in an important role in apoptosis pathway after irradiation. In addition, there is no direct evidence in the activation of DNA repair during the cell cycle arrest. Therefore, identification of factors directly acting on radiation sensitivity will offer new strategies in cancer predictical assay using biopsied tumor specimens in radiotherapy. Further studies are must to be carried out for detection of common mutations in cancer-related genes for predictical assay and the potential for induction of apoptosis by radiotherapy and genetherapy. (author). 107 refs.

  16. Genes Expressed Differentially in Hessian Fly Larvae Feeding in Resistant and Susceptible Plants

    Directory of Open Access Journals (Sweden)

    Ming-Shun Chen

    2016-08-01

    Full Text Available The Hessian fly, Mayetiola destructor, is a destructive pest of wheat worldwide and mainly controlled by deploying resistant cultivars. In this study, we investigated the genes that were expressed differentially between larvae in resistant plants and those in susceptible plants through RNA sequencing on the Illumina platform. Informative genes were 11,832, 14,861, 15,708, and 15,071 for the comparisons between larvae in resistant versus susceptible plants for 0.5, 1, 3, and 5 days, respectively, after larvae had reached the feeding site. The transcript abundance corresponding to 5401, 6902, 8457, and 5202 of the informative genes exhibited significant differences (p ≤ 0.05 in the respective paired comparisons. Overall, genes involved in nutrient metabolism, RNA and protein synthesis exhibited lower transcript abundance in larvae from resistant plants, indicating that resistant plants inhibited nutrient metabolism and protein production in larvae. Interestingly, the numbers of cytochrome P450 genes with higher transcript abundance in larvae from resistant plants were comparable to, or higher than those with lower transcript abundance, indicating that toxic chemicals from resistant plants may have played important roles in Hessian fly larval death. Our study also identified several families of genes encoding secreted salivary gland proteins (SSGPs that were expressed at early stage of 1st instar larvae and with more genes with higher transcript abundance in larvae from resistant plants. Those SSGPs are candidate effectors with important roles in plant manipulation.

  17. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci.

    Science.gov (United States)

    Coetzee, Simon G; Shen, Howard C; Hazelett, Dennis J; Lawrenson, Kate; Kuchenbaecker, Karoline; Tyrer, Jonathan; Rhie, Suhn K; Levanon, Keren; Karst, Alison; Drapkin, Ronny; Ramus, Susan J; Couch, Fergus J; Offit, Kenneth; Chenevix-Trench, Georgia; Monteiro, Alvaro N A; Antoniou, Antonis; Freedman, Matthew; Coetzee, Gerhard A; Pharoah, Paul D P; Noushmehr, Houtan; Gayther, Simon A

    2015-07-01

    Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.

  18. Psychological impact of genetic testing for cancer susceptibility: an update of the literature.

    Science.gov (United States)

    Meiser, Bettina

    2005-12-01

    This article presents an overview of the rapidly evolving body of literature on the psychological impact of genetic testing for hereditary breast/ovarian cancer susceptibility, hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Uptake of genetic testing for BRCA1/2 and HNPCC-related mutations is more consistently related to psychological factors, rather than sociodemographic variables. Most studies on the psychological impact of genetic testing amongst individuals who have never been affected by cancer demonstrate that non-carriers derive significant psychological benefits from genetic testing, while no adverse effects have been observed amongst carriers. These benefits are more clear-cut for HNPCC, compared to hereditary breast/ovarian cancer, reflecting differences in risk management options. The few studies available on individuals affected with cancer indicate that the impact of genetic testing is mediated and amplified by their former experience of cancer. Future directions and challenges of research in this area are reviewed. In particular, more empirical data are needed on the broader impact of genetic testing on those with inconclusive results or results of uncertain significance. As genetic testing is becoming available for other types of familial cancer, additional investigations will be needed as there is evidence to suggest that the impact of genetic testing may be unique to each type of familial cancer.

  19. Mining susceptibility gene modules and disease risk genes from SNP data by combining network topological properties with support vector regression.

    Science.gov (United States)

    Hua, Lin; Zhou, Ping; Liu, Hong; Li, Lin; Yang, Zheng; Liu, Zhi-cheng

    2011-11-21

    Genome-wide association study is a powerful approach to identify disease risk loci. However, the molecular regulatory mechanisms for most complex diseases are still not well understood. Therefore, further investigating the interplay between genetic factors and biological networks is important for elucidating the molecular mechanisms of complex diseases. Here, we proposed a novel framework to identify susceptibility gene modules and disease risk genes by combining network topological properties with support vector regression from single nucleotide polymorphism (SNP) level. We assigned risk SNPs to genes using the University of California at Santa Cruz (UCSC) genome database, and then mapped these genes to protein-protein interaction (PPI) networks. The gene modules implicated by hub genes were extracted using the PPI networks and the topological property was analyzed for these gene modules. For each gene module, risk feature genes were determined by topological property analysis and support vector regression. As a result, five shared risk feature genes, CD80, EGFR, FN1, GSK3B and TRAF6 were found and proven to be associated with rheumatoid arthritis by previous reports. Our approach showed a good performance in comparison with other approaches and can be used for prioritizing candidate genes associated with complex diseases.

  20. Heat induces gene amplification in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Bin, E-mail: yanbin@mercyhealth.com [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Mercy Cancer Center, Mercy Medical Center-North Iowa, Mason City, IA 50401 (United States); Ouyang, Ruoyun [Department of Respiratory Medicine, The Second Xiangya Hospital, Xinagya School of Medicine, Central South University, Changsha 410011 (China); Huang, Chenghui [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Department of Oncology, The Third Xiangya Hospital, Xinagya School of Medicine, Central South University, Changsha 410013 (China); Liu, Franklin [Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710 (United States); Neill, Daniel [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS 39213 (United States); Li, Chuanyuan [Dermatology, Duke University Medical Center, Durham, NC 27710 (United States); Dewhirst, Mark [Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710 (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer This study discovered that heat exposure (hyperthermia) results in gene amplification in cancer cells. Black-Right-Pointing-Pointer Hyperthermia induces DNA double strand breaks. Black-Right-Pointing-Pointer DNA double strand breaks are considered to be required for the initiation of gene amplification. Black-Right-Pointing-Pointer The underlying mechanism of heat-induced gene amplification is generation of DNA double strand breaks. -- Abstract: Background: Hyperthermia plays an important role in cancer therapy. However, as with radiation, it can cause DNA damage and therefore genetic instability. We studied whether hyperthermia can induce gene amplification in cancer cells and explored potential underlying molecular mechanisms. Materials and methods: (1) Hyperthermia: HCT116 colon cancer cells received water-submerged heating treatment at 42 or 44 Degree-Sign C for 30 min; (2) gene amplification assay using N-(phosphoacetyl)-L-aspartate (PALA) selection of cabamyl-P-synthetase, aspartate transcarbarmylase, dihydro-orotase (cad) gene amplified cells; (3) southern blotting for confirmation of increased cad gene copies in PALA-resistant cells; (4) {gamma}H2AX immunostaining to detect {gamma}H2AX foci as an indication for DNA double strand breaks. Results: (1) Heat exposure at 42 or 44 Degree-Sign C for 30 min induces gene amplification. The frequency of cad gene amplification increased by 2.8 and 6.5 folds respectively; (2) heat exposure at both 42 and 44 Degree-Sign C for 30 min induces DNA double strand breaks in HCT116 cells as shown by {gamma}H2AX immunostaining. Conclusion: This study shows that heat exposure can induce gene amplification in cancer cells, likely through the generation of DNA double strand breaks, which are believed to be required for the initiation of gene amplification. This process may be promoted by heat when cellular proteins that are responsible for checkpoints, DNA replication, DNA repair and

  1. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

    Science.gov (United States)

    Horne, Hisani N.; Chung, Charles C.; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H.; ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J.; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; Haiman, Christopher A.; Marchand, Loic Le; Goldberg, Mark S.; Teo, Soo H.; Taib, Nur A. M.; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L.; Knight, Julia A.; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W. M.; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S.; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D. P.

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive. PMID:27556229

  2. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

    Science.gov (United States)

    Horne, Hisani N; Chung, Charles C; Zhang, Han; Yu, Kai; Prokunina-Olsson, Ludmila; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Hopper, John L; Southey, Melissa C; Schmidt, Marjanka K; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Hamann, Ute; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Iwata, Hiroji; Dörk, Thilo; Bogdanova, Natalia V; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Chenevix-Trench, Georgia; Wu, Anna H; Ven den Berg, David; Smeets, Ann; Zhao, Hui; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Vachon, Celine; Giles, Graham G; Milne, Roger L; Haiman, Christopher A; Marchand, Loic Le; Goldberg, Mark S; Teo, Soo H; Taib, Nur A M; Kristensen, Vessela; Borresen-Dale, Anne-Lise; Zheng, Wei; Shrubsole, Martha; Winqvist, Robert; Jukkola-Vuorinen, Arja; Andrulis, Irene L; Knight, Julia A; Devilee, Peter; Seynaeve, Caroline; García-Closas, Montserrat; Czene, Kamila; Darabi, Hatef; Hollestelle, Antoinette; Martens, John W M; Li, Jingmei; Lu, Wei; Shu, Xiao-Ou; Cox, Angela; Cross, Simon S; Blot, William; Cai, Qiuyin; Shah, Mitul; Luccarini, Craig; Baynes, Caroline; Harrington, Patricia; Kang, Daehee; Choi, Ji-Yeob; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Slager, Susan; Yannoukakos, Drakoulis; Shen, Chen-Yang; Hou, Ming-Feng; Swerdlow, Anthony; Orr, Nick; Simard, Jacques; Hall, Per; Pharoah, Paul D P; Easton, Douglas F; Chanock, Stephen J; Dunning, Alison M; Figueroa, Jonine D

    2016-01-01

    The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

  3. Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

    Directory of Open Access Journals (Sweden)

    Alexey V. Polonikov

    2014-01-01

    Full Text Available Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE. We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase and PON2 (paraoxonase 2 as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma.

  4. Association between DNA repair gene XRCC3 Thr241 Met single nucleotide polymorphisms and colorectal cancer susceptibility:a meta-analysis%DNA修复基因XRCC3Thr241Met多态性与结直肠癌易感的Meta分析

    Institute of Scientific and Technical Information of China (English)

    梁天伟; 孙轶; 卢永刚

    2011-01-01

    AIM: To evaluate the association between single nucleotide polymorphisms of the X-ray repair cross-complementing group 3 (XRCC3) gene and colorectal cancer susceptibility.METHODS: By searching EMBSE (1974-2010.11), Pubmed (1966-2010.11), CNKI (1994-2010.11) and CBM (1978-2010.11), We collected studies evaluating the association between XRCC3 gene polymorphisms and colorectal cancer susceptibility. The effect size was odds ratios (OR) of variant allele of XRCC3Thr241Met in the case and control groups. Random or fixed effect model was selected according to the results of heterogeneity test. The OR and publication bias were calculated using Review Manager 5.0 and STATA11.0 software.RESULTS: Nine case-control studies involving 3 294 cases and 3 947 controls were included. In the Met/Met versus Thr/Thr group, the odds ratio was 1.30 (95%CI: 0.86-1.98, P = 0.22). For the dominant genetic model, the OR in the Met/ Met+Met/Thr versus Thr/Thr group was 1.05 (95%CI: 0.67-1.66 P = 0.83). For the recessive genetic model, the OR in the Met/Met versus Thr/ Thr+Thr/Met group was 1.45 (95%CI: 0.94-2.25, P = 0.09).CONCLUSION: There was no close association between XRCC3 Thr241 Met single nucleotide polymorphisms and colorectal cancer susceptibility.%目的:探讨DNA 修复基因X线修复交叉互补因子3(XRCC3) Thr241Met 单核苷酸多态性与结直肠癌易感性的关系.方法:检索EMBASE(1974/2010-11)、PubMed (1966/2010-11)、中国期刊全文数据库CNKI (1994/2010-11)、中国生物医学文献数据库CBM(1978/2010-11)公开发表的DNA 修复基因XRCC3 Thr241Met 单核苷酸多态性与结直肠癌易感性关系的研究.病例组及对照组XRCC3 Thr241Met 等位基因分布的优势比(OR )为效应指标,根据异质性检验结果,选择随机效应模型或固定效应模型对OR 进行合并,同时进行偏倚评估.结果:共查到符合要求的文献9篇,病例组3 29 4例,对照组3 947 例.分析结果显示:XRCC3 Thr241Met点突变纯合子(Met/Met)

  5. Meta Analysis on DNA Repair Gene XRCC1- 26304C>T Single Neucleotide Polymorphisms and Oral Cancer Susceptibility%DNA修复基因XRCC1-26304C>T多态性与口腔癌易感性关系的meta分析

    Institute of Scientific and Technical Information of China (English)

    姚红磊; 陈涌; 纳应坤; 骆奇; 刘华

    2012-01-01

    Objictive: To evaluate the relationship between X-ray cross-complementing group KXRCCDgene single neucleotide polymorphisms and oral cancer susceptibility. Methods: By searching Medline, EMBSE, CBM and CNKI et al, we collect studies about DNA X -ray cross -complementing group KXRCC1) gene polymorphisms and oral cancer susceptibility. The odds ratios COR) of variant allele of XRCC3-26304OT was calculated by using statistic software RevievMan5. 0 and STATA11. 0. Results: 7 case-control studies were identified for the meta-analysis, a total of 1155 cases and 2036 controls were included. In the (T/T)VS(C/C) group the odds ratio was I. 46(0. 93-2. 28 ); For the recessive genetic model, in the (T/T)VS(C/C) + (C/T) group the odds ratio was 1.30 (0.84 - 2.00)s For the dominint genetic model, in the (T/T) + (C/T)VS(C/C) group the odds ratio was OR = 1.34(1.02-1.76). Conclusion: In the dominant genetic mode, carrying XRCC1 gene mutations (TT + CT) of Asians may be susceptible of oral cancer, but more researches are needed to confirm.%目的:采用系统评价的方法综合分析DNA修复基因(X-ray cross-complementing group 1,XRCC1)26304C>T位点单核苷酸多态性与口腔癌易感性的关系.方法:检索PubMed(1966~2011.4)、EMBASE( 1974~2011.4)、中国生物医学文献数据库CBM(1978~2011.3)、中国期刊全文数据库CNKI(1994~2011.3)等数据库收录的XRCC1-26304C>T单核苷酸多态性与口腔癌易感性的研究.以病例组和对照组等位基因分布的比值比(odds ratio OR)为效应指标,根据异质性检验结果,选择固定效应模型或随机效应模型对OR进行合并.结果:本次meta分析共纳入文献7篇,病例组1155例,对照组2036例.分析结果显示:突变纯合子(T/T)患口腔癌的风险与野生型纯合子(C/C)相比OR=1.46 (0.93~2.28);隐性模式下,突变纯合子(T/T)患口腔癌的风险与野生型(纯合子+杂合子)(C/C)+(C/T)相比OR=1.30 (0.84~2.00);显性模式下,突变个体(突变

  6. Cytochrome P450 gene polymorphism and cancer.

    Science.gov (United States)

    Agundez, Jose A G

    2004-06-01

    Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.

  7. Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women

    Directory of Open Access Journals (Sweden)

    Do Kyeong Song

    2014-08-01

    Full Text Available BackgroundThe fat mass and obesity-associated (FTO gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS. Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.MethodsWe recruited 432 women with PCOS (24±5 years and 927 healthy women with regular menstrual cycles (27±5 years and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.ResultsLogistic regression revealed that the G/G genotype (rs1421085, 1.6%, the C/C genotype (rs17817449, 1.6%, and the A/A genotype (rs8050136, 1.6% were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05. The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05 and higher free testosterone levels (P=0.053 to 0.063 compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI. When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.ConclusionThe rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

  8. Association of genetic polymorphism of glutathione S-transferase (GSTM1, GSTT1, GSTP1) with bladder cancer susceptibility.

    Science.gov (United States)

    Safarinejad, Mohammad Reza; Safarinejad, Saba; Shafiei, Nayyer; Safarinejad, Shiva

    2013-10-01

    The glutathione-S-transferases (GSTs) comprise a class of enzymes that detoxify carcinogenic compounds by conjugating glutathione to facilitate their removal. Polymorphisms in GSTM1, GSTT1, and GSTP1 genes have been related to risk for bladder cancer. Studies focusing on GSTs gene variants relationship with the risk of bladder cancer have produced conflicting and inconsistent results. We examine the association between genetic polymorphism of glutathione S-transferase P1, GSTM1, GSTT1 genes and development of bladder transitional cell carcinoma (TCC). The study population consisted of 166 histologically confirmed male bladder TCC cases and 332 healthy male controls. Genotyping was done using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and also investigated combined gene interactions. The GSTP1 Val/Val genotype was significantly associated with bladder cancer (OR = 4.32, 95% CI: 2.64-6.34), whereas the association observed for GSTM1 null (OR = 1.32, 95% CI: 0.82-2.62; P = 0.67) and GSTT1 null genotype (OR = 1.18, 95% CI: 0.79-1.67; P = 0.74) did not reach statistical significance. There was a significant multiple interaction between GSTM1, GSTT1, and GSTP1 genotypes in risk of bladder cancer (P for interaction = 0.02). The risk associated with the concurrent presence of GSTM1 positive and GSTP1 Ile/Val or Val/Val (OR = 3.71, 95% CI: 2.34-5.54) and GSTT1 positive and GSTP1 Ile/Val or Val/Val (OR = 2.66, 95% CI: 1.54-4.72) was statistically significant. Patients carrying GSTP1 Val/Val genotype were at increased risk for developing high-grade (OR = 7.68, 95% CI: 4.73-19.25) and muscle invasive (OR = 10.67, 95% CI: 6.34-21.75) bladder cancer. High risk for bladder TCC also was observed with respect to combined GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 4.76, 95% CI: 2.68-18.72) and GSTM1 null/GSTT1 null/GSTP1 Ile/Val or Val/Val (OR = 6.42, 95% CI: 4.76-14.72) genotype variant. This study suggests that the GSTP1 polymorphism

  9. Bipolar disorder: idioms of susceptibility and disease and the role of 'genes' in illness explanations.

    Science.gov (United States)

    Baart, Ingrid; Widdershoven, Guy

    2013-11-01

    This qualitative study explores (1) how members of the Dutch Association for People with Bipolar Disorder explain the affliction of bipolar disorder; (2) the relationship between genetic, environmental and personal factors in these explanations and (3) the relationship between illness explanations, self-management and identity. A total of 40 participants took part in seven different focus group discussions. The results demonstrate that there are two different explanatory idioms, each one centred around an opposing concept, that is, susceptibility and disease. Individuals who construct explanations around the concept of 'disease' attach more importance to 'genes and chemicals' than to environmental components in the onset of the disorder, whereas individuals adhering to the central concept of 'susceptibility' tend to do this much less. Compared with individuals using the 'susceptibility' idiom, those who use a 'disease' idiom tend to observe fewer possibilities for self-management and are less inclined to construct normalcy through a quest for personal growth. Stories of suffering seem more integral to the 'disease' idiom than to the 'susceptibility' idiom. The 'disease' idiom seems less integrated in a contemporary surveillance psychiatric discourse than the 'susceptibility' idiom; however, both vocabularies can offer normative constraints.

  10. Matrix metalloproteinase gene polymorphisms and periodontitis susceptibility: a meta-analysis involving 6,162 individuals.

    Science.gov (United States)

    Weng, Hong; Yan, Yan; Jin, Ying-Hui; Meng, Xiang-Yu; Mo, Yuan-Yuan; Zeng, Xian-Tao

    2016-04-20

    We aimed to systematically investigate the potential association of matrix metalloproteinase (MMP)-9, -3, -2, and -8 gene polymorphisms with susceptibility to periodontitis using meta-analysis. A literature search in PubMed, Embase, and Web of Science was conducted to obtain relevant publications. Finally a total of 16 articles with 24 case-control studies (nine on MMP-9-1562 C/T, seven on MMP-3-1171 A5/A6, four on MMP-2-753C/T, and four on MMP-8-799 C/T) were considered in this meta-analysis. The results based on 2,724 periodontitis patients and 3,438 controls showed that MMP-9-1562C/T, MMP-3-1171 A5/A6, and MMP-8-799C/T polymorphisms were associated with periodontitis susceptibility. No significant association was found between MMP-2-753 C/T and periodontitis susceptibility. Subgroup analyses suggested that the MMP-9-1562 C/T polymorphism reduced chronic periodontitis susceptibility and MMP-3-1171 A5/A6 polymorphism increased chronic periodontitis susceptibility. In summary, current evidence demonstrated that MMP-9-753 C/T polymorphism reduced the risk of periodontitis, MMP-3-1171 5A/6A and MMP-8-799 C/T polymorphisms increased the risk of periodontitis, and MMP-2-753 C/T was not associated with risk of periodontitis.

  11. Colorectal cancer and the KIR genes in the human genome: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Koroush Ghanadi

    2016-12-01

    Full Text Available Colorectal cancer is one of the most common types of inflammation-based cancers and is occurred due to growth and spread of cancer cells in colon and/or rectum. Previously genetic association of cell cycle genes, both proto-oncogenes and the tumor suppressors has been proved. But there were few studies about association of immune related genes such as killer-cell immunoglobulin-like receptors (KIRs. Thus we intend to perform a meta-analysis to find the association of different genes of KIR and susceptibility to be affected by colorectal cancer. The overall population of the four studies investigated in our meta-analysis was 953 individuals (470 individuals with colorectal cancer and 483 individuals in control groups. After the analyses, we concluded that colorectal cancer is affected by KIR2DS5 and also there were no protecting gene. This result shows the inflammatory basis of this cancer. In other words, in contrast to leukemia and blood cancers, colorectal cancers seem to be affected by hyper activity of natural killer-cells (NKs. Whys and therefore of this paradox, is suggested to be investigated further.

  12. Colorectal cancer and the KIR genes in the human genome: A meta-analysis.

    Science.gov (United States)

    Ghanadi, Koroush; Shayanrad, Bahareh; Ahmadi, Seyyed Amir Yasin; Shahsavar, Farhad; Eliasy, Hossein

    2016-12-01

    Colorectal cancer is one of the most common types of inflammation-based cancers and is occurred due to growth and spread of cancer cells in colon and/or rectum. Previously genetic association of cell cycle genes, both proto-oncogenes and the tumor suppressors has been proved. But there were few studies about association of immune related genes such as killer-cell immunoglobulin-like receptors (KIRs). Thus we intend to perform a meta-analysis to find the association of different genes of KIR and susceptibility to be affected by colorectal cancer. The overall population of the four studies investigated in our meta-analysis was 953 individuals (470 individuals with colorectal cancer and 483 individuals in control groups). After the analyses, we concluded that colorectal cancer is affected by KIR2DS5 and also there were no protecting gene. This result shows the inflammatory basis of this cancer. In other words, in contrast to leukemia and blood cancers, colorectal cancers seem to be affected by hyper activity of natural killer-cells (NKs). Whys and therefore of this paradox, is suggested to be investigated further.

  13. Alphavirus vectors for cancer gene therapy (review).

    Science.gov (United States)

    Yamanaka, Ryuya

    2004-04-01

    Alphaviruses have several characteristics that make them attractive as gene therapy vectors such as transient and high-level expression of a heterologous gene. Alphavirus vectors, Semliki Forest virus (SFV), Sindbis virus (SIN) and Venezuelan equine encephalitis virus (VEE) have been developed as gene expression vectors. Alphaviruses are positive-strand RNA viruses that can mediate efficient cytoplasmic gene expression in mammalian cells. The alphavirus RNA replication machinery has been engineered for high level heterologous gene expression. Since an RNA virus vector cannot integrate into chromosomal DNA, concerns about cell transformation are reduced. Alphavirus vectors demonstrate promise for the safe tumor-killing and tumor-specific immune responses. Recombinant alphavirus RNA replicons may facilitate gene therapy of cancer.

  14. 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.

  15. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition.

    Science.gov (United States)

    Ollier, Marie; Radosevic-Robin, Nina; Kwiatkowski, Fabrice; Ponelle, Flora; Viala, Sandrine; Privat, Maud; Uhrhammer, Nancy; Bernard-Gallon, Dominique; Penault-Llorca, Frédérique; Bignon, Yves-Jean; Bidet, Yannick

    2015-01-01

    Among breast cancers, 10 to 15% of cases would be due to hereditary risk. In these familial cases, mutations in BRCA1 and BRCA2 are found in only 15% to 20%, meaning that new susceptibility genes remain to be found. Triple-negative breast cancers represent 15% of all breast cancers, and are generally aggressive tumours without targeted therapies available. Our hypothesis is that some patients with triple negative breast cancer could share a genetic susceptibility different from other types of breast cancers. We screened 36 candidate genes, using pyrosequencing, in all the 50 triple negative breast cancer patients with familial history of cancer but no BRCA1 or BRCA2 mutation of a population of 3000 families who had consulted for a familial breast cancer between 2005 and 2013. Any mutations were also sequenced in available relatives of cases. Protein expression and loss of heterozygosity were explored in tumours. Seven deleterious mutations in 6 different genes (RAD51D, MRE11A, CHEK2, MLH1, MSH6, PALB2) were observed in one patient each, except the RAD51D mutation found in two cases. Loss of heterozygosity in the tumour was found for 2 of the 7 mutations. Protein expression was absent in tumour tissue for 5 mutations. Taking into consideration a specific subtype of tumour has revealed susceptibility genes, most of them in the homologous recombination DNA repair pathway. This may provide new possibilities for targeted therapies, along with better screening and care of patients.

  16. Many Early Colon Cancers Linked to Inherited Genes

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_162574.html Many Early Colon Cancers Linked to Inherited Genes One in 6 diagnosed ... inherited condition. It increases the rate of many cancers, including colon cancer, according to the U.S. National Library of ...

  17. From mouse to humans: discovery of the CACNG2 pain susceptibility gene.

    Science.gov (United States)

    Nissenbaum, J

    2012-10-01

    Chronic pain is a major healthcare problem affecting the daily lives of millions with enormous financial costs. The notorious variability and lack of efficient pain relief pharmaceuticals provide both genetic and therapeutic challenge. There are several genetic approaches that aim to uncover the molecular nature of pain phenotypes into their genetic components. Gene mapping using model organisms for various pain phenotypes has led to the identification of novel genes affecting susceptibility and response to pain stimuli. Translational studies have succeeded to tie those genes to human pain syndromes, thus suggesting new targets for drug discovery. In this short review, a perspective on pain genetics and the trajectory from pain phenotype to pain gene involving fine-mapping strategies, bioinformatic analysis and microarray profiling alongside human association analysis will be introduced. This integrated approach has led to identification of CACNG2 as a novel neuropathic pain gene affecting pain susceptibility both in mice and humans. It also serves as a prototype for efficient and economic discovery of pain genes. Comparisons to other methods as well as future directions of pain genetics will be discussed as well.

  18. Association of polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis

    Institute of Scientific and Technical Information of China (English)

    JieTang; ChengZhou; Zhi-JunZhang; Shu-SenZheng

    2012-01-01

    BACKGROUND: Autoimmune hepatitis is a chronic, generally progressive inflammatory disorder of the liver, of which the cause is unclear. It was demonstrated that genetic factors are involved in its pathogenesis. Previous studies showed that human leukocyte antigen in the major histocompatibility complex (MHC) is associated with susceptibility to autoimmune hepatitis. Current genome scanning studies suggest that genes outside the MHC also play a critical role in autoimmune disorders. This article focuses on our current understanding of the polymorphisms of these genes and their roles in the pathogenesis of autoimmune hepatitis. DATA  SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords autoimmune hepatitis, polymorphism, CTLA-4, Fas, TNF-α, TGF-β1, TBX21 and VDR up to May 2011. Additional papers were identified by a manual search of the references from key articles. RESULTS:  According to the case-control studies on genetic polymorphisms, at least six genes (CTLA-4, Fas, TNF-α, TGF-β1, TBX21 and VDR) are involved in autoimmune hepatitis besides HLA. So far, there has been no agreement about gene susceptibility and the actual clinical significance of these genes is still controversial. CONCLUSION: Studies on gene polymorphisms outside the MHC and knowledge of genetic predispositions for autoimmune hepatitis may not only elucidate pathogenic mechanisms, but also provide new targets for therapy in the future.

  19. Investigation of Gamma-aminobutyric acid (GABA A receptors genes and migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Ciccodicola Alfredo

    2008-12-01

    Full Text Available Abstract Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ, which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE and type θ (GABRQ genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls examining a set of 3 single nucleotide polymorphisms (SNPs in the coding region (exons 3, 5 and 9 of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05. Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

  20. Characterization of the Breast Cancer Susceptibility Gene, BRCA2

    Science.gov (United States)

    1998-09-01

    retrieval solution (BioGenex, San Ramon CA) for 2C9 or 0.01M citrate solution for cytokeratins, 2 x 5 minutes at 600 Watts using a microwave oven , prior...response to puberty , pregnancy and parity, three different stages in which the breast is actively undergoing differentiation as well as proliferation (9). As...of the breasts and ovaries at the onset of puberty is a cyclic pattern of high estradiol (E2) levels, the most active endogenous estrogen. Furthermore

  1. The localization of type 2 diabetes susceptibility gene loci in northern Chinese Han families

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    We conducted a genome-wide scan,in which 358 well distributed fluorescent dye-labe- led microsatellite marker sets were applied in 32 Chinese Han type 2 diabetes families from Northern China to search for the susceptibility gene loci.The data collected from screening all the chromosomes of genome were genotyped by using genescan and genotyping software,then,parametric and non-parametric multipoint test,and affected sib-pair analysis as well,were used to analyze the data.We identified some susceptibility gene loci residing in chromosomes 1,12,18,20,respectively,or precisely,located around D1S214,D1S207,D1S218,D1S235,D12S336,D18S61 and D20S118.The comparison of this result with those from other regions and races reflected the complexity and heterogeneity of type 2 diabetes.

  2. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

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    Steve P. Crampton

    2014-09-01

    Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

  3. Gene variant linked to lung cancer risk

    Science.gov (United States)

    A variation of the gene NFKB1, called rs4648127, is associated with an estimated 44 percent reduction in lung cancer risk. When this information, derived from samples obtained as part of a large NCI-sponsored prevention clinical trial, was compared with d

  4. Gene sensitizes cancer cells to chemotherapy drugs

    Science.gov (United States)

    NCI scientists have found that a gene, Schlafen-11 (SLFN11), sensitizes cells to substances known to cause irreparable damage to DNA.  As part of their study, the researchers used a repository of 60 cell types to identify predictors of cancer cell respons

  5. Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones

    Directory of Open Access Journals (Sweden)

    Morioka Mizue

    2003-08-01

    Full Text Available Abstract Background It is well known that expression of certain bacterial genes responds rapidly to such stimuli as exposure to toxic chemicals and physical agents. It is generally believed that the proteins encoded in these genes are important for successful survival of the organism under the hostile conditions. Analogously, the proteins induced in bacterial cells exposed to antibiotics are believed to affect the organisms' susceptibility to these agents. Results We demonstrated that Escherichia coli cells exposed to levofloxacin (LVFX, a fluoroquinolone (FQ, induce the syntheses of heat shock proteins and RecA. To examine whether the heat shock proteins affect the bactericidal action of FQs, we constructed E. coli strains with mutations in various heat shock genes and tested their susceptibility to FQs. Mutations in dnaK, groEL, and lon increased this susceptibility; the lon mutant exhibited the greatest effects. The increased susceptibility of the lon mutant was corroborated by experiments in which the gene encoding the cell division inhibitor, SulA, was subsequently disrupted. SulA is induced by the SOS response and degraded by the Lon protease. The findings suggest that the hypersusceptibility of the lon mutant to FQs could be due to abnormally high levels of SulA protein resulting from the depletion of Lon and the continuous induction of the SOS response in the presence of FQs. Conclusion The present results show that the bactericidal action of FQs is moderately affected by the DnaK and GroEL chaperones and strongly affected by the Lon protease. FQs have contributed successfully to the treatment of various bacterial infections, but their widespread use and often misuse, coupled with emerging resistance, have gradually compromised their utility. Our results suggest that agents capable of inhibiting the Lon protease have potential for combination therapy with FQs.

  6. SCAR Markers Assisted Selection for a Bentazon Susceptible Lethality Gene (ben) in Rice

    Institute of Scientific and Technical Information of China (English)

    XIANG; Tai-he; YANG; Jian-bo; YANG; Qian-jin; ZHU; Qi-sheng; LI; Li; HUANG; Da-nian

    2003-01-01

    In progenies resulting from crosses involving rice cultivar Norin 8m susceptible to bentazon as the donor of ben gene, SCARs tightly linked to ben were utilized for selection of ben. The homozygous and heterozygous genotypes with ben could be identified with the SCARs. The molecular markers offer a powerful tool for indirect selection of ben and can accelerate the introgression of ben into current rice cultivars.

  7. 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

    2016-04-27

    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.

  8. 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

  9. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium

    NARCIS (Netherlands)

    H. Warren (Helen); F. Dudbridge (Frank); O. Fletcher (Olivia); N. Orr (Nick); N. Johnson (Nichola); J.L. Hopper (John); C. Apicella (Carmel); M.C. Southey (Melissa); M. Mahmoodi (Maryam); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Cornelissen (Sten); L.M. Braaf (Linde); K.R. Muir (Kenneth); A. Lophatananon (Artitaya); A. Chaiwerawattana (Arkom); S. Wiangnon (Surapon); P.A. Fasching (Peter); M.W. Beckmann (Matthias); A.B. Ekici (Arif); R. Schulz-Wendtland (Rüdiger); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Christof); P. Guénel (Pascal); T. Truong (Thérèse); P. Laurent-Puig (Pierre); C. Mulot (Claire); S.E. Bojesen (Stig); S.F. Nielsen (Sune); H. Flyger (Henrik); B.G. Nordestgaard (Børge); R.L. Milne (Roger); J. Benítez (Javier); J.I. Arias Pérez (José Ignacio); M.P. Zamora (Pilar); H. Anton-Culver (Hoda); A. Ziogas (Argyrios); L. Bernstein (Leslie); C.C. Dur (Christina Clarke); H. Brenner (Hermann); H. Müller (Heike); V. Arndt (Volker); A. Langheinz (Anne); A. Meindl (Alfons); M. Golatta (Michael); C.R. Bartram (Claus); R.K. Schmutzler (Rita); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); U. Eilber (Ursula); T. Dörk (Thilo); P. Schürmann (Peter); M. Bremer (Michael); P. Hillemanns (Peter); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); N.N. Antonenkova (Natalia); Y.I. Rogov (Yuri); M. Bermisheva (Marina); D. Prokofyeva (Darya); G. Zinnatullina (Guzel); E.K. Khusnutdinova (Elza); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V-M. Kosma (Veli-Matti); J. Hartikainen (Jaana); V. Kataja (Vesa); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); X. Chen (Xiaoqing); D. Lambrechts (Diether); A. Smeets (Ann); R. Paridaens (Robert); C. Weltens (Caroline); D. Flesch-Janys (Dieter); K. Buck (Katharina); T.W. Behrens (Timothy); P. Peterlongo (Paolo); L. Bernard (Loris); S. Manoukian (Siranoush); P. Radice (Paolo); F.J. Couch (Fergus); C. Vachon (Celine); X. Wang (Xing); J.E. Olson (Janet); G.G. Giles (Graham); L. Baglietto (Laura); C.A. McLean (Cariona); G. Severi (Gianluca); E.M. John (Esther); A. Miron (Alexander); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); A.M. Mulligan (Anna Marie); N. Weerasooriya (Nayana); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); J.W.M. Martens (John); C.M. Seynaeve (Caroline); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); A. Jager (Agnes); M.M.A. Tilanus-Linthorst (Madeleine); P. Hall (Per); K. Czene (Kamila); J. Liu (Jianjun); J. Li (Jingmei); A. Cox (Angela); S.S. Cross (Simon); I.W. Brock (Ian); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); F. Blows (Fiona); A.M. Dunning (Alison); M. Ghoussaini (Maya); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Marta); M. Schoemaker (Minouk); D.F. Easton (Douglas); M.K. Humphreys (Manjeet); Q. Wang (Qing); J. Peto (Julian); I. dos Santos Silva (Isabel)

    2012-01-01

    textabstractBackground: 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

  10. Gene expression profiling in the thiamethoxam resistant and susceptible B-biotype sweetpotato whitefly, Bemisia tabaci.

    Science.gov (United States)

    Xie, Wen; Yang, Xin; Wang, Shao-Ii; Wu, Qing-jun; Yang, Ni-na; Li, Ru-mei; Jiao, Xiao-guo; Pan, Hui-peng; Liu, Bai-ming; Feng, Yun-tao; Xu, Bao-yun; Zhou, Xu-guo; Zhang, You-jun

    2012-01-01

    Thiamethoxam has been used as a major insecticide to control the B-biotype sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). Due to its excessive use, a high level of resistance to thiamethoxam has developed worldwide over the past several years. To better understand the molecular mechanisms underlying this resistance in B. tabaci, gene profiles between the thiamethoxam-resistant and thiamethoxam-susceptible strains were investigated using the suppression subtractive hybridization (SSH) library approach. A total of 72 and 52 upand down-regulated genes were obtained from the forward and reverse SSH libraries, respectively. These expressed sequence tags (ESTs) belong to several functional categories based on their gene ontology annotation. Some categories such as cell communication, response to abiotic stimulus, lipid particle, and nuclear envelope were identified only in the forward library of thiamethoxam-resistant strains. In contrast, categories such as behavior, cell proliferation, nutrient reservoir activity, sequence-specific DNA binding transcription factor activity, and signal transducer activity were identified solely in the reverse library. To study the validity of the SSH method, 16 differentially expressed genes from both forward and reverse SSH libraries were selected randomly for further analyses using quantitative realtime PCR (qRT-PCR). The qRT-PCR results were fairly consistent with the SSH results; however, only 50% of the genes showed significantly different expression profiles between the thiamethoxam-resistant and thiamethoxam-susceptible whiteflies. Among these genes, a putative NAD-dependent methanol dehydrogenase was substantially over-expressed in the thiamethoxamresistant adults compared to their susceptible counterparts. The distributed profiles show that it was highly expressed during the egg stage, and was most abundant in the abdomen of adult females.

  11. CREB1 gene polymorphisms combined with environmental risk factors increase susceptibility to major depressive disorder (MDD).

    Science.gov (United States)

    Wang, Peng; Yang, Yanjie; Yang, Xiuxian; Qiu, Xiaohui; Qiao, Zhengxue; Wang, Lin; Zhu, Xiongzhao; Sui, Hong; Ma, Jingsong

    2015-01-01

    Major depressive disorder (MDD) is one of the most severe psychiatric disorders. The objective of this study was to explore the effects of CREB1 gene polymorphisms on risk of developing MDD and the joint effects of gene-environment interactions. Genotyping was performed by Taqman allelic discrimination assay among 586 patients and 586 healthy controls. A significant impact on rs6740584 genotype distribution was found for childhood trauma (P = 0.015). We did not find an association of CREB1 polymorphisms with MDD susceptibility. However, we found a significantly increased risk associated with the interactions of CREB1 polymorphisms and drinking (OR = 11.67, 95% CI = 2.52-54.18; OR = 11.52, 95% CI = 2.55-51.95 for rs11904814; OR = 4.18, 95% CI = 1.87-9.38; OR = 5.02, 95% CI = 2.27-11.14 for rs6740584; OR = 7.58, 95% CI = 2.05-27.98; OR = 7.59, 95% CI = 2.12-27.14 for rs2553206; OR = 8.37, 95% CI = 3.02-23.23; OR = 7.84, 95% CI = 2.93-20.98 for rs2551941). We also noted that CREB polymorphisms combined with family harmony and childhood trauma conferred increased susceptibility for MDD. In conclusion, polymorphisms in the CREB gene may not be independently associated with MDD risk, but they are likely to confer increased susceptibility by interacting with environmental risk factors in the Chinese population.

  12. Gene Prospector: An evidence gateway for evaluating potential susceptibility genes and interacting risk factors for human diseases

    Directory of Open Access Journals (Sweden)

    Khoury Muin J

    2008-12-01

    Full Text Available Abstract Background Millions of single nucleotide polymorphisms have been identified as a result of the human genome project and the rapid advance of high throughput genotyping technology. Genetic association studies, such as recent genome-wide association studies (GWAS, have provided a springboard for exploring the contribution of inherited genetic variation and gene/environment interactions in relation to disease. Given the capacity of such studies to produce a plethora of information that may then be described in a number of publications, selecting possible disease susceptibility genes and identifying related modifiable risk factors is a major challenge. A Web-based application for finding evidence of such relationships is key to the development of follow-up studies and evidence for translational research. We developed a Web-based application that selects and prioritizes potential disease-related genes by using a highly curated and updated literature database of genetic association studies. The application, called Gene Prospector, also provides a comprehensive set of links to additional data sources. Results We compared Gene Prospector results for the query "Parkinson" with a list of 13 leading candidate genes (Top Results from a curated, specialty database for genetic associations with Parkinson disease (PDGene. Nine of the thirteen leading candidate genes from PDGene were in the top 10th percentile of the ranked list from Gene Prospector. In fact, Gene Prospector included more published genetic association studies for the 13 leading candidate genes than PDGene did. Conclusion Gene Prospector provides an online gateway for searching for evidence about human genes in relation to diseases, other phenotypes, and risk factors, and provides links to published literature and other online data sources. Gene Prospector can be accessed via http://www.hugenavigator.net/HuGENavigator/geneProspectorStartPage.do.

  13. Lung Cancer Susceptibility and hOGG1 Ser326Cys Polymorphism: A Meta-Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kiyohara, Chikako, E-mail: chikako@phealth.med.kyushu-u.ac.jp [Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Takayama, Koichi; Nakanishi, Yoichi [Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2010-10-28

    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

  14. Interaction between γ-aminobutyric acid A receptor genes: new evidence in migraine susceptibility.

    Directory of Open Access Journals (Sweden)

    Marlene Quintas

    Full Text Available Migraine is a common neurological episodic disorder with a female-to-male prevalence 3- to 4-fold higher, suggesting a possible X-linked genetic component. Our aims were to assess the role of common variants of gamma-aminobutyric acid A receptor (GABAAR genes, located in the X-chromosome, in migraine susceptibility and the possible interaction between them. An association study with 188 unrelated cases and 286 migraine-free controls age- and ethnic matched was performed. Twenty-three tagging SNPs were selected in three genes (GABRE, GABRA3 and GABRQ. Allelic, genotypic and haplotypic frequencies were compared between cases and controls. We also focused on gene-gene interactions. The AT genotype of rs3810651 of GABRQ gene was associated with an increased risk for migraine (OR: 4.07; 95% CI: 1.71-9.73, p=0.002, while the CT genotype of rs3902802 (OR: 0.41; 95% CI: 0.21-0.78, p=0.006 and GA genotype of rs2131190 of GABRA3 gene (OR: 0.53; 95% CI: 0.32-0.88, p=0.013 seem to be protective factors. All associations were found in the female group and maintained significance after Bonferroni correction. We also found three nominal associations in the allelic analyses although there were no significant results in the haplotypic analyses. Strikingly, we found strong interactions between six SNPs encoding for different subunits of GABAAR, all significant after permutation correction. To our knowledge, we show for the first time, the putative involvement of polymorphisms in GABAAR genes in migraine susceptibility and more importantly we unraveled a role for novel gene-gene interactions opening new perspectives for the development of more effective treatments.

  15. 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.

  16. 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.

  17. 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 J; 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 J; 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 W R; 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 W M; 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, Dimitrios; 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 A E M; 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 P D P; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

    2015-04-01

    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 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

  18. 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

  19. COX-2 gene promoter haplotypes and prostate cancer risk.

    Science.gov (United States)

    Panguluri, Ramesh C K; Long, Layron O; Chen, Weidong; Wang, Songping; Coulibaly, Aoua; Ukoli, Flora; Jackson, Aaron; Weinrich, Sally; Ahaghotu, Chiledum; Isaacs, William; Kittles, Rick A

    2004-06-01

    Cyclooxygenase-2 (COX-2) is a key rate-limiting enzyme that converts arachidonic acid into pro-inflammatory prostaglandins. COX-2 expression is strongly correlated with increased tumor microvasculature density and plays an important role in inhibiting apoptosis, stimulating angiogenesis and promoting tumor cell metastasis and invasion. However, little is known about the role that sequence variation of the COX-2 gene contributes to prostate cancer. Thus, we searched for polymorphisms in the promoter region of the COX-2 gene using denaturing high-performance liquid chromatography. Four single nucleotide polymorphisms (SNPs), -1285A/G, -1265G/A, -899G/C and -297C/G, were detected and confirmed by direct sequencing. Three of the SNPs in the promoter region of COX-2 gene create at least three putative transcription factor binding sites and eliminate CCAAT/enhancer binding protein alpha (C/EBP alpha) and NF-kappa B binding sites. A case-control study of the four SNPs in African American (n = 288), Bini Nigerian (n = 264) and European American (n = 184) prostate cancer cases and age-matched controls revealed that SNP -297G was associated with a decreased risk for prostate cancer [odds ratio (OR) = 0.49; CI = 0.2-0.9; P = 0.01]. The effect on risk was observed in both African Americans (OR = 0.51; CI = 0.2-0.9; P = 0.01) and European Americans (OR = 0.33; CI = 0.1-0.9; P = 0.02). In addition, SNPs -1265A and -899C were associated with increased prostate cancer risk in African Americans (OR = 2.72; CI = 1.3-5.8; P = 0.007 and OR = 3.67; CI = 1.4-9.9; P = 0.007, respectively). Haplotype analyses revealed modest effects on susceptibility to prostate cancer across populations. Haplotype GGCC conferred increased risk in the African American and Nigerian populations. Conversely, haplotype AGGG exhibited a negative association with prostate cancer risk in African Americans (OR = 0.4; CI = 0.1-0.9; P = 0.02) and European Americans (OR = 0.2; CI = 0.1-0.9; P = 0.03). These data

  20. Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene

    DEFF Research Database (Denmark)

    hart, Leen M; Hansen, Torben; Rietveld, Ingrid;

    2005-01-01

    Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNA(Leu(UUR)) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA(Leu(UUR)). In this study, we have examined whether variants in the leucyl tRNA synthetase...... gene (LARS2), involved in aminoacylation of tRNA(Leu(UUR)), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations...... no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established...

  1. Experimental strategy to identify genes susceptible to oxidative stress in nigral dopaminergic neurons.

    Science.gov (United States)

    Yoo, Myung S; Kawamata, Hibiki; Kim, Dae J; Chun, Hong S; Son, Jin H

    2004-06-01

    Neuropathological evidence from both human and experimental models of Parkinson's disease (PD) firmly supports a significant role for oxidative stress (OS) in the death of dopaminergic (DA) neurons in substantia nigra. Largely unknown are the genes underlying selective susceptibility of nigral DA neuron to OS and how they effect nigral DA cell death. The major barriers to high-throughput identification of candidate genes are the paucity of nigral DA neurons as well as the dilution effect of non-DA cells both in primary cultures and brain tissues. To overcome these barriers, we have developed a DA cell line model, SN4741, appropriate for cDNA microarray analysis. Candidate genes were selected from both the microarray analysis and the molecular implication of their pathological mechanisms (i.e., decreased mitochondrial complex I activity and proteasomal dysfunction) of PD. Subsequent secondary validation tests were devised to characterize genes including clone #45 that may underlie selective vulnerability of nigral DA neuron to OS.

  2. Cancer-testis genes as candidates for immunotherapy in breast cancer.

    Science.gov (United States)

    Ghafouri-Fard, Soudeh; Shamsi, Roshanak; Seifi-Alan, Mahnaz; Javaheri, Mona; Tabarestani, Sanaz

    2014-01-01

    Cancer-testis (CT) antigens are tumor-associated antigens attracting immunologists for their possible application in the immunotherapy of cancer. Several clinical trials have assessed their therapeutic potentials in cancer patients. Breast cancers, especially triple-negative cancers are among those with significant expression of CT genes. Identification of CT genes with high expression in cancer patients is the prerequisite for any immunotherapeutic approach. CT genes have gained attention not only for immunotherapy of cancer patients, but also for immunoprevention in high-risk individuals. Many CT genes have proved to be immunogenic in breast cancer patients suggesting the basis for the development of polyvalent vaccines.

  3. Association of Single Nucleotide Polymorphisms of NBS1 Gene With Genetic Susceptibility to Primary Liver Cancer in a Chinese Han Population%NBS1基因SNPs与中国汉族人群原发性肝癌的遗传易感性

    Institute of Scientific and Technical Information of China (English)

    黄坚; 赵艳平; 李倩; 张俊霞; 王岩; 张蓓

    2012-01-01

    As DNA repair associated gene, NBS1 plays a key role in the rep