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Sample records for brca1 founder mutation

  1. BRCA1/BRCA2 founder mutations and cancer risks

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Nilbert, Mef; Petersen, Janne; Ladelund, Steen; Thomassen, Mads; Pedersen, Inge Søkilde; Hansen, Thomas V O; Skytte, Anne-Bine; Borg, Åke; Therkildsen, Christina

    2016-01-01

    Mutations in the BRCA1 and BRCA2 genes significantly contribute to hereditary breast cancer and ovarian cancer, but the phenotypic effect from different mutations is insufficiently recognized. We used a western Danish clinic-based cohort of 299 BRCA families to study the female cancer risk in...... mutation carriers and their untested first-degree relatives. Founder mutations were characterized and the risk of cancer was assessed in relation to the specific mutations. In BRCA1, the cumulative cancer risk at age 70 was 35 % for breast cancer and 29 % for ovarian cancer. In BRCA2, the cumulative risk...... was 44 % for breast cancer and 15 % for ovarian cancer. We identified 47 distinct BRCA1 mutations and 48 distinct mutations in BRCA2. Among these, 8 founder mutations [BRCA1 c.81-?_4986+?del, c.3319G>T (p.Glu1107*), c.3874delT and c.5213G>A (p.Gly1738Glu) and BRCA2 c.6373delA, c.7008-1G>A, c.7617+1G...

  2. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, Thomas; Ejlertsen, Bent; Albrechtsen, Anders;

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 e...... possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented.......Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the...

  3. A common Greenlandic Inuit BRCA1 RING domain founder mutation

    DEFF Research Database (Denmark)

    Hansen, T.v.O.; Ejlertsen, B.; Albrechtsen, Anders;

    2009-01-01

    Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 e...... possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented Udgivelsesdato: 2009/5......Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1...... exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn(2+) site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the...

  4. Evidence of a founder BRCA1 mutation in Scotland

    OpenAIRE

    Liede, A; Cohen, B.; Black, D. M.; Davidson, R H; Renwick, A; Hoodfar, E; Olopade, O.I.; Micek, M; Anderson, V.; Mey, R De; Fordyce, A; Warner, E.; Dann, J L; King, M-C; Weber, B.

    2000-01-01

    BRCA1 mutations have been identified in breast and ovarian cancer families from diverse ethnic backgrounds. We studied 17 different families with the BRCA1 2800delAA mutation; seven were ascertained in Scotland (Dundee, Edinburgh, Glasgow, St Andrews), five in Canada (Toronto, Victoria) and five in the United States (Chicago, Philadelphia, Seattle). Overall there was a clear preponderance of Scottish ancestry. Genotype analysis performed on key members from 17 families was consistent with a c...

  5. A Rapid and Reliable Test for BRCA1 and BRCA2 Founder Mutation Analysis in Paraffin Tissue Using Pyrosequencing

    OpenAIRE

    Zhang, Liying; Kirchhoff, Tomas; Yee, Cindy J; Offit, Kenneth

    2009-01-01

    The founder mutations in BRCA (BRCA1*185delAG, BRCA1*5382insC, and BRCA2*6174delT) account for 95% of the detectable BRCA mutations in breast and ovarian cancer families of Ashkenazi Jewish ancestry. Optimal clinical management of individuals from these high-risk families relies on the identification of BRCA founder mutations in the laboratory. We have therefore developed a rapid and reliable approach using pyrosequencing, which allows for the detection of these frequent frameshift mutations ...

  6. A high frequent BRCA1 founder mutation identified in the Greenlandic population

    DEFF Research Database (Denmark)

    Harboe, Theresa Larriba; Eiberg, Hans; Kern, Peder;

    2009-01-01

    carrying a BRCA1 mutation known to trigger the development of potentially lethal diseases leads us to recommend an offer of genetic counselling and test for the mutation to all females of Inuit origin, thereby hopefully preventing a number of breast and ovarian cancer deaths.......Approximately 10% of all breast and ovarian cancers are dominantly inherited and mutations are mainly found in the BRCA 1 and 2 genes. The penetrance of BRCA1 mutations is reported to be between 68 and 92% and confers a 36-92% life time risk of breast cancer. Most mutations in BRCA1 are uniquely...... clinical relevance of the mutation, we have examined ten breast cancer patients and nine ovarian cancer patients from Greenland for the presence of the p.Cys39Gly mutation. We found three ovarian cancer patients (33%) and one breast cancer patient (10%) carrying the mutation. The high number of women...

  7. BRCA Genetic Screening in Middle Eastern and North African: Mutational Spectrum and Founder BRCA1 Mutation (c.798_799delTT in North African

    Directory of Open Access Journals (Sweden)

    Abdelilah Laraqui

    2015-01-01

    Full Text Available Background. The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC has not yet been thoroughly investigated in MENA. Methods. To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted. Results. Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71% patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected. Conclusion. The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling.

  8. TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival

    International Nuclear Information System (INIS)

    Ovarian carcinomas from 30 BRCA1 germ-line carriers of two distinct high penetrant founder mutations, 20 carrying the 1675delA and 10 the 1135insA, and 100 sporadic cases were characterized for somatic mutations in the TP53 gene. We analyzed differences in relation to BRCA1 germline status, TP53 status, survival and age at diagnosis, as previous studies have not been conclusive. DNA was extracted from paraffin embedded formalin fixed tissues for the familial cases, and from fresh frozen specimen from the sporadic cases. All cases were treated at our hospital according to protocol. Mutation analyses of exon 2 – 11 were performed using TTGE, followed by sequencing. Survival rates for BRCA1-familial cases with TP53 mutations were not significantly lower than for familial cases without TP53 mutations (p = 0.25, RR = 1.64, 95% CI [0.71–3.78]). Median age at diagnosis for sporadic (59 years) and familial (49 years) cases differed significantly (p < 0.001) with or without TP53 mutations. Age at diagnosis between the two types of familial carriers were not significantly different, with median age of 47 for 1675delA and 52.5 for 1135insA carriers (p = 0.245). For cases ≥50 years at diagnosis, a trend toward longer survival for sporadic over familial cases was observed (p = 0.08). The opposite trend was observed for cases <50 years at diagnosis. There do not seem to be a protective advantage for familial BRCA1 carriers without TP53 mutations over familial cases with TP53 mutations. However, there seem to be a trend towards initial advantage in survival for familial cases compared to sporadic cases diagnosed before the age of 50 both with and without TP53 mutations. However, this trend diminishes over time and for cases diagnosed ≥50 years the sporadic cases show a trend towards an advantage in survival over familial cases. Although this data set is small, if confirmed, this may be a link in the evidence that the differences in ovarian cancer survival reported, are

  9. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis.

    Directory of Open Access Journals (Sweden)

    Ava Kwong

    Full Text Available BACKGROUND: Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China. METHODOLOGY/PRINCIPAL FINDINGS: A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM analysis. Among the 451 probands analyzed, 69 (15.3% deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT accounted for 34.5% (10/29 of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA accounted for 40% (16/40 of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated. CONCLUSION: In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.

  10. Prevalence of the BRCA1 founder mutation c.5266dupin Brazilian individuals at-risk for the hereditary breast and ovarian cancer syndrome

    Directory of Open Access Journals (Sweden)

    Ewald Ingrid P

    2011-12-01

    Full Text Available Abstract About 5-10% of breast and ovarian carcinomas are hereditary and most of these result from germline mutations in the BRCA1 and BRCA2 genes. In women of Ashkenazi Jewish ascendance, up to 30% of breast and ovarian carcinomas may be attributable to mutations in these genes, where 3 founder mutations, c.68_69del (185delAG and c.5266dup (5382insC in BRCA1 and c.5946del (6174delT in BRCA2, are commonly encountered. It has been suggested by some authors that screening for founder mutations should be undertaken in all Brazilian women with breast cancer. Thus, the goal of this study was to determine the prevalence of three founder mutations, commonly identified in Ashkenazi individuals in a sample of non-Ashkenazi cancer-affected Brazilian women with clearly defined risk factors for hereditary breast and ovarian cancer (HBOC syndrome. Among 137 unrelated Brazilian women from HBOC families, the BRCA1c.5266dup mutation was identified in seven individuals (5%. This prevalence is similar to that encountered in non-Ashkenazi HBOC families in other populations. However, among patients with bilateral breast cancer, the frequency of c.5266dup was significantly higher when compared to patients with unilateral breast tumors (12.1% vs 1.2%, p = 0.023. The BRCA1 c.68_69del and BRCA2 c.5946del mutations did not occur in this sample. We conclude that screening non-Ashkenazi breast cancer-affected women from the ethnically heterogeneous Brazilian populations for the BRCA1 c.68_69del and BRCA2 c.5946del is not justified, and that screening for BRCA1c.5266dup should be considered in high risk patients, given its prevalence as a single mutation. In high-risk patients, a negative screening result should always be followed by comprehensive BRCA gene testing. The finding of a significantly higher frequency of BRCA1 c.5266dup in women with bilateral breast cancer, as well as existence of other as yet unidentified founder mutations in this population, should be

  11. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families

    Energy Technology Data Exchange (ETDEWEB)

    Friedman, L.S.; Szabo, C.I.; Ostermeyer, E.A. [Univ. of California, Berkeley, CA (United States)] [and others

    1995-12-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning {approximately}850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3{prime}-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. 57 refs., 5 figs., 3 tabs.

  12. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

    Science.gov (United States)

    Friedman, L S; Szabo, C I; Ostermeyer, E A; Dowd, P; Butler, L; Park, T; Lee, M K; Goode, E L; Rowell, S E; King, M C

    1995-12-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2. PMID:8533757

  13. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

    OpenAIRE

    Friedman, L S; Szabo, C.I.; Ostermeyer, E A; Dowd, P; Butler, L; Park, T.; Lee, M K; Goode, E.L.; Rowell, S E; King, M C

    1995-01-01

    Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer with...

  14. Comprehensive BRCA1 and BRCA2 mutational profile in Lithuania.

    Science.gov (United States)

    Janavičius, Ramūnas; Rudaitis, Vilius; Mickys, Ugnius; Elsakov, Pavel; Griškevičius, Laimonas

    2014-05-01

    There is limited knowledge about the BRCA1/2 mutational profile in Lithuania. We aimed to define the full BRCA1 and BRCA2 mutational spectrum and the clinically relevant prevalence of these gene mutations in Lithuania. A data set of 753 unrelated probands, recruited through a clinical setting, was used and consisted of 380 female breast cancer cases, 213 epithelial ovarian cancer cases, 20 breast and ovarian cancer cases, and 140 probands with positive family history of breast or ovarian cancer. A comprehensive mutation analysis of the BRCA1/2 genes by high resolution melting analysis coupled with Sanger sequencing and multiplex ligation-dependent probe amplification analysis was performed. Genetic analysis revealed 32 different pathogenic germline BRCA1/2 mutations: 20 in the BRCA1 gene and 12 in the BRCA2 gene, including four different large genomic rearrangements in the BRCA1 gene. In all, 10 novel BRCA1/2 mutations were found. Nine different recurrent BRCA1 mutations and two recurrent BRCA2 mutations were identified, which comprised 90.4% of all BRCA1/2 mutations. BRCA1 exon 1-3 deletion and BRCA2 c.658_659del are reported for the first time as recurrent mutations, pointing to a possible Baltic founder effect. Approximately 7% of breast cancer and 22% of ovarian cancer patients without family history and an estimated 0.5-0.6% of all Lithuanian women were found to be carriers of mutations in the BRCA1 or BRCA2 gene. PMID:25066507

  15. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance

    OpenAIRE

    Swisher, Elizabeth M.; Sakai, Wataru; Karlan, Beth Y.; Wurz, Kaitlyn; Urban, Nicole; Taniguchi, Toshiyasu

    2008-01-01

    Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated 9 recurrent BRCA1-mutated o...

  16. BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.

    Science.gov (United States)

    Infante, M; Durán, M; Acedo, A; Pérez-Cabornero, L; Sanz, D J; García-González, M; Beristain, E; Esteban-Cardeñosa, E; de la Hoya, M; Teulé, A; Vega, A; Tejada, M-I; Lastra, E; Miner, C; Velasco, E A

    2010-01-01

    The distribution of BRCA1 and BRCA2 germ line mutations in breast/ovarian cancer families varies among different populations, which typically present a wide spectrum of unique mutations. Splicing mutation 5272-1G>A of BRCA1 and frameshift mutation 5374delTATG of BRCA2 are highly prevalent mutations in Castilla-León (Spain), accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively. To test the presence of founder effects, 9 Spanish 5272-1G>A and 13 5374delTATG families were genotyped with polymorphic markers linked to BRCA1 or BRCA2. All the 5272-1G>A families shared a common haplotype in eight markers (1.1 Mb region) and the mutation age was estimated in 15 generations (approximately 380 years). A conserved haplotype associated to 5374delTATG was observed in four markers (0.82 Mb). The mutation occurred approximately 48 generations ago (approximately 1200 years). Each mutation likely arose from a common ancestor that could be traced to a small area of Castilla-León and expanded to other Spanish regions. They can have a significant impact on the clinical management of asymptomatic carriers as well as on the genetic screening strategy to be followed in populations with Spanish ancestries. PMID:19912264

  17. The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies

    Directory of Open Access Journals (Sweden)

    Zhang Jinghui

    2007-10-01

    Full Text Available Abstract Background We studied linkage disequilibrium (LD patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient. Results BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG. Conclusion Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.

  18. BRCA1 and BRCA2 mutations in Iranian breast cancer patients: A systematic review

    OpenAIRE

    Hossein Neamatzadeh; Seyed Mostafa Shiryazdi; Seyed Mahdi Kalantar

    2015-01-01

    Background: BRCA1/2 genes mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Understanding BRCA1/2 genes mutations is important for reducing breast cancer (BC) incidence, accurate risk assessment and counseling. This systematic review of the literature was conducted to addressing BRCA1/2 mutations in Iranian BC patients. Materials and Methods: A search for relevant articles was run on before January 2014 using MedLine, PubMed, Science Iranian Database, ...

  19. High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series

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    Møller Pål

    2010-01-01

    Full Text Available Abstract Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results. We have followed women at risk for breast and/or ovarian cancer for two decades, and report the prospectively observed age-related annual incidence rates to contract breast or ovarian cancer for women with deleterious BRCA1 or BRCA2 mutations based on 4830 observation years. Patients were grouped according to mutation, age and having/not having had previous cancer. In women not having had previous cancer and aged 40-59 years, the annual incidence rate to contract breast or ovarian cancer in those having the most frequent BRCA1 founder mutations was 4.0%, for women in this age group and with less frequent BRCA1 mutations annual incidence rate was 5.9%, and for women with BRCA2 mutations 3.5%. The observed figures may be used for genetic counseling of healthy mutation carriers in the respective age groups. The results may indicate that less frequent BRCA1 mutations have higher penetrances than BRCA1 founder mutations.

  20. BRCA1 mutations in Brazilian patients

    Directory of Open Access Journals (Sweden)

    Juliano Javert Lourenço

    2004-01-01

    Full Text Available BRCA1 mutations are known to be responsible for the majority of hereditary breast and ovarian cancers in women with early onset and a family history of the disease. In this paper we present a mutational survey conducted in 47 Brazilian patients with breast/ovarian cancer, selected based on age at diagnosis, family history, tumor laterality, and presence of breast cancer in male patients. All 22 coding exons and intron-exon junctions were sequenced. Constitutional mutations were found in seven families, consisting of one insertion (insC5382 in exon 20 (four patients, one four base-pair deletion (3450-3453delCAAG in exon 11 resulting in a premature stop codon (one patient, one transition (IVS17+2T> C in intron 17 affecting a mRNA splicing site (one patient, and a C> T transition resulting in a stop-codon (Q1135X in exon 11 (one patient. The identification of these mutations which are associated to hereditary breast and ovarian cancers will contribute to the characterization of the mutational spectrum of BRCA1 and to the improvement of genetic counseling for familial breast/ovarian cancer patients in Brazil.

  1. Survival in Norwegian BRCA1 mutation carriers with breast cancer

    OpenAIRE

    Hagen Anne; Tretli Steinar; Mæhle Lovise; Apold Jaran; Vedå Nina; Møller Pål

    2009-01-01

    Abstract Several studies of survival in women with BRCA1 mutations have shown either reduced survival or no difference compared to controls. Programmes for early detection and treatment of inherited breast cancer, have failed to demonstrate a significant improvement in survival in BRCA1 mutation carriers. One hundred and sixty-seven women with disease-associated germline BRCA1 mutations and breast cancer from 1980 to 2001 were identified. Tumour characteristics, treatment given and survival w...

  2. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu;

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele fre...

  3. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Im, Kate M.; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y.; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M.; Fredericksen, Zachary; Pankratz, V. Shane; Guiducci, Candace; Crenshaw, Andrew; McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Sinilnikova, Olga M.; Mai, Phuong L.; Greene, Mark H.; Piedmonte, Marion; Rubinstein, Wendy S.; Hogervorst, Frans B.; Rookus, Matti A.; Collee, J. Margriet; Hoogerbrugge, Nicoline; van Asperen, Christi J.; Meijers-Heijboer, Hanne E. J.; van Roozendaal, Cees E.; Caldes, Trinidad; Perez-Segura, Pedro; Jakubowska, Anna; Lubinski, Jan; Huzarski, Tomasz; Blecharz, Pawel; Nevanlinna, Heli; Aittomaki, Kristiina; Lazaro, Conxi; Blanco, Ignacio; Barkardottir, Rosa B.; Montagna, Marco; D'Andrea, Emma; Devilee, Peter; Olopade, Olufunmilayo I.; Neuhausen, Susan L.; Peissel, Bernard; Bonanni, Bernardo; Peterlongo, Paolo; Singer, Christian F.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Toland, Amanda Ewart; Caligo, Maria Adelaide; Beattie, Mary S.; Chan, Salina; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Phelan, Catherine; Narod, Steven; John, Esther M.; Hopper, John L.; Buys, Saundra S.; Daly, Mary B.; Southey, Melissa C.; Terry, Mary-Beth; Tung, Nadine; Hansen, Thomas V. O.; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N.; Garber, Judy; Hamann, Ute; Peock, Susan; Cook, Margaret; Oliver, Clare T.; Frost, Debra; Platte, Radka; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Paterson, Joan; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Porteous, Mary; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Laitman, Yael; Meindl, Alfons; Deissler, Helmut; Varon-Mateeva, Raymonda; Preisler-Adams, Sabine; Kast, Karin; Venat-Bouvet, Laurence; Stoppa-Lyonnet, Dominique; Chenevix-Trench, Georgia; Easton, Douglas F.; Klein, Robert J.; Daly, Mark J.; Friedman, Eitan; Dean, Michael; Clark, Andrew G.; Altshuler, David M.; Antoniou, Antonis C.; Couch, Fergus J.; Offit, Kenneth; Gold, Bert

    2011-01-01

    Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele freque

  4. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

    LENUS (Irish Health Repository)

    Stordal, Britta

    2013-06-01

    Mutations in BRCA1\\/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1\\/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1\\/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1\\/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1\\/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1\\/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1\\/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1\\/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1\\/2 deleterious mutations 1\\/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective

  5. Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Jønson, Lars; Ejlertsen, Bent; Gerdes, Anne-Marie; Nielsen, Finn C; Hansen, Thomas V O

    2010-01-01

    Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. Here we report the first identification of a Danish...... breast and ovarian cancer family heterozygote for mutations in the BRCA1 and BRCA2 genes. The BRCA1 nucleotide 5215G > A/c.5096G > A mutation results in the missense mutation Arg1699Gln, while the BRCA2 nucleotide 859 + 4A > G/c.631 + 4A > G is novel. Exon trapping experiments and reverse transcriptase...... (RT)-PCR analysis revealed that the BRCA2 mutation results in skipping of exon 7, thereby introducing a frameshift and a premature stop codon. We therefore classify the mutation as disease causing. Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family...

  6. BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Ainur R. Akilzhanova

    2013-05-01

    Full Text Available Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05; higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation. 

  7. BRCA1 and BRCA2 Mutations

    Science.gov (United States)

    ... risk of cancer of the ovary , fallopian tube , peritoneum , and pancreas. Men who have a BRCA1 or ... one of the previous criteria? *Cancer of the peritoneum and fallopian tubes should be considered a part ...

  8. Aromatase expression is increased in BRCA1 mutation carriers

    International Nuclear Information System (INIS)

    Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women. We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts. Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers

  9. A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

    International Nuclear Information System (INIS)

    In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764-8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations

  10. BRCA1 and BRCA2 mutations in central and southern Italian patients

    International Nuclear Information System (INIS)

    Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied. Germline BRCA1 and BRCA2 mutations account for most hereditary breast/ovarian cancers and are associated with male breast cancer. Furthermore, constitutional mutations in these genes may occur in breast/ovarian cancer patients that do not meet stringent criteria of autosomal-dominant predisposition. The relevance of BRCA1 and BRCA2 mutations in such patients is still debated. We sought to determine the impact of BRCA1 and BRCA2 mutations in a population of patients from central and southern Italy. We analyzed the BRCA1 and BRCA2 coding regions in 136 unrelated probands: 117 females with breast/ovarian cancer and 19 males with breast cancer. This population of patients was mostly representative of cases who are at risk for hereditary susceptibility, but who do not meet stringent criteria of autosomal-dominant predisposition. Probands, subclassified as follows, were consecutively recruited depending on informed consent from patients attending breast cancer clinics in Rome and Naples. Selection criteria for females were as follows: breast cancer with breast cancer

  11. BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases

    Directory of Open Access Journals (Sweden)

    Nancy Uhrhammer, Amina Abdelouahab, Laurence Lafarge, Viviane Feillel, Ahmed Ben Dib, Yves-Jean Bignon

    2008-01-01

    Full Text Available Breast cancer rates and median age of onset differ between Western Europe and North Africa. In Western populations, 5 to 10 % of breast cancer cases can be attributed to major genetic factors such as BRCA1 and BRCA2, while this attribution is not yet well defined among Africans. To help determine the contribution of BRCA1 mutations to breast cancer in a North African population, we analysed genomic DNA from breast cancer cases ascertained in Algiers. Both familial cases (at least three breast cancers in the same familial branch, or two with one bilateral or diagnosed before age 40 and sporadic cases less than 38 years of age were studied. Complete sequencing plus quantitative analysis of the BRCA1 gene was performed. 9.8 % (5/51 of early-onset sporadic and 36.4 % (4/11 of familial cases were found to be associated with BRCA1 mutations. This is in contrast 10.3 % of French HBOC families exhibiting a BRCA1 mutation. One mutation, c.798_799delTT, was observed in two Algerian families and in two families from Tunisia, suggesting a North African founder allele. Algerian non-BRCA1 tumors were of significantly higher grade than French non-BRCA tumors, and the age at diagnosis for Algerian familial cases was much younger than that for French non-BRCA familial cases. In conclusion, we observed a much higher frequency of BRCA1 mutations among young breast cancer patients than observed in Europe, suggesting biological differences and that the inclusion criterea for analysis in Western Europe may not be applicable for the Northern African population.

  12. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Kan, Charlene; Zhang, Junran, E-mail: Junran.zhang@case.edu

    2015-10-01

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.

  13. BRCA1 Mutation: A Predictive Marker for Radiation Therapy?

    International Nuclear Information System (INIS)

    DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations

  14. Loss of nuclear BRCA1 protein staining in normal tissue cells derived from BRCA1 and BRCA2 mutation carriers

    International Nuclear Information System (INIS)

    Enhanced genomic instability has been recently reported in normal cells derived from BRCA1/2 mutation carriers when placed in vitro in non-physiological stress conditions. We present here original data which help to explain the observed genomic instability. Leucocytes from BRCA1/2 mutation carriers, sporadic breast cancer patients and controls were prepared for BRCA1 immunocytochemistry. We show that BRCA1 containing nuclear dot like structures are detectable in about 80% of the leucocytes from controls and sporadic breast cancer patients, but are absent in the majority of normal cells from BRCA1 as well as BRCA2 mutation carriers (also in their normal breast cells). Our results thus indicate that the genomic instability observed in normal cells from BRCA1 and BRCA2 mutation carriers is associated with a down-regulation of nuclear BRCA1 protein accumulation in the dot like structures. These results suggest in addition that immunocytochemical or alternative molecular screening strategies might help to identify women with a high risk for breast (ovarian) cancer even when the underlying genetic defect remains undetectable

  15. Loss of nuclear BRCA1 protein staining in normal tissue cells derived from BRCA1 and BRCA2 mutation carriers

    Energy Technology Data Exchange (ETDEWEB)

    Brakeleer, Sylvia de [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Bogdani, Marika [Department of Experimental Pathology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Greve, Jacques de [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Decock, Julie [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium); Sermijn, Erica [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Bonduelle, Maryse [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Goelen, Guido [Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium); Teugels, Erik [Laboratory of Molecular Oncology (Department of Medical Oncology), UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels (Belgium) and Familial Cancer Clinic, UZ Brussel, Laarbeeklaan 101, 1090 Brussels (Belgium)]. E-mail: eteugels@uzbrussel.be

    2007-06-01

    Enhanced genomic instability has been recently reported in normal cells derived from BRCA1/2 mutation carriers when placed in vitro in non-physiological stress conditions. We present here original data which help to explain the observed genomic instability. Leucocytes from BRCA1/2 mutation carriers, sporadic breast cancer patients and controls were prepared for BRCA1 immunocytochemistry. We show that BRCA1 containing nuclear dot like structures are detectable in about 80% of the leucocytes from controls and sporadic breast cancer patients, but are absent in the majority of normal cells from BRCA1 as well as BRCA2 mutation carriers (also in their normal breast cells). Our results thus indicate that the genomic instability observed in normal cells from BRCA1 and BRCA2 mutation carriers is associated with a down-regulation of nuclear BRCA1 protein accumulation in the dot like structures. These results suggest in addition that immunocytochemical or alternative molecular screening strategies might help to identify women with a high risk for breast (ovarian) cancer even when the underlying genetic defect remains undetectable.

  16. Population testing for cancer predisposing BRCA1/BRCA2 mutations

    OpenAIRE

    Wardle, J

    2014-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the...

  17. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples

    Directory of Open Access Journals (Sweden)

    Sin Hang Lee

    2016-02-01

    Full Text Available Three sets of polymerase chain reaction (PCR primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine.

  18. Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples.

    Science.gov (United States)

    Lee, Sin Hang; Zhou, Shaoxia; Zhou, Tianjun; Hong, Guofan

    2016-01-01

    Three sets of polymerase chain reaction (PCR) primers were designed for heminested PCR amplification of the target DNA fragments in the human genome which include the site of BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del respectively, to prepare the templates for direct Sanger sequencing screen of these three founder mutations. With a robust PCR mixture, crude proteinase K digestate of the fixed cervicovaginal cells in the liquid-based Papanicolaou (Pap) cytology specimens can be used as the sample for target DNA amplification without pre-PCR DNA extraction, purification and quantitation. The post-PCR products can be used directly as the sequencing templates without further purification or quantitation. By simplifying the frontend procedures for template preparation, the cost for screening these three founder mutations can be reduced to about US $200 per test when performed in conjunction with human papillomavirus (HPV) assays now routinely ordered for cervical cancer prevention. With this projected price structure, selective patients in a high-risk population can be tested and each provided with a set of DNA sequencing electropherograms to document the absence or presence of these founder mutations in her genome to help assess inherited susceptibility to breast and ovarian cancer in this era of precision molecular personalized medicine. PMID:26867194

  19. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    Science.gov (United States)

    Cox, David G.; Simard, Jacques; Sinnett, Daniel; Hamdi, Yosr; Soucy, Penny; Ouimet, Manon; Barjhoux, Laure; Verny-Pierre, Carole; McGuffog, Lesley; Healey, Sue; Szabo, Csilla; Greene, Mark H.; Mai, Phuong L.; Andrulis, Irene L.; Thomassen, Mads; Gerdes, Anne-Marie; Caligo, Maria A.; Friedman, Eitan; Laitman, Yael; Kaufman, Bella; Paluch, Shani S.; Borg, Åke; Karlsson, Per; Stenmark Askmalm, Marie; Barbany Bustinza, Gisela; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Benítez, Javier; Hamann, Ute; Rookus, Matti A.; van den Ouweland, Ans M.W.; Ausems, Margreet G.E.M.; Aalfs, Cora M.; van Asperen, Christi J.; Devilee, Peter; Gille, Hans J.J.P.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Paterson, Joan; Eason, Jacqueline; Godwin, Andrew K.; Remon, Marie-Alice; Moncoutier, Virginie; Gauthier-Villars, Marion; Lasset, Christine; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Eisinger, François; Bressac de Paillerets, Brigitte; Caron, Olivier; Delnatte, Capucine; Goldgar, David; Miron, Alex; Ozcelik, Hilmi; Buys, Saundra; Southey, Melissa C.; Terry, Mary Beth; Singer, Christian F.; Dressler, Anne-Catharina; Tea, Muy-Kheng; Hansen, Thomas V.O.; Johannsson, Oskar; Piedmonte, Marion; Rodriguez, Gustavo C.; Basil, Jack B.; Blank, Stephanie; Toland, Amanda E.; Montagna, Marco; Isaacs, Claudine; Blanco, Ignacio; Gayther, Simon A.; Moysich, Kirsten B.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Gadzicki, Dorothea; Fiebig, Britta; Caldes, Trinidad; Laframboise, Rachel; Nevanlinna, Heli; Chen, Xiaoqing; Beesley, Jonathan; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Radice, Paolo; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Stoppa-Lyonnet, Dominique; Mazoyer, Sylvie; Sinilnikova, Olga M.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77–0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription. PMID:21890493

  20. Ovarian cancer risk in Polish BRCA1 mutation carriers is not associated with the prohibitin 3' untranslated region polymorphism

    Directory of Open Access Journals (Sweden)

    Benner Axel

    2008-04-01

    Full Text Available Abstract Background The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations. Methods To investigate whether the PHB 3'UTR polymorphism also modifies hereditary ovarian cancer risk, we performed a case-control study among Polish women carrying one of the three common founder mutations (5382insC, 300 T > G, 4154delA including 127 ovarian cases and 127 unaffected controls who had both breasts and ovaries intact. Controls were matched to cases by year of birth and BRCA1 mutation. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios (OR were calculated using conditional and penalized univariable and multivariable logistic regression. Results A comparison of the genotype frequencies between cases and controls revealed no association of the PHB 3'UTR _CT+TT genotypes with ovarian cancer risk (ORadj 1.34; 95% CI, 0.59–3.11. Conclusion Our data suggest that the PHB 3'UTR polymorphism does not modify ovarian cancer risk in women carrying one of the three Polish BRCA1 founder mutations.

  1. Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bernstein, Jonine L; Thomas, Duncan C; Shore, Roy E;

    2013-01-01

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with...

  2. Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

    Directory of Open Access Journals (Sweden)

    Novakovic Srdjan

    2008-09-01

    Full Text Available Abstract Background Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations. The current study was aimed at establishing the mutation spectrum of BRCA1/2 in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families. Methods The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the BRCA1/2 screening were: (i probands with at least two first degree relatives with breast and ovarian cancer; (ii probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family. Results Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A BRCA1/2 mutation was found in 56 (39%. Two novel large deletions covering consecutive exons of BRCA1 were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the BRCA1 gene and IVS16-2A>G in the BRCA2 gene. The IVS16-2A>G in the BRCA2 gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the BRCA1/2 positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of

  3. Immunolocalization of BRCA1 protein in tumor breast tissue: prescreening of BRCA1 mutation in Tunisian patients with hereditary breast cancer?

    Directory of Open Access Journals (Sweden)

    W Troudi

    2009-08-01

    Full Text Available BRCA1 is a tumor suppressor gene which is inactivated by mutation in familial breast and ovarian cancers. Over 300 different disease causing germ-line mutations have been described; 60% are unique to an individual family. This diversity and the large size of the gene lead us to search for a prescreening method for BRCA1 mutations. Since BRCA1 is a nuclear protein in normal cells, but reported by some authors to be cytoplasmic in breast tumor cells of patients with BRCA1 mutation, we evaluated immunohistochemistry as a prescreening technique to identify BRCA1 mutations in patients with familial presentation of breast cancer. Using a monoclonal antibody against the carboxy-terminal region of BRCA1, we performed immunohistochemistry on 18 tumor samples from patients with hereditary breast cancer. Cytoplasmic staining of BRCA1 was observed in 10 cases. Of the 18 tumors, 12 (66% showed either BRCA mutation or BRCA1 accumulation or both, indicating that BRCA1 function might be lost in breast tumor cells not only through mutation, but also via abnormal cytoplasmic location. The immunohistochemical test used in this study would not be efficient as a pre-screening method of deleterious mutations, but it appeared useful to investigate tumor physiology.

  4. BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark

    DEFF Research Database (Denmark)

    Soegaard, M.; Kjaer, S.K.; Cox, M.; Wozniak, E.; Hogdall, E.; Blaakaer, J.; Jacobs, I.J.; Gayther, S.A.; Ramus, S.J.; Høgdall, Claus Kim

    2008-01-01

    PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the...... BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors....... RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in...

  5. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Phillips, Kelly-Anne; Milne, Roger L; Rookus, Matti A;

    2013-01-01

    To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.......To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers....

  6. Should we screen BRCA1 mutation carriers only with MRI? A multicenter study

    NARCIS (Netherlands)

    Obdeijn, I.-M.; Winter-Warnars, G.A.O.; Mann, R.M.; Hooning, M.J.; Hunink, M.G.M.; Tilanus-Linthorst, M.M.

    2014-01-01

    BRCA1 mutation carriers are offered screening with MRI and mammography. Aim of the study was to investigate the additional value of digital mammography over MRI screening. BRCA1 mutation carriers, who developed breast cancer since the introduction of digital mammography between January 2003 and Marc

  7. Pathology of Breast and Ovarian Cancers among BRCA1 and BRCA2 Mutation Carriers: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    DEFF Research Database (Denmark)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L;

    2012-01-01

    BACKGROUND: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. METHODS: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the...

  8. Mutation Screening of the BRCA1 Gene in Early Onset and Familial Breast/Ovarian Cancer in Moroccan Population

    Directory of Open Access Journals (Sweden)

    Abdelilah Laraqui, Nancy Uhrhammer, Idriss Lahlou-Amine, Hicham EL Rhaffouli, Jamila El Baghdadi, Mohamed Dehayni, Rahali Driss Moussaoui, Mohamed Ichou, Yassir Sbitti, Abderrahman Al Bouzidi, Said Amzazi, Yves-Jean Bignon

    2013-01-01

    Full Text Available Worldwide variation in the distribution of BRCA mutations is well recognised, and for the Moroccan population no comprehensive studies about BRCA mutation spectra or frequencies have been published. We therefore performed mutation analysis of the BRCA1 gene in 121 Moroccan women diagnosed with breast cancer. All cases completed epidemiology and family history questionnaires and provided a DNA sample for BRCA testing. Mutation analysis was performed by direct DNA sequencing of all coding exons and flanking intron sequences of the BRCA1 gene. 31.6 % (6/19 of familial cases and 1 % (1/102 of early-onset sporadic (< 45 years were found to be associated with BRCA1 mutations. The pathogenic mutations included two frame-shift mutations (c.798_799delTT, c.1016dupA, one missense mutation (c.5095C>T, and one nonsense mutation (c.4942A>T. The c.798_799delTT mutation was also observed in Algerian and Tunisian BC families, suggesting the first non-Jewish founder mutation to be described in Northern Africa. In addition, ten different unclassified variants were detected in BRCA1, none of which were predicted to affect splicing. Most unclassified variants were placed in Align-GVGD classes suggesting neutrality. c.5117G>C involves a highly conserved amino acid suggestive of interfering with function (Align-GVGD class C55, but has been observed in conjunction with a deleterious mutation in a Tunisian family. These findings reflect the genetic heterogeneity of the Moroccan population and are relevant to genetic counselling and clinical management. The role of BRCA2 in BC is also under study.

  9. Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

    OpenAIRE

    Iofrida Caterina; Melissari Erika; Mariotti Veronica; Guglielmi Chiara; Guidugli Lucia; Caligo Maria; Pellegrini Silvia

    2012-01-01

    Abstract Background BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and t...

  10. Screening for Del 185 AG and 4627C>A BRCA1 Mutations in Breast Cancer Patients from Lahore, Pakistan.

    Science.gov (United States)

    Aziz, Faiza; Fatima, Warda; Mahmood, Saqib; Khokher, Samina

    2016-01-01

    Breast cancer contributes to approximately 23% of the cancer cases identified and 14% of cancer related deaths worldwide. Including a strong association between genetic and environmental factors, breast cancer is a complex and multi factorial disorder. Two high penetration breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germ line mutations in these are thought to account for between 5% and 10% of all breast cancer cases. The human BRCA1 gene, located on 17q, is involved in the regulation of cell proliferation by aiding in DNA repair, transcriptional responses to DNA damage and cell cycle check points. Mutations in this gene enhance cell proliferation and facilitate formation of tumors. Two mutations, the 185 deletion of AG and the 4627 substitution from C to A, are founder mutations in the BRCA1 gene for breast cancer in Asian populations. Allele specific PCR was performed to detect these selected mutations in 120 samples. No mutation of 4627 C to A was detected in the samples and only one of the patients had the 185 del AG mutation in the heterozygous condition. Our collected samples had lower consanguinity and family history indicating the greater involvement of environmental as compared to genetic factors. PMID:27221844

  11. Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers:

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Rookus, Matti; Andrieu, Nadine;

    2009-01-01

    BACKGROUND: Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a...... small number of studies. METHODS: We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox...... proportional hazards framework. RESULTS: There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had...

  12. Effects of BRCA1 and BRCA2 mutations on female fertility

    OpenAIRE

    Smith, Ken R.; Hanson, Heidi A.; Mineau, Geraldine P; Buys, Saundra S.

    2011-01-01

    Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into m...

  13. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    NARCIS (Netherlands)

    D.G. Cox; J. Simard; D. Sinnett; Y. Hamdi; P. Soucy; M. Ouimet; L. Barjhoux; C. Verny-Pierre; L. McGuffog; S. Healey; C. Szabo; M.H. Greene; P.L. Mai; I.L. Andrulis; M. Thomassen; A.M. Gerdes; M.A. Caligo; E. Friedman; Y. Laitman; B. Kaufman; S.S. Paluch; A. Borg; P. Karlsson; M.S. Askmalm; G.B. Bustinza; K.L. Nathanson; S.M. Domchek; T.R. Rebbeck; J. Benitez; U. Hamann; M.A. Rookus; A.M.W. van den Ouweland; M.G.E.M. Ausems; C.M. Aalfs; C.J. van Asperen; P. Devilee; H.J.J.P. Gille; S. Peock; D. Frost; D.G. Evans; R. Eeles; L. Izatt; J. Adlard; J. Paterson; J. Eason; A.K. Godwin; M.A. Remon; V. Moncoutier; M. Gauthier-Villars; C. Lasset; S. Giraud; A. Hardouin; P. Berthet; H. Sobol; F. Eisinger; B.B. de Paillerets; O. Caron; C. Delnatte; D. Goldgar; A. Miron; H. Ozcelik; S. Buys; M.C. Southey; M.B. Terry; C.F. Singer; A.C. Dressler; M.K. tea; T.V.O. Hansen; O. Johannsson; M. Piedmonte; G.C. Rodriguez; J.B. Basil; S. Blank; A.E. Toland; M. Montagna; C. Isaacs; I. Blanco; S.A. Gayther; K.B. Moysich; R.K. Schmutzler; B. Wappenschmidt; C. Engel; A. Meindl; N. Ditsch; N. Arnold; D. Niederacher; C. Sutter; D. Gadzicki; B. Fiebig; T. Caldes; R. Laframboise; H. Nevanlinna; X. Chen; J. Beesley; A.B. Spurdle; S.L. Neuhausen; Y.C. Ding; F.J. Couch; X. Wang; P. Peterlongo; S. Manoukian; L. Bernard; P. Radice; D.F. Easton; G. Chenevix-Trench; A.C. Antoniou; D. Stoppa-Lyonnet; S. Mazoyer; O.M. Sinilnikova

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly in

  14. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

    NARCIS (Netherlands)

    Cox, D.G.; Simard, J.; Sinnett, D.; Hamdi, Y.; Soucy, P.; Ouimet, M.; Barjhoux, L.; Verny-Pierre, C.; McGuffog, L.; Healey, S.; Szabo, C.; Greene, M.H.; Mai, P.L.; Andrulis, I.L.; Thomassen, M.; Gerdes, A.M.; Caligo, M.A.; Friedman, E.; Laitman, Y.; Kaufman, B.; Paluch, S.S.; Borg, A.; Karlsson, P.; Askmalm, M.S.; Bustinza, G.B.; Nathanson, K.L.; Domchek, S.M.; Rebbeck, T.R.; Benitez, J.; Hamann, U.; Rookus, M.A.; Ouweland, A.M. van den; Ausems, M.G.; Aalfs, C.M.; Asperen, C.J. van; Devilee, P.; Gille, H.J.; Peock, S.; Frost, D.; Evans, D.G.; Eeles, R.; Izatt, L.; Adlard, J.; Paterson, J.; Eason, J.; Godwin, A.K.; Remon, M.A.; Moncoutier, V.; Gauthier-Villars, M.; Lasset, C.; Giraud, S.; Hardouin, A.; Berthet, P.; Sobol, H.; Eisinger, F.; Bressac de Paillerets, B.; Caron, O.; Delnatte, C.; Goldgar, D.; Miron, A.; Ozcelik, H.; Buys, S.; Southey, M.C.; Terry, M.B.; Singer, C.F.; Dressler, A.C.; Tea, M.K.; Hansen, T.V.; Johannsson, O.; Piedmonte, M.; Rodriguez, G.C.; Basil, J.B.; Blank, S.; Toland, A.E.; Montagna, M.; Isaacs, C.; Blanco, I.; Gayther, S.A.; Moysich, K.B.; Schmutzler, R.K.; Wappenschmidt, B.; Engel, C.; Meindl, A.; Ditsch, N.; Arnold, N.; Niederacher, D.; Sutter, C.; Gadzicki, D.; Fiebig, B.; Caldes, T.; Laframboise, R.; Nevanlinna, H.; Chen, X.; Beesley, J.; Spurdle, A.B.; Neuhausen, S.L.; Ding, Y.C.; Couch, F.J.; Wang, X.; Peterlongo, P.; Manoukian, S.; Bernard, L.; Radice, P.; Easton, D.F.; Chenevix-Trench, G.; Antoniou, A.C.; Stoppa-Lyonnet, D.; Mazoyer, S.; Sinilnikova, O.M.; Ligtenberg, M.J.L.; Hoogerbrugge, N.

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly in

  15. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel;

    2011-01-01

    Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly...

  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. Founder Mutations in Xeroderma Pigmentosum

    OpenAIRE

    Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth H.

    2010-01-01

    In this issue, Soufir et al. report a founder mutation in the XPC DNA repair gene in 74% of families with xeroderma pigmentosum (XP) in the Maghreb region (Algeria, Morocco, and Tunisia) of northern Africa. These patients have a high frequency of skin cancer. The presence of this founder mutation provides an opportunity for genetic counseling and early diagnosis of XP.

  18. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Marquart, Louise; McGuffog, Lesley;

    2011-01-01

    Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies....

  19. Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

    DEFF Research Database (Denmark)

    Cox, David G; Simard, Jacques; Sinnett, Daniel;

    2011-01-01

    instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation...... carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence...... interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy...

  20. Role of BRCA1 and BRCA2 mutations in pancreatic cancer

    OpenAIRE

    Greer, Julia B; David C. Whitcomb

    2006-01-01

    Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by “allelic” or “phenotypic” heterogeneity, in that they demonstrate differing cancer expressivity between and withi...

  1. RANKL/RANK control Brca1 mutation-driven mammary tumors.

    Science.gov (United States)

    Sigl, Verena; Owusu-Boaitey, Kwadwo; Joshi, Purna A; Kavirayani, Anoop; Wirnsberger, Gerald; Novatchkova, Maria; Kozieradzki, Ivona; Schramek, Daniel; Edokobi, Nnamdi; Hersl, Jerome; Sampson, Aishia; Odai-Afotey, Ashley; Lazaro, Conxi; Gonzalez-Suarez, Eva; Pujana, Miguel A; Cimba, For; Heyn, Holger; Vidal, Enrique; Cruickshank, Jennifer; Berman, Hal; Sarao, Renu; Ticevic, Melita; Uribesalgo, Iris; Tortola, Luigi; Rao, Shuan; Tan, Yen; Pfeiler, Georg; Lee, Eva Yhp; Bago-Horvath, Zsuzsanna; Kenner, Lukas; Popper, Helmuth; Singer, Christian; Khokha, Rama; Jones, Laundette P; Penninger, Josef M

    2016-07-01

    Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients. PMID:27241552

  2. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Rebbeck, Timothy R; Mitra, Nandita; Wan, Fei;

    2015-01-01

    IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained...

  3. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

    NARCIS (Netherlands)

    R. Rebbeck (Timothy); N. Mitra (Nandita); F. Wan (Fei); O. Sinilnikova (Olga); S. Healey (Sue); L. McGuffog (Lesley); G. Chenevix-Trench (Georgia); D.F. Easton (Douglas); A.C. Antoniou (Antonis C.); K.L. Nathanson (Katherine); Y. Laitman (Yael); A. Kushnir (Anya); S. Paluch-Shimon (Shani); R. Berger (Raanan); J. Zidan (Jamal); E. Friedman (Eitan); H. Ehrencrona (Hans); M. Stenmark-Askmalm (Marie); Z. Einbeigi (Zakaria); N. Loman (Niklas); K. Harbst (Katja); J. Rantala (Johanna); B. Melin (Beatrice); D. Huo (Dezheng); O.I. Olopade (Olofunmilayo); J.L. Seldon (Joyce); P.A. Ganz (Patricia); R.L. Nussbaum (Robert L.); S. Chan (Salina); K. Odunsi (Kunle); S.A. Gayther (Simon); S.M. Domchek (Susan); B.K. Arun (Banu); K.H. Lu (Karen); G. Mitchell (Gillian); B. Karlan; C.S. Walsh (Christine); K.J. Lester (Kathryn); A.K. Godwin (Andrew); S.S. Pathak; E.B. Ross (Eric); M.J. Daly (Mark); A.S. Whittemore (Alice); E.M. John (Esther); A. Miron (Alexander); M.B. Terry (Mary Beth); W.K. Chung (Wendy K.); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); L. Tihomirova (Laima); N. Tung (Nadine); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); L. Steele (Linda); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); B. Ejlertsen (Bent); A-M. Gerdes (Anne-Marie); T.V.O. Hansen (Thomas); T. Ramon Y Cajal; A. Osorio (Ana); J. Benítez (Javier); J. Godino (Javier); M.I. Tejada; M. Duran (Mercedes); J.N. Weitzel (Jeffrey); K.A. Bobolis (Kristie A.); S.R. Sand (Sharon); A. Fontaine (Annette); A. Savarese (Antonella); B. Pasini (Barbara); B. Peissel (Bernard); B. Bonnani (Bernardo); D. Zaffaroni (Daniela); F. Vignolo-Lutati (Francesca); G. Scuvera (Giulietta); G. Giannini (Giuseppe); L. Bernard (Loris); M. Genuardi (Maurizio); P. Radice (Paolo); R. Dolcetti (Riccardo); S. Manoukian (Siranoush); V. Pensotti (Valeria); V. Gismondi (Viviana); D. Yannoukakos (Drakoulis); F. Fostira (Florentia); J. Garber (Judy); D. Torres (Diana); M.U. Rashid (Muhammad); U. Hamann (Ute); S. Peock (Susan); D. Frost (Debra); R. Platte (Radka); D.G. Evans (Gareth); R. Eeles (Rosalind); R. Davidson (Rosemarie); D. Eccles (Diana); T. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); S. Hodgson (Shirley); P.J. Morrison (Patrick); L.J. Walker (Lisa); M.E. Porteous (Mary); M.J. Kennedy (John); L. Izatt (Louise); L. Adlard; A. Donaldson (Alan); S.D. Ellis (Steve); P. Sharma (Priyanka); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Becker (Alexandra); K. Rhiem (Kerstin); E. Hahnen (Eric); C. Engel (Christoph); A. Meindl (Alfons); S. Engert (Stefanie); N. Ditsch (Nina); N. Arnold (Norbert); H. Plendl (Hansjoerg); C. Mundhenke (Christoph); D. Niederacher (Dieter); M.C. Fleisch (Markus); C. Sutter (Christian); C.R. Bartram; N. Dikow (Nicola); S. Wang-Gohrke (Shan); D. Gadzicki (Dorothea); D. Steinemann (Doris); K. Kast (Karin); M. Beer (Marit); R. Varon-Mateeva (Raymonda); P.A. Gehrig (Paola A.); B.H.F. Weber (Bernhard); D. Stoppa-Lyonnet (Dominique); M. Belotti (Muriel); M. Gauthier-Villars (Marion); F. Damiola (Francesca); N. Boutry-Kryza (N.); C. Lasset (Christine); H. Sobol (Hagay); J.-P. Peyrat; D.W. Muller (Danièle); J.P. Fricker (Jean Pierre); M.-A. Collonge-Rame; I. Mortemousque (Isabelle); C. Nogues (Catherine); E. Rouleau (Etienne); C. Isaacs (Claudine); A. de Paepe (Anne); B. Poppe (Bruce); K. Claes (Kathleen); K. De Leeneer (Kim); M. Piedmonte (Marion); G. Rodriguez (Gustavo); K. Wakely (Katie); J.F. Boggess (John); S.V. Blank (Stephanie); J. Basil (Jack); M. Azodi (Masoud); K.-A. Phillips (Kelly-Anne); T. Caldes (Trinidad); M. de La Hoya (Miguel); A. Romero (Atocha); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); A.H. van der Hout (Annemarie); F.B.L. Hogervorst (Frans); S. Verhoef; J.M. Collee (Margriet); C.M. Seynaeve (Caroline); J.C. Oosterwijk (Jan); J.J. Gille (Johan); J.T. Wijnen (Juul); E.B. Gómez García (Encarna); C.M. Kets; M.G.E.M. Ausems (Margreet); C.M. Aalfs (Cora); P. Devilee (Peter); A.R. Mensenkamp (Arjen); A. Kwong (Ava); E. Olah; J. Papp (Janos); O. Díez (Orland); C. Lazaro (Conxi); E. Darder (Esther); I. Blanco (Ignacio); M. Salinas; A. Jakubowska (Anna); J. Lubinski (Jan); J. Gronwald (Jacek); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); G. Sukiennicki (Grzegorz); T. Huzarski (Tomasz); T. Byrski (Tomasz); C. Cybulski (Cezary); A. Toloczko-Grabarek (Aleksandra); E. Złowocka-Perłowska (Elzbieta); J. Menkiszak (Janusz); A. Arason (Adalgeir); R.B. Barkardottir (Rosa); J. Simard (Jacques); R. Laframboise (Rachel)

    2015-01-01

    textabstractImportance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere asce

  4. Recurrent BRCA1 and BRCA2 mutations in breast cancer patients of African ancestry.

    Science.gov (United States)

    Zhang, Jing; Fackenthal, James D; Zheng, Yonglan; Huo, Dezheng; Hou, Ningqi; Niu, Qun; Zvosec, Cecilia; Ogundiran, Temidayo O; Hennis, Anselm J; Leske, Maria Cristina; Nemesure, Barbara; Wu, Suh-Yuh; Olopade, Olufunmilayo I

    2012-07-01

    Recurrent mutations constituted nearly three quarters of all BRCA1 mutations and almost half of all BRCA2 mutations identified in the first cohort of the Nigerian Breast Cancer Study. To further characterize breast/ovarian cancer risks associated with BRCA1/BRCA2 mutations in the African diaspora, we genotyped recurrent mutations among Nigerian, African American, and Barbadian breast cancer patients. A replication cohort of 356 Nigerian breast cancer patients was genotyped for 12 recurrent BRCA1/2 mutant alleles (Y101X, 1742insG, 4241delTG, M1775R, 4359insC, C64Y, 1623delTTAAA, Q1090X, and 943ins10 from BRCA1, and 1538delAAGA, 2630del11, and 9045delGAAA from BRCA2) by means of SNaPshot followed by direct sequencing or by direct sequencing alone. In addition, 260 African Americans and 118 Barbadians were genotyped for six of the recurrent BRCA1 mutations by SNaPshot assay. Of all the BRCA1/2 recurrent mutations we identified in the first cohort, six were identified in 11 patients in the replication study. These mutation carriers constitute 3.1 % [95 % Confidence Interval (CI) 1.6-5.5 %] of the replication cohort. By comparison, 6.9 % (95 % CI 4.7-9.7 %) of the discovery cohort carried BRCA1/2 recurrent mutations. For the subset of recurrent mutations we tested in breast cancer cases from Barbados or the United States, only two 943ins10 carriers were identified in African Americans. Nigerian breast cancer patients from Ibadan carry a broad and unique spectrum of BRCA1/2 mutations. Our data suggest that BRCA1/2 mutation testing limited to recurrent mutations is not sufficient to understand the BRCA1/2-associated breast cancer risk in African populations in the diaspora. As the cost of Sanger sequencing is considerably reduced, deploying innovative technologies such as high throughput DNA sequencing of BRCA1/2 and other cancer susceptibility genes will be essential for identifying high-risk individuals and families to reduce the burden of aggressive early onset breast

  5. Telomere length shows no association with BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Killick, Emma; Tymrakiewicz, Malgorzata; Cieza-Borrella, Clara;

    2014-01-01

    time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from...... DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2...

  6. Mutation analysis of the BRCA1 gene in Breast cancer Families

    International Nuclear Information System (INIS)

    Mutations in two genes, BRCA1 and BRCA2, are responsible for approximately two thirds of all hereditary breast and ovarian cancers. In this study, we have examined patients from breast and/or ovarian cancer families in BRCA1, using the protein truncation test. The protein truncation test was used to screen for mutations leading to premature translational termination. The PCR-products were added to the TnT/T7 coupled reticulocyte lysate system (Promega) and the 35S-Met-labelled proteins were analyzed by gel electrophoresis and autoradiography. In a group of 26 tested patients we have detected one mutation affecting exon 11 in one of the BRCA1 alleles because, in addition to the normal product, a truncated protein was found after in vitro transcription and translation. The low frequency of BRCA1 mutations in the present study could be explained by the role of additional genes (e.g. BRCA2) in predisposed families. (authors)

  7. Women with BRCA1 and BRCA2 mutations survive ovarian cancer at higher rates

    Science.gov (United States)

    Results from a National Cancer Institute (NCI) sponsored multicenter study published in the Journal of the American Medical Association on January 25, 2012, provides strong evidence that BRCA1 and BRCA2 gene mutation carriers with ovarian cancer were more

  8. Mutations in BRCA1 and BRCA2 Uruguayan families with breast / ovarian

    International Nuclear Information System (INIS)

    Germline mutations in BRCA1 and BRCA2 are associated with susceptibility hereditary to breast (CM) and ovarian cancer (OC). The proportion of high risk families carrying mutations in BRCA1 / 2 (20% -70%) and the spectrum of mutations are variable and dependent on the location and type of families studied. In this communication we update our results on the frequency and type of mutations in BRCA1 / 2 families in Uruguayan breast / ovarian cancer. Patients and methods. 39 selected families were included in the study from patients referred to the Unit of the Hospital de Clinicas Oncogene tics for genetic risk assessment and who had at least 3 cases of CM (at least one diagnosed before age 50) or 2 cases with any of the following sub: Parental transmittance, bilateral breast cancer, breast cancer male, ovarian cancer. Results. 8 8 families different mutations (20%), 6 were identified in BRCA1 and BRCA2 2, all resulting in premature termination codon. Regarding family history, 33 families had history of CM and 6 remaining history of CM and CO. Among the first 6 mutations diagnosed (Five in BRCA1 and one in BRCA2) and between the latter 2 mutations (1 in BRCA1 and 1 in BRCA2). Regarding the index cases, all BRCA2 mutations were detected in patients in whom the disease was diagnosed before the 50, 5 of them carrying CM and CO. The BRCA1 were found in a patient with CO diagnosed at age 55 and a patient with CM diagnosed before 50 years. Conclusions. The proportion of flamilies with BRCA1 / 2 is of agreement with that reported in previous studies involving selected families based on similar criteria, but the relative frequency of engagement

  9. Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

    Science.gov (United States)

    Laitman, Yael; Simeonov, Monica; Herskovitz, Liron; Kushnir, Anya; Shimon-Paluch, Shani; Kaufman, Bella; Zidan, Jamal; Friedman, Eitan

    2012-06-01

    The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations

  10. Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients

    International Nuclear Information System (INIS)

    Purpose: The dose intensity of radiotherapy (RT) used in cancer treatment is limited in rare individuals who display severe normal tissue reactions after standard RT treatments. Novel predictive assays are required to identify these individuals prior to treatment. The mechanisms responsible for such reactions are unknown, but may involve dysfunction of genes involved in the sensing and response of cells to DNA damage. The breast cancer susceptibility genes BRCA1 and BRCA2 are implicated in DNA damage repair and the control of genome stability. The purpose of this study was to determine if clinical radiation hypersensitivity is related to mutations of the BRCA1 and BRCA2 genes. Such information is of potential use in the clinical management of BRCA mutation carriers and their families. Methods and Materials: Twenty-two cancer patients who developed severe normal tissue reactions after RT were screened for mutations of BRCA1 and BRCA2, using various methods including protein truncation testing, direct DNA sequencing, and a PCR-based BRCA1 exon 13 duplication test. Results: No mutations were detected in the 22 patients tested, despite screening for the majority of commonly described types of mutations of BRCA1 and BRCA2. Conclusion: These early results suggest that genes other than BRCA1 and BRCA2 probably account for most cases of clinical radiation hypersensitivity, and that screening for mutations of BRCA1 and BRCA2 is unlikely to be useful in predicting response to radiotherapy. However, it has not been excluded that some BRCA1 or BRCA2 heterozygotes might experience unexpected RT toxicity; further BRCA mutation screening on radiation sensitive individuals is warranted

  11. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    CERN Document Server

    Nato, A Q J

    2003-01-01

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for approx 45% of families with multiple breast carcinomas and for approx 80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms whi...

  12. Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    Background: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA ...... cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative echanisms....... repair and is associated with treatment outcome in ovarian cancer. Methods and Results: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous...... mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. Conclusions: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with highgrade serous ovarian cancer carrying BRCA1 or BRCA2...

  13. Contribution of BRCA1 and BRCA2 Germline Mutations to Early Algerian Breast Cancer.

    Science.gov (United States)

    Henouda, Sarra; Bensalem, Assia; Reggad, Rym; Serrar, Nedda; Rouabah, Leila; Pujol, Pascal

    2016-01-01

    Breast cancer is the most common female malignancy and the leading cancer mortality cause among Algerian women. Germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast cancer have not been clearly identified within the Algerian population. It is necessary to study the BRCA1/2 genes involvement in the Algerian breast cancer occurrence. We performed this study to define germline mutations in BRCA1/2 and their implication in breast cancer among young women from eastern Algeria diagnosed or treated with primary invasive breast cancer at the age of 40 or less who were referred to Anti-Cancer Center of Setif, Algeria. Case series were unselected for family history. Eight distinct pathogenic mutations were identified in eight unrelated families. Three deleterious mutations and one large genomic rearrangement involving deletion of exon 2 were found in BRCA1 gene. In addition, four mutations within the BRCA2 gene and one large genomic rearrangement were identified. Novel mutation was found among Algerian population. Moreover, five variants of uncertain clinical significance and favor polymorphisms were identified. Our data suggest that BRCA1/2 mutations are responsible for a significant proportion of breast cancer in Algerian young women. PMID:26997744

  14. Expression of estrogen receptor beta in the breast carcinoma of BRCA1 mutation carriers

    International Nuclear Information System (INIS)

    Breast cancers (BC) in women carrying mutations in BRCA1 gene are more frequently estrogen receptor negative than the nonhereditary BC. Nevertheless, tamoxifen has been found to have a protective effect in preventing contralateral tumors in BRCA1 mutation carriers. The identification of the second human estrogen receptor, ERβ, raised a question of its role in hereditary breast cancer. The aim of this study was to assess the frequency of ERα, ERβ, PgR (progesterone receptor) and HER-2 expression in breast cancer patients with mutated BRCA1 gene and in the control group. The study group consisted of 48 women with BRCA1 gene mutations confirmed by multiplex PCR assay. The patients were tested for three most common mutations of BRCA1 affecting the Polish population (5382insC, C61G, 4153delA). Immunostaining for ERα, ERβ and PgR (progesterone receptor) was performed using monoclonal antibodies against ERα, PgR (DakoCytomation), and polyclonal antibody against ERβ (Chemicon). The EnVision detection system was applied. The study population comprised a control group of 120 BC operated successively during the years 1998–99. The results of our investigation showed that BRCA1 mutation carriers were more likely to have ERα-negative breast cancer than those in the control group. Only 14.5% of BRCA1-related cancers were ERα-positive compared with 57.5% in the control group (P < 0.0001). On the contrary, the expression of ERβ protein was observed in 42% of BRCA1-related tumors and in 55% of the control group. An interesting finding was that most hereditary cancers (75% of the whole group) were triple-negative: ERα(-)/PgR(-)/HER-2(-) but almost half of this group (44.4%) showed the expression of ERβ. In the case of BRCA1-associated tumors the expression of ERβ was significantly higher than the expression of ERα. This may explain the effectiveness of tamoxifen in preventing contralateral breast cancer development in BRCA1 mutation carriers

  15. Refined histopathological predictors of BRCA1 and BRCA2 mutation status

    DEFF Research Database (Denmark)

    Spurdle, Amanda B; Couch, Fergus J; Parsons, Michael T;

    2014-01-01

    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to asse...

  16. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kosinova Veronika

    2008-05-01

    Full Text Available Abstract Background The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic during 1999–2006. Methods The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing. Results In 294 unrelated families (29.1% of the 1,010 probands pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2 represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G were demonstrated to result in aberrant transcripts and are considered as deleterious mutations. Conclusion This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.

  17. Telomere length shows no association with BRCA1 and BRCA2 mutation status.

    Directory of Open Access Journals (Sweden)

    Emma Killick

    Full Text Available This study aimed to determine whether telomere length (TL is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years, all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years, half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL.

  18. Detection of somatic BRCA1/2 mutations in ovarian cancer - next-generation sequencing analysis of 100 cases.

    Science.gov (United States)

    Koczkowska, Magdalena; Zuk, Monika; Gorczynski, Adam; Ratajska, Magdalena; Lewandowska, Marzena; Biernat, Wojciech; Limon, Janusz; Wasag, Bartosz

    2016-07-01

    The overall prevalence of germline BRCA1/2 mutations is estimated between 11% and 15% of all ovarian cancers. Individuals with germline BRCA1/2 alterations treated with the PARP1 inhibitors (iPARP1) tend to respond better than patients with wild-type BRCA1/2. Additionally, also somatic BRCA1/2 alterations induce the sensitivity to iPARP1. Therefore, the detection of both germline and somatic BRCA1/2 mutations is required for effective iPARP1 treatment. The aim of this study was to identify the frequency and spectrum of germline and somatic BRCA1/2 alterations in a group of Polish patients with ovarian serous carcinoma. In total, 100 formalin-fixed paraffin-embedded (FFPE) ovarian serous carcinoma tissues were enrolled to the study. Mutational analysis of BRCA1/2 genes was performed by using next-generation sequencing. The presence of pathogenic variants was confirmed by Sanger sequencing. In addition, to confirm the germline or somatic status of the mutation, the nonneoplastic tissue was analyzed by bidirectional Sanger sequencing. In total, 27 (28% of patient samples) mutations (20 in BRCA1 and 7 in BRCA2) were identified. For 22 of 27 patients, nonneoplastic cells were available and sequencing revealed the somatic character of two BRCA1 (2/16; 12.5%) and two BRCA2 (2/6; 33%) mutations. Notably, we identified six novel frameshift or nonsense BRCA1/2 mutations. The heterogeneity of the detected mutations confirms the necessity of simultaneous analysis of BRCA1/2 genes in all patients diagnosed with serous ovarian carcinoma. Moreover, the use of tumor tissue for mutational analysis allowed the detection of both somatic and germline BRCA1/2 mutations. PMID:27167707

  19. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y; Andersen, Mette K; Kjaergaard, Susanne; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C

    2011-01-01

    Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1 and...... BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion, the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations...

  20. Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Steffensen, Ane Y; Andersen, Mette K; Kjaergaard, Susanne; Gerdes, Anne-Marie; Ejlertsen, Bent; Nielsen, Finn C

    2011-01-01

    Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1 and...... BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1......, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion,the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations...

  1. Mutational analysis of the BRCA1 gene in 30 Czech ovarian cancer patients

    Indian Academy of Sciences (India)

    M. Zikan; P. Pohlreich; J. Stribrna

    2005-04-01

    Ovarian cancer is one of the most severe of oncological diseases. Inherited mutations in cancer susceptibility genes play a causal role in 5–10% of newly diagnosed tumours. BRCA1 and BRCA2 gene alterations are found in the majority of these cases. The aim of this study was to analyse the BRCA1 gene in the ovarian cancer risk group to characterize the spectrum of its mutations in the Czech Republic. Five overlapping fragments amplified on both genomic DNA and cDNA were used to screen for the whole protein-coding sequence of the BRCA1 gene. These fragments were analysed by the protein truncation test (PTT) and direct sequencing. Three inactivating mutations were identified in the group of 30 Czech ovarian cancer patients: the 5382insC mutation in two unrelated patients and a deletion of exons 21 and 22 in another patient. In addition, we have found an alternatively spliced product lacking exon 5 in two other unrelated patients. The 5382insC is the most frequent alteration of the BRCA1 gene in Central and Eastern Europe. The deletion of exons 21 and 22 affects the BRCT functional domain of the BRCA1 protein. Although large genomic rearragements are known to be relatively frequent in Western European populations, no analyses have been performed in our region yet.

  2. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

    Science.gov (United States)

    Mavaddat, Nasim; Barrowdale, Daniel; Andrulis, Irene L.; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Spurdle, Amanda; Robson, Mark; Sherman, Mark; Mulligan, Anna Marie; Couch, Fergus J.; Engel, Christoph; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Southey, Melissa C.; Terry, Mary Beth; Goldgar, David; O’Malley, Frances; John, Esther M.; Janavicius, Ramunas; Tihomirova, Laima; Hansen, Thomas v O; Nielsen, Finn C.; Osorio, Ana; Stavropoulou, Alexandra; Benítez, Javier; Manoukian, Siranoush; Peissel, Bernard; Barile, Monica; Volorio, Sara; Pasini, Barbara; Dolcetti, Riccardo; Putignano, Anna Laura; Ottini, Laura; Radice, Paolo; Hamann, Ute; Rashid, Muhammad U.; Hogervorst, Frans B.; Kriege, Mieke; van der Luijt, Rob B.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Brewer, Carole; Walker, Lisa; Rogers, Mark T.; Side, Lucy E.; Houghton, Catherine; Weaver, JoEllen; Godwin, Andrew K.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Kast, Karin; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Doroteha; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schönbuchner, Ines; Gevensleben, Heidrun; Stoppa-Lyonnet, Dominique; Belotti, Muriel; Barjhoux, Laure; Isaacs, Claudine; Peshkin, Beth N.; Caldes, Trinidad; de al Hoya, Miguel; Cañadas, Carmen; Heikkinen, Tuomas; Heikkilä, Päivi; Aittomäki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Brunet, Joan; Agnarsson, Bjarni A.; Arason, Adalgeir; Barkardottir, Rosa B.; Dumont, Martine; Simard, Jacques; Montagna, Marco; Agata, Simona; D’Andrea, Emma; Yan, Max; Fox, Stephen; Rebbeck, Timothy R.; Rubinstein, Wendy; Tung, Nadine; Garber, Judy E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia M.; Singer, Christian F.; Tea, Muy-Kheng; Rappaport, Christine; Mai, Phuong L.; Greene, Mark H.; Sokolenko, Anna; Imyanitov, Evgeny; Toland, Amanda Ewart; Senter, Leigha; Sweet, Kevin; Thomassen, Mads; Gerdes, Anne-Marie; Kruse, Torben; Caligo, Maria; Aretini, Paolo; Rantala, Johanna; von Wachenfeld, Anna; Henriksson, Karin; Steele, Linda; Neuhausen, Susan L.; Nussbaum, Bob; Beattie, Mary; Odunsi, Kunle; Sucheston, Lara; Gayther, Simon A; Nathanson, Kate; Gross, Jenny; Walsh, Christine; Karlan, Beth; Chenevix-Trench, Georgia; Easton, Douglas F.; Antoniou, Antonis C.

    2011-01-01

    Background Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers. Results There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%). Conclusions/Impact Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis. PMID:22144499

  3. A germline mutation in the BRCA1 3’UTR predicts Stage IV breast cancer

    International Nuclear Information System (INIS)

    A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer. The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the

  4. A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival.

    OpenAIRE

    Anjum, S; Fourkala, E O; Zikan, M.; Wong, A.; Gentry-Maharaj, A.; Jones, A.; HARDY, R.; Cibula, D.; Kuh, D.; Jacobs, I. J.; Teschendorff, A.E.; Menon, U; Widschwendter, M

    2014-01-01

    Background BRCA1 mutation carriers have an 85% risk of developing breast cancer but the risk of developing non-hereditary breast cancer is difficult to assess. Our objective is to test whether a DNA methylation (DNAme) signature derived from BRCA1 mutation carriers is able to predict non-hereditary breast cancer. Methods In a case/control setting (72 BRCA1 mutation carriers and 72 BRCA1/2 wild type controls) blood cell DNA samples were profiled on the Illumina 27 k methylation array. Using th...

  5. A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes

    International Nuclear Information System (INIS)

    Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical amplification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the amplicon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the amplicons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of samples enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to individuals who currently do not undergo mutation testing because of the significant costs involved

  6. Risk modeling and screening for BRCA1 mutations among Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Breast cancer susceptibility gene, type 1(BRCA1) has been thought to be responsible for ∼45% of families with multiple breast carcinomas and for ∼80% of breast and ovarian cancer families. In this study, we investigated 34 familial Filipino breast cancer (BC) patients to: (a) estimate breast cancer risks and BRCA1/2 mutation carrier probabilities using risk assessment and prior probability models, respectively; (b) screen for putative polymorphisms at selected smaller exons of BRCA1 by single-strand conformation polymorphism (SSCP) analysis; (c) screen for truncated mutations at BRCA1 exon 11 by radioactive protein truncation test (PTT); and (d) estimate posterior probabilities upon incorporation of screening results. SSCP analysis revealed 8 unique putative polymorphisms. Low prevalence of unique putative polymorphisms at exon 2, 5, 17, and 22 may indicate probable mutations. Contrastingly, high prevalence of unique putative polymorphisms at exons 13, 15, and 16 may suggest true polymorphisms which are biologically insignificant. PTT, DHPLC, and sequence analyses revealed a novel mutation in exon 11 involving GT insertion that resulted to a stop codon which generated a 29.7 kDa truncated protein product. This is the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. Initial genotype-phenotype correlations in Filipino BC patients may be elucidated based on screening tests performed. Our results corroborate the findings of a study on unselected incident Filipino BC cases where the reported prevalence of BRCA1 mutation is low. The higher prevalence of putative polypmorphisms may be attributed to the increased stringency in patient prospecting. The Gail, Claus, and BRCAPRO models can be utilized to estimate BC risk in unaffected high-risk individuals but validation is needed. Most of the BRCAPRO and Myriad.com prior probability estimates coincide with the presence of BRCA1 mutation and/or putative polymorphisms. This pioneering

  7. Breast conservation in BRCA1 or BRCA2 mutation carriers with early stage breast cancer

    International Nuclear Information System (INIS)

    The role of breast conservation therapy (limited surgery and irradiation of the breast with/without axilla) in the approximately 5% of breast cancer patients who harbour a germline mutation in BRCA1 or BRCA2, is a largely unexplored area and is seen by some as controversial. The relatively high cumulative risk of second primary cancers in such patients and concern about a possible decreased ability of mutation carriers to repair DNA damage caused by radiation has fuelled this controversy. Published studies of breast conservation therapy in carriers of a mutation in BRCA1 or BRCA2 are reviewed, with particular attention to their methodology. These studies have not demonstrated any increase in radiation sensitivity of normal tissues in mutation carriers, either in terms of increased early or late toxicity or tumourigenesis. Likewise, tumour sensitivity to radiotherapy, which might be expected based on the known functions of the BRCA1 and BRCA2 genes, has not been documented to date in mutation carriers. Further, methodologically rigorous studies of large numbers of breast cancer patients who carry a mutation in BRCA1 or BRCA2 are required to fully elucidate these issues. Copyright (2001) Blackwell Science Pty Ltd

  8. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    International Nuclear Information System (INIS)

    Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2). The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT) and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE). All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%). Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer

  9. The prevalence of BRCA1 mutations among young women with triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    DeSai Damini

    2009-03-01

    Full Text Available Abstract Background Molecular screening for BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer. Features of hereditary breast cancer include an early age-of-onset and over-representation of the 'triple-negative' phenotype (negative for estrogen-receptor, progesterone-receptor and HER2. The decision to offer genetic testing to a breast cancer patient is usually based on her family history, but in the absence of a family history of cancer, some women may qualify for testing based on the age-of-onset and/or the pathologic features of the breast cancer. Methods We studied 54 women who were diagnosed with high-grade, triple-negative invasive breast cancer at or before age 40. These women were selected for study because they had little or no family history of breast or ovarian cancer and they did not qualify for genetic testing using conventional family history criteria. BRCA1 screening was performed using a combination of fluorescent multiplexed-PCR analysis, BRCA1 exon-13 6 kb duplication screening, the protein truncation test (PTT and fluorescent multiplexed denaturing gradient gel electrophoresis (DGGE. All coding exons of BRCA1 were screened. The two large exons of BRCA2 were also screened using PTT. All mutations were confirmed with direct sequencing. Results Five deleterious BRCA1 mutations and one deleterious BRCA2 mutation were identified in the 54 patients with early-onset, triple-negative breast cancer (11%. Conclusion Women with early-onset triple-negative breast cancer are candidates for genetic testing for BRCA1, even in the absence of a family history of breast or ovarian cancer.

  10. Chromosomal radiosensitivity in breast cancer patients and BRCA1 and 2 mutation carriers

    International Nuclear Information System (INIS)

    Enhanced chromosomal radiosensitivity is observed in significant proportions of cancer patients. In breast cancer patients, this elevated sensitivity is confirmed in several independent studies with the G2 assay as well as with the GO micronucleus (MN) assay for peripheral blood lymphocytes (PBL). Enhanced chromosomal radiosensitivity is a common feature of sporadic breast cancer patients as well as breast cancer patients with a family history of the disease. Segregation analysis showed Mendelian heritability of chromosomal radiosensitivity. As mutations in the highly penetrant breast cancer predisposing genes, BRCA1 and 2, are only present in about 3-5 % of familial breast cancer patients, they cannot solely account for the high proportion of radiosensitive cases found among all breast cancer patients. A review on chromosomal radiosensitivity in BRCA1 and 2 mutation carriers shows that breast cancer patients with a BRCAl or 2 mutation are on the average more radiosensitive than healthy individuals, but not different from breast cancer patients without a BRCA mutation. The radiation response of healthy BRCA1/2 mutation carriers, on the contrary, is not significantly different from controls. Most studies performed on wild type and BRCA +/- EBV lymphoblastoid cell lines also could not demonstrate any differences in MN response between both groups. These findings suggest that mutations in BRCA 1 and 2 are not playing a major role in chromosomal radiosensitivity as measured by G2 and MN assay. The enhanced sensitivity observed in a substantial proportion of breast cancer patients, irrespective of a BRCA1/2 mutation or not, suggests that this feature may be related to the presence of other mutations in low penetrance breast cancer predisposing genes, which may be involved in the process of DNA damage. (author)

  11. Validation study suggested no differential misclassification of self-reported mammography history in BRCA1/2 mutation carriers

    NARCIS (Netherlands)

    Pijpe, Anouk; Mulder, Renee L.; Manders, Peggy; van Leeuwen, Flora E.; Rookus, Matti A.

    2011-01-01

    Objectives: We assessed accuracy of self-reported lifetime mammography history by BRCA1/2 mutation carriers with and without breast cancer. Study Design and Setting: Within the framework of the HEBON study (The Netherlands Collaborative Group on Hereditary Breast Cancer), 218 Dutch BRCA1/2 mutation

  12. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer

    DEFF Research Database (Denmark)

    Thomassen, Mads; Hansen, Thomas V O; Borg, Ake;

    2008-01-01

    A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six muta...

  13. BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells.

    Science.gov (United States)

    Woolery, Kamisha T; Mohamed, Mai; Linger, Rebecca J; Dobrinski, Kimberly P; Roman, Jesse; Kruk, Patricia A

    2015-01-01

    Familial history remains the strongest risk factor for developing ovarian cancer (OC) and is associated with germline BRCA1 mutations, such as the 185delAG founder mutation. We sought to determine whether normal human ovarian surface epithelial (OSE) cells expressing the BRCA1 185delAG mutant, BRAT, could promote an inflammatory phenotype by investigating its impact on expression of the proinflammatory cytokine, Interleukin-1β (IL-1β). Cultured OSE cells with and without BRAT were analyzed for differential target gene expression by real-time PCR, western blot, ELISA, luciferase reporter, and siRNA assays. We found that BRAT cells expressed increased cellular and secreted levels of active IL-1β. BRAT-expressing OSE cells exhibited 3-fold enhanced IL-1β mRNA expression, transcriptionally regulated, in part, through CREB sites within the (-1800) to (-900) region of its promoter. In addition to transcriptional regulation, BRAT-mediated IL-1β expression appears dualistic through enhanced inflammasome-mediated caspase-1 cleavage and activation of IL-1β. Further investigation is warranted to elucidate the molecular mechanism(s) of BRAT-mediated IL-1β expression since increased IL-1β expression may represent an early step contributing to OC. PMID:26357657

  14. BRCA1 185delAG Mutation Enhances Interleukin-1β Expression in Ovarian Surface Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Kamisha T. Woolery

    2015-01-01

    Full Text Available Familial history remains the strongest risk factor for developing ovarian cancer (OC and is associated with germline BRCA1 mutations, such as the 185delAG founder mutation. We sought to determine whether normal human ovarian surface epithelial (OSE cells expressing the BRCA1 185delAG mutant, BRAT, could promote an inflammatory phenotype by investigating its impact on expression of the proinflammatory cytokine, Interleukin-1β (IL-1β. Cultured OSE cells with and without BRAT were analyzed for differential target gene expression by real-time PCR, western blot, ELISA, luciferase reporter, and siRNA assays. We found that BRAT cells expressed increased cellular and secreted levels of active IL-1β. BRAT-expressing OSE cells exhibited 3-fold enhanced IL-1β mRNA expression, transcriptionally regulated, in part, through CREB sites within the (−1800 to (−900 region of its promoter. In addition to transcriptional regulation, BRAT-mediated IL-1β expression appears dualistic through enhanced inflammasome-mediated caspase-1 cleavage and activation of IL-1β. Further investigation is warranted to elucidate the molecular mechanism(s of BRAT-mediated IL-1β expression since increased IL-1β expression may represent an early step contributing to OC.

  15. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    Veltman, J.; Mann, R.; Kok, T.; Obdeijn, I. M.; Hoogerbrugge, N.; Blickman, J. G.; Boetes, C.

    2008-01-01

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control g

  16. Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Bancroft, Elizabeth K; Page, Elizabeth C; Castro, Elena;

    2014-01-01

    BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in ...

  17. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    NARCIS (Netherlands)

    J. Veltman; R. Mann; T. Kok (Theo); A.I.M. Obdeijn (Inge-Marie); N. Hoogerbrugge (Nicoline); J.G. Blickman; C. Boetes

    2008-01-01

    textabstractThe appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type match

  18. Classifications within molecular subtypes enables identification of BRCA1/BRCA2 mutation carriers by RNA tumor profiling

    DEFF Research Database (Denmark)

    Larsen, Martin J; Kruse, Torben A; Tan, Qihua;

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of...... unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic......-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement ("BRCAness") by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations...

  19. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Bolton, Kelly L; Chenevix-Trench, Georgia; Goh, Cindy; Sadetzki, Siegal; Ramus, Susan J; Karlan, Beth Y; Lambrechts, Diether; Despierre, Evelyn; Barrowdale, Daniel; McGuffog, Lesley; Healey, Sue; Easton, Douglas F; Sinilnikova, Olga; Benítez, Javier; García, María J; Neuhausen, Susan; Gail, Mitchell H; Hartge, Patricia; Peock, Susan; Frost, Debra; Evans, D Gareth; Eeles, Rosalind; Godwin, Andrew K; Daly, Mary B; Kwong, Ava; Ma, Edmond S K; Lázaro, Conxi; Blanco, Ignacio; Montagna, Marco; D'Andrea, Emma; Nicoletto, Maria Ornella; Johnatty, Sharon E; Kjær, Susanne Krüger; Jensen, Allan; Høgdall, Estrid; Goode, Ellen L; Fridley, Brooke L; Loud, Jennifer T; Greene, Mark H; Mai, Phuong L; Chetrit, Angela; Lubin, Flora; Hirsh-Yechezkel, Galit; Glendon, Gord; Andrulis, Irene L; Toland, Amanda E; Senter, Leigha; Gore, Martin E; Gourley, Charlie; Michie, Caroline O; Song, Honglin; Tyrer, Jonathan; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Kristoffersson, Ulf; Olsson, Håkan; Borg, Åke; Levine, Douglas A; Steele, Linda; Beattie, Mary S; Chan, Salina; Nussbaum, Robert L; Moysich, Kirsten B; Gross, Jenny; Cass, Ilana; Walsh, Christine; Li, Andrew J; Leuchter, Ronald; Gordon, Ora; Garcia-Closas, Montserrat; Gayther, Simon A; Chanock, Stephen J; Antoniou, Antonis C; Pharoah, Paul D P

    2012-01-01

    Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear....

  20. Exome mutation burden predicts clinical outcome in ovarian cancer carrying mutated BRCA1 and BRCA2 genes

    DEFF Research Database (Denmark)

    Birkbak, Nicolai Juul; Kochupurakkal, Bose; Gonzalez-Izarzugaza, Jose Maria;

    2013-01-01

    Reliable biomarkers predicting resistance or sensitivity to anti-cancer therapy are critical for oncologists to select proper therapeutic drugs in individual cancer patients. Ovarian and breast cancer patients carrying germline mutations in BRCA1 or BRCA2 genes are often sensitive to DNA damaging......-type BRCA1 and BRCA2 genes. These results suggest that in cancers with DNA repair deficiency caused by functional BRCA loss, higher versus lower Nmut may reflect the status of deficiency or rescue by alternative mechanism(s) for DNA repair, with lower Nmut predicting for resistance to DNA-damaging drugs in...... drugs and relative to non-mutation carriers present a favorable clinical outcome following therapy. Genome sequencing studies have shown a high number of mutations in the tumor genome in patients carrying BRCA1 or BRCA2 mutations (mBRCA). The present study used exome-sequencing and SNP 6 array data of...

  1. Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

    International Nuclear Information System (INIS)

    BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity

  2. Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families

    International Nuclear Information System (INIS)

    Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families. Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases. BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups. BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker

  3. Evidence for a pathogenic role of BRCA1 L1705P and W1837X germ-line mutations.

    Science.gov (United States)

    Sokolenko, Anna P; Volkov, Nikita M; Preobrazhenskaya, Elena V; Suspitsin, Evgeny N; Garifullina, Aigul R; Ivantsov, Alexandr V; Togo, Alexandr V; Imyanitov, Evgeny N

    2016-05-01

    BRCA1 L1705P (c.5114T>C) has been classified in the NCBI SNP database as the variant with uncertain significance and is absent in major BRCA1 databases. BRCA1 W1837X (c.5511G>A) results in a loss of only last 27 residues of BRCA1 protein, thus its pathogenic role still requires a confirmation. This report describes two breast cancer (BC) patients carrying BRCA1 L1705P and W1837X germ-line mutations, respectively. Significant evidence for BC-predisposing impact of the mentioned mutations have been obtained: (1) both index cases presented with the triple-negative receptor status of BC disease; (2) complete segregation with BRCA1-related cancers was observed in the families of these patients; (3) somatic loss of the remaining (wild-type) BRCA1 allele was detected in tumor tissues of the affected women. The results of this study have to be taken into account while providing genetic counseling to cancer patients and while considering the use of BRCA1-specific therapeutic compounds for BC treatment. PMID:26951538

  4. Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

    International Nuclear Information System (INIS)

    The TP53 polymorphisms Arg72Pro (Ex4+199 G>C) and Ins16 (IVS3+24 ins16) have been proposed to modify risk of breast cancer associated with germline BRCA1 and BRCA2 mutations. Allele frequencies of these polymorphisms were investigated to determine if they modify risk in BRCA mutation carriers in breast cancer cases drawn from French Canadian cancer families, a population shown to exhibit strong founder effects. The frequencies of the TP53 alleles, genotypes and haplotypes of 157 index breast cancer cases comprised of 42 BRCA1 mutation carriers, 57 BRCA2 mutation carriers, and 58 BRCA mutation-negative cases, where each case was drawn from independently ascertained families were compared. The effect of TP53 variants on the age of diagnosis was also investigated for these groups. The TP53 polymorphisms were also investigated in 112 women of French Canadian descent with no personal history of cancer. The BRCA mutation-positive groups had the highest frequency of homozygous carriers of the 72Pro allele compared with mutation-negative group. The TP53 polymorphisms exhibited linkage disequilibrium (p < 0.001), where the 72Arg and Ins16minus alleles occurred in strong disequilibrium. The highest frequency of carriers of Ins16minus-72Arg haplotype occurred in the BRCA mutation-negative groups. The BRCA1 mutation carriers homozygous for the 72Pro allele had the youngest ages of diagnosis of breast cancer. However none of these observations were statistically significant. In contrast, the BRCA2 mutation carriers homozygous for the 72Pro allele had a significantly older age of diagnosis of breast cancer (p = 0.018). Moreover, in this group, the mean age of diagnosis of breast cancer in carriers of the Ins16minus-72Arg haplotype was significantly younger than that of the individuals who did not this carry this haplotype (p = 0.009). We observed no significant association of breast cancer risk with TP53 genetic variants based on BRCA1/2 mutation carrier status. Although the

  5. Impact of heterozygous mutations in BRCA1 and BRCA2. Sensitivity to genotoxic drugs

    International Nuclear Information System (INIS)

    The carriers of heterozygous mutations in BRCA1 / 2 have a high risk of developing breast cancer. The loss of the normal allele with consequent loss of function is frequently observed in tumor level. Since these genes involved in the cellular response to genetic damage, loss of function can determine differences in sensitivity to genotoxic agents. In this study investigated whether heterozygous mutations in BRCA1 / 2 modify the sensitivity to genotoxic drugs using lymphoblastic cell lines developed from individuals who carry no mutation carriers and heterozygous for BRCA1 / 2. Materials and methods. Chemo sensitivity of the cell lines was compared lymphoblastoid GM13709 (mutation in exon 11 of BRCA1 2187delA), GM14622 (level 607stop mutation in exon 11 of BRCA2) and GM 14453 (normal BRCA1 / 2) from exposure to Adriamycin (0.2-2.5 mM) and Cisplatin (0.625- 80mM) through the test of cell viability based on MTT reduction. It determined the inhibitory concentration 50 (IC50) from curves regression dose-response obtained after 24 hours of drug exposure. It 5 independent experiments performed in triplicate. Results. The line GM14622 was significantly (P = 0.003) more sensitive to Adriamycin (IC50: 0.585 mM) than the Control GM14453 (IC50: 1.364 mM) online while GM13709 was similar to the control (IC50: 1.324 mM) response. Turn the line GM14622 was also significantly (P = 0.01) more sensitive cisplatin (IC50: 12.7 mM) than the line GM14453 (IC50: 28.6mm) and GM13709 had the same response as the (IC50: 28.6 mM) control. Discussion and Conclusions. Our results suggest that mutations deleterious heterozygous BRCA2 may confer increased sensitivity to drugs genotoxic, which may have implications in the management of patients carrying or BRCA2 mutations in women with sporadic breast cancer exhibit low expression of BRCA2

  6. Reliability of self-reported diagnostic radiation history in BRCA1/2 mutation carriers

    International Nuclear Information System (INIS)

    We assessed reliability of self-reported diagnostic radiation history in BRCA1/2 mutation carriers with and without breast cancer. Within the frame-work of the HEBON study, 401 BRCA1/2 mutation carriers completed a baseline (1999-2004) and a follow-up questionnaire (2006-2007). Test-retest reliability of self-reported exposure to chest X-rays, fluoroscopies and mammograms was assessed for the entire study population and by case status. Overall proportion agreement on reporting ever/never exposure was good (> 75%), while the corresponding kappa coefficients were between 0.40 and 0.75, indicating at least moderate reliability beyond chance. Reliability of number of exposures was also good (> 75%). Proportion agreement on reporting age at first mammogram was low (40%) for exact consistency and moderate (60%) for consistency ± 1 year. Reliability of age at first mammogram was higher for cases than for unaffected carriers (P < 0.001) but this difference disappeared when excluding diagnostic mammograms (P = 0.60). In unaffected carriers proportion agreement on age at last mammogram was 50%. In general, the direction of disagreement on all items was equally distributed. More consistent reporting was mainly determined by a younger age at questionnaire completion. In conclusion, inconsistent self-report of diagnostic radiation by BRCA1/2 mutation carriers was mainly non-differential by disease status.

  7. Prophylactic and Therapeutic Breast Conservation in BRCA1/2 Mutation Carriers

    International Nuclear Information System (INIS)

    Breast-conserving therapy (BCT) for sporadic breast cancer has been widely accepted by surgeons and patients alike. While BCT is associated with a higher risk of ipsilateral breast tumor recurrence (IBTR), it has not been shown to decrease overall survival (OS) in comparison with mastectomy. Many women with a BRCA1/2 mutation opt for mastectomy instead of breast-conserving measures at the time of a breast cancer diagnosis. In some cases, this is due to fear of aggressive disease, but to date, there have been no studies offering strong evidence that breast conservation should not be offered to these women. BRCA1/2-associated breast cancer has not been found to be more aggressive or resistant to treatment than comparable sporadic tumors, and no study has shown an actual survival advantage for mastectomy in appropriately treated affected mutation carriers. This paper reviews the available literature for breast conservation and surgical decision making in BRCA1/2 mutation carriers

  8. Data mining approach to predict BRCA1 gene mutation

    Directory of Open Access Journals (Sweden)

    Olegas Niakšu

    2013-09-01

    Full Text Available Breast cancer is the most frequent women cancer form and one of the leading mortality causes among women around the world. Patients with pathological mutation of a BRCA gene have 65% lifelong breast cancer probability. It is known that such patients have different cause of illness. In this study, we have proposed a new approach for the prediction of BRCA mutation carriers by methodically applying knowledge discovery steps and utilizing data mining methods. An alternative BRCA risk assessment model has been created utilizing decision tree classifier model. The biggest challenge was a very small size and imbalanced nature of the initial dataset, which have been collected by clinicians during 4 years of clinical trial. Iterative optimization of initial dataset, optimal algorithms selection and their parameterization have resulted in higher classifier model performance, with acceptable prediction accuracy for the clinical usage. In this study, three data mining problems have been analyzed using eleven data mining algorithms.

  9. Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: A systematic review.

    Science.gov (United States)

    Arts-de Jong, Marieke; de Bock, Geertruida H; van Asperen, Christi J; Mourits, Marian J E; de Hullu, Joanne A; Kets, C Marleen

    2016-07-01

    The presence of a germline BRCA1/2 mutation improves options for tailored risk-reducing strategies and treatment in both breast and ovarian cancer patients and their relatives. Currently, referral for germline BRCA1/2 mutation testing of women with epithelial ovarian cancer (EOC) varies widely, based on different criteria, such as age of onset, family history of breast and/or ovarian cancer and histological type of EOC. The overall probability of a germline BRCA1/2 mutation in women with EOC is above 10%, and a substantial part of the germline BRCA1/2 mutation carriers is missed when applying these criteria for referral. Therefore, we strongly recommend referral of all women with EOC for genetic counselling and DNA analysis. PMID:27209246

  10. [Founder mutation in Lynch syndrome].

    Science.gov (United States)

    Cajal, Andrea R; Piñero, Tamara A; Verzura, Alicia; Santino, Juan Pablo; Solano, Angela R; Kalfayan, Pablo G; Ferro, Alejandra; Vaccaro, Carlos

    2016-01-01

    Lynch syndrome is the most frequent syndrome in hereditary colorectal cancer, a family-specific deleterious mutations in genes encoding DNA reparation proteins: MLH1 (mutL homolog 1), MSH2, MSH6 (mutS homolog 2 y 6, respectively), PMS2 (PMS1 homolog 2, mismatch repair system component) y MUTYH (mutY DNA glycosylase). The c.2252_2253delAA, p.Lys751Serfs*3 mutation in MLH1 gene segregates with a haplotype reported in the northern region of Italy and whose origin was attributed to a founder effect. This mutation co-segregates with typical characteristics of Lynch syndrome, including early age at onset and multiple primary tumors in the same individual, a high frequency of pancreatic cancer, high microsatellite instability and lack of PMS2 expression. This report describes a mutation in an Argentinian patient with endometrioid adenocarcinoma of uterus. Her first-degree relatives had a history of colon cancer diagnosed before 50 years, fulfilling the Amsterdam Criteria I and Lynch syndrome II. The high pathogenicity associated to this mutation makes necessary the study of all members from families with hereditary cancer, allowing pre-symptomatic genetic diagnosis, early assessment and the instauration of preventive treatments. PMID:27295708

  11. Comparison of risk assessment models of BRCA1 and BRCA2 mutation carrier in patients with breast cancer

    Directory of Open Access Journals (Sweden)

    Rybchenko L.A.

    2013-12-01

    Full Text Available Analysis of efficiency of the algorithm BOADICEA using and Manchester scoring system to predict the carrier of BRCA1 and BRCA2 mutations in Ukranian patients with breast cancer was performed. Materials for this study were the results of clinical, imunogistological, pathogistological, genealogical, molecular genetic researches of 146 patients with breast cancer. Calculations of mutations risk were performed using BOADICEA algorithm and Manchester scoring system. In the total group of patients the area under the curve while predicting BRCA1 mutations with algorithm BOADICEA was 0.86, with Manchester scoring system - 0.84, and in calculation of the combined risk of BRCA mutations - 0.83 and 0.84, respectively. However, statistical difference between the areas of algorithms has not been established (p> 0.05, it indicates to the same discriminatory power of the test models. Better sensitivity, specificity, positive and negative predictive value of results of BOADICEA algorithm was reached in 6% of BRCA1 probability and in 8% threshold of BRCA1/2 mutations. The Manchester scoring system has showed the best operating characteristics with 6 and 13-point probability of BRCA1 and BRCA1/2 mutations respectively. Patients with probability of mutations with such thresholds may be offered molecular study of pathogenic alleles.

  12. Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families

    International Nuclear Information System (INIS)

    Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease

  13. Breast and ovarian cancer risk evaluation in families with a disease-causing mutation in BRCA1/2.

    Science.gov (United States)

    Beristain, Elena; Ibáñez, Berta; Vergara, Itziar; Martínez-Bouzas, Cristina; Guerra, Isabel; Tejada, Maria Isabel

    2010-06-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, and their identification allows genetic testing of at-risk relatives. However, estimates of these risks illustrate controversies, depending on the published series. The penetrance, the earlier onset of the disease and the effect of mutations on the risk of developing breast and ovarian cancer were evaluated in 344 females belonging to 34 families from the Basque Country in Spain, in which BRCA1 or BRCA2 mutations were transmitted. Kaplan-Meier survival curves were used to derive cumulative probability curves for breast and ovarian cancer by mutation status, birth cohort and mutation position, and significance of the differences was assessed using the log-rank test. The estimated probability for breast cancer by age 70 is about 64% in BRCA1 and 69% in BRCA2, whereas the probability of developing ovarian cancer is about 37% and 25% for BRCA1 and BRCA2, respectively. There is a marginally significant higher risk of developing ovarian cancer in BRCA1 families than in BRCA2 families. The effect of birth cohort on breast cancer cumulative incidence presents an increased risk for females born after 1966 and a decreased risk for those born before 1940. There is no association between mutation position and breast cancer; however, ovarian cancer is associated to BRCA1, presenting exon 11 as an ovarian cluster. These results are important for the breast and ovarian cancer diagnosis and prevention in at-risk families. PMID:22460208

  14. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, Anna Marie; Couch, Fergus J.; Barrowdale, Daniel; Domchek, Susan M.; Eccles, Diana; Nevanlinna, Heli; Ramus, Susan J.; Robson, Mark; Sherman, Mark; Spurdle, Amanda B.; Wappenschmidt, Barbara; Lee, Andrew; McGuffog, Lesley; Healey, Sue; Sinilnikova, Olga M.; Janavicius, Ramunas; Hansen, Thomas V. O.; Nielsen, Finn C.; Ejlertsen, Bent; Osorio, Ana; Munoz-Repeto, Ivan; Duran, Mercedes; Godino, Javier; Pertesi, Maroulio; Benitez, Javier; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Cattaneo, Elisa; Bonanni, Bernardo; Viel, Alessandra; Pasini, Barbara; Papi, Laura; Ottini, Laura; Savarese, Antonella; Bernard, Loris; Radice, Paolo; Hamann, Ute; Verheus, Martijn; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Nelen, Marcel R.; Kets, C. Marleen; Seynaeve, Caroline; Tilanus-Linthorst, Madeleine M. A.; van der Luijt, Rob B.; van Os, Theo; Rookus, Matti; Frost, Debra; Jones, J. Louise; Evans, D. Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Adlard, Julian; Davidson, Rosemarie; Cook, Jackie; Donaldson, Alan; Dorkins, Huw; Gregory, Helen; Eason, Jacqueline; Houghton, Catherine; Barwell, Julian; Side, Lucy E.; McCann, Emma; Murray, Alex; Peock, Susan; Godwin, Andrew K.; Schmutzler, Rita K.; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ruehl, Ina; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Deissler, Helmut; Gadzicki, Dorothea; Kast, Karin; Preisler-Adams, Sabine; Varon-Mateeva, Raymonda; Schoenbuchner, Ines; Fiebig, Britta; Heinritz, Wolfram; Schaefer, Dieter; Gevensleben, Heidrun; Caux-Moncoutier, Virginie; Fassy-Colcombet, Marion; Cornelis, Francois; Mazoyer, Sylvie; Leone, Melanie; Boutry-Kryza, Nadia; Hardouin, Agnes; Berthet, Pascaline; Muller, Daniele; Fricker, Jean-Pierre; Mortemousque, Isabelle; Pujol, Pascal; Coupier, Isabelle; Lebrun, Marine; Kientz, Caroline; Longy, Michel; Sevenet, Nicolas; Stoppa-Lyonnet, Dominique; Isaacs, Claudine; Caldes, Trinidad; de la Hoya, Miguel; Heikkinen, Tuomas; Aittomaki, Kristiina; Blanco, Ignacio; Lazaro, Conxi; Barkardottir, Rosa B.; Soucy, Penny; Dumont, Martine; Simard, Jacques; Montagna, Marco; Tognazzo, Silvia; D'Andrea, Emma; Fox, Stephen; Yan, Max; Rebbeck, Tim; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Ganz, Patricia A.; Tomlinson, Gail E.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Szabo, Csilla; Offit, Kenneth; Sakr, Rita; Gaudet, Mia; Bhatia, Jasmine; Kauff, Noah; Singer, Christian F.; Tea, Muy-Kheng; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Mai, Phuong L.; Greene, Mark H.; Imyanitov, Evgeny; O'Malley, Frances P.; Ozcelik, Hilmi; Glendon, Gordon; Toland, Amanda E.; Gerdes, Anne-Marie; Thomassen, Mads; Kruse, Torben A.; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Soller, Maria; Henriksson, Karin; Wachenfeldt, von Anna; Arver, Brita; Stenmark-Askmalm, Marie; Karlsson, Per; Ding, Yuan Chun; Neuhausen, Susan L.; Beattie, Mary; Pharoah, Paul D. P.; Moysich, Kirsten B.; Nathanson, Katherine L.; Karlan, Beth Y.; Gross, Jenny; John, Esther M.; Daly, Mary B.; Buys, Saundra M.; Southey, Melissa C.; Hopper, John L.; Terry, Mary Beth; Chung, Wendy; Miron, Alexander F.; Goldgar, David; Chenevix-Trench, Georgia; Easton, Douglas F.; Andrulis, Irene L.; Antoniou, Antonis C.

    2011-01-01

    Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 an

  15. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers

    International Nuclear Information System (INIS)

    The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9–32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42–1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55–2.25; P = 0.8) for BRCA2 carriers. The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers

  16. Clinical Considerations of BRCA1- and BRCA2-Mutation Carriers: A Review

    Directory of Open Access Journals (Sweden)

    O. Bougie

    2011-01-01

    Full Text Available Individuals who carry an inherited mutation in the breast cancer 1 (BRCA1 and BRCA2 genes have a significant risk of developing breast and ovarian cancer over the course of their lifetime. As a result, there are important considerations for the clinician in the counseling, followup and management of mutation carriers. This review outlines salient aspects in the approach to patients at high risk of developing breast and ovarian cancer, including criteria for genetic testing, screening guidelines, surgical prophylaxis, and chemoprevention.

  17. The CASP8 rs3834129 polymorphism and breast cancer risk in BRCA1 mutation carriers

    OpenAIRE

    2010-01-01

    Abstract The rs3834129 polymorphism, in the promoter of CASP8 gene, has been recently reported as associated with breast cancer risk in the general population, with the minor allele del having a protective effect. Some of the genetic variants found associated with breast cancer risk were reported as risk modifiers in individuals with mutations in BRCA1 and BRCA2 genes. Here, we tested the effect of the rs3834129 del allele on breast cancer risk in BRCA mutation carriers. The rs3834...

  18. Prospective study of high-risk, BRCA1/2-mutation negative women: the ‘negative study’

    OpenAIRE

    Kotsopoulos, Joanne; Metcalfe, Kelly; Alston, Jill; Nikitina, Dina; Ginsburg, Ophira; Eisen, Andrea; Demsky, Rochelle; Akbari, Mohammad; Zbuk, Kevin; Narod, Steven A.

    2014-01-01

    Background We previously reported that women from high-risk families who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation were four times more likely to develop breast cancer compared to women in the general population. Preventive measures and risk factors for breast cancer development in these high-risk women have not been evaluated to the same extent as BRCA1/2 positive women. Further, there is virtually no scientific evidence about best practices in their management and care. The pr...

  19. Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.

    Science.gov (United States)

    Lewin, R; Sulkes, A; Shochat, T; Tsoref, D; Rizel, S; Liebermann, N; Hendler, D; Neiman, V; Ben-Aharon, I; Friedman, E; Paluch-Shimon, S; Margel, D; Kedar, I; Yerushalmi, R

    2016-06-01

    Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1 % had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50 % in BRCA1 patients, and 18.4, 52.6, and 29 % in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45 months. Four BRCA patients (7 %) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naïve patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group. PMID:27225387

  20. Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

    Science.gov (United States)

    Bu, Rong; Siraj, Abdul K; Al-Obaisi, Khadija A S; Beg, Shaham; Al Hazmi, Mohsen; Ajarim, Dahish; Tulbah, Asma; Al-Dayel, Fouad; Al-Kuraya, Khawla S

    2016-09-01

    Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy. PMID:27082205

  1. Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

    Directory of Open Access Journals (Sweden)

    Hashishe Mervat M

    2010-06-01

    Full Text Available Abstract Background Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, BRCA1 and BRCA2, are considered in breast, ovarian and other common cancers etiology. BRCA1 and BRCA2 genes have been identified that confer a high degree of breast cancer risk. Objective Our study was performed to identify germline mutations in some exons of BRCA1 and BRCA2 genes for the early detection of presymptomatic breast cancer in females. Methods This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of BRCA1 and BRCA2 genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the BRCA1 gene (exons 2,8,13 and 22 and one region (exon 9 of BRCA2 gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed. Results Mutations in both BRCA1 and BRCA2 genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to BRCA1 mutations, while 26.7% of them were attributable to BRCA2 mutations. Results showed that four mutations were detected in the BRCA1 gene, while one mutation was detected in the BRCA2 gene. Asymptomatic relatives, 80(67% out of total 120, were mutation carriers. Conclusions BRCA1 and BRCA2 genes mutations are responsible for a significant proportion of breast cancer. BRCA mutations

  2. Evaluation of the Needs of Male Carriers of Mutations in BRCA1 or BRCA2 Who Have Undergone Genetic Counseling

    OpenAIRE

    Liede, Alexander; Metcalfe, Kelly; Hanna, Danielle; Hoodfar, Elizabeth; Snyder, Carrie; Durham, Carolyn; Lynch, Henry T.; Narod, Steven A.

    2000-01-01

    To date, the concerns of men at risk of inheriting a BRCA1 mutation or a BRCA2 mutation have received little attention. It had been anticipated that few men would be interested in predictive testing when a BRCA mutation was identified in their family. However, these men are often affected emotionally by diagnoses of breast cancer in their relatives and may themselves harbor fears that cancer will develop. Male carriers of BRCA1/2 mutations are at increased risk of development of cancers of se...

  3. Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Mitra, A V; Jameson, C; Barbachano, Y;

    2010-01-01

    Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic...... and benign tissues (p0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is...... against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent...

  4. First application of next-generation sequencing in Moroccan breast/ovarian cancer families and report of a novel frameshift mutation of the BRCA1 gene

    Science.gov (United States)

    Jouali, Farah; Laarabi, Fatima-Zahra; Marchoudi, Nabila; Ratbi, Ilham; Elalaoui, Siham Chafai; Rhaissi, Houria; Fekkak, Jamal; Sefiani, Abdelaziz

    2016-01-01

    At present, breast cancer is the most common type of cancer in females. The majority of cases are sporadic, but 5–10% are due to an inherited predisposition to develop breast and ovarian cancers, which are transmitted as an autosomal dominant form with incomplete penetrance. The beneficial effects of clinical genetic testing, including next generation sequencing (NGS) for BRCA1/2 mutations, is major; in particular, it benefits the care of patients and the counseling of relatives that are at risk of breast cancer, in order to reduce breast cancer mortality. BRCA genetic testing was performed in 15 patients with breast cancer and a family with positivity for the heterozygous c.6428C>A mutation of the BRCA2 gene. Informed consent was obtained from all the subjects. Genomic DNAs were extracted and the NGS for genes was performed using the Ion Torrent Personal Genome Machine (PGM) with a 316 chip. The reads were aligned with the human reference HG19 genome to elucidate variants in the BRCA1 and BRCA2 genes. Mutations detected by the PGM platform were confirmed by target direct Sanger sequencing on a second patient DNA sample. In total, 4 BRCA variants were identified in 6 families by NGS. Of these, 3 mutations had been previously reported: c.2126insA of BRCA1, and c.1310_1313delAAGA and c.7235insG of BRCA2. The fourth variant, c.3453delT in BRCA1, has, to the best of our knowledge, never been previously reported. The present study is the first to apply NGS of the BRCA1 and BRCA2 genes to a Moroccan population, prompting additional investigation into local founder mutations and variant characteristics in the region. The variants with no clear clinical significance may present a diagnostic challenge when performing targeted resequencing. These results confirm that an NGS approach based on Ampliseq libraries and PGM sequencing is a highly efficient, speedy and high-throughput mutation detection method, which may be preferable in lower income countries.

  5. Prevalence and impact of founder mutations in hereditary breast cancer in Latin America

    Directory of Open Access Journals (Sweden)

    Patricia Ashton-Prolla

    2014-01-01

    Full Text Available Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the influx of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53.

  6. Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

    Science.gov (United States)

    Evans, D G; Lalloo, F; Howell, S; Verhoef, S; Woodward, E R; Howell, A

    2016-02-01

    The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates. PMID:26888723

  7. Relationship Between Mutations In BRCA1 And BRCA2 Genes And Breast Cancer Prevalence Among Egyptian Women

    International Nuclear Information System (INIS)

    Breast cancer represents the most common cancer of women in the world and it is a biologically heterogeneous disease influenced by complex interactions between multiple genetic and environmental risk factors. In Egypt, breast cancer is classified as the first rank cancer case among women. The present study included 55 patients with breast cancer from Upper Egypt of which 40 patients had sporadic and 15 had familial breast cancers. Mutations in DNA of exons 10 and 11 of BRCA1 and BRCA2 were detected by single strand conformation polymorphisms (SSCPs) and sequencing. Moreover, BRCA1 protein expression was detected by immunostaining technique and correlation between risk factors and incidence rate of breast cancer. The results revealed 5 mutations (unclassified variants); three mutations (60%) were recorded internationally in Breast Information Cancer (BIC), one of them was 1767 C→T(550 Asn→His) and previously recorded in the Arabic world and the other 2 novel mutations were 1663 T→ C(479 Asp→Gly) and del AG 6079. The results obtained in the present study also demonstrated that the increase of the negative immunostaining of ''BRCA1'' protein in the tumour cells of BRCA1 mutation carriers was comparable to familial and sporadic breast cancer non-carrier. Accurate estimation of the relative frequency of BRCA1 and BRCA2 mutations in Egyptian breast cancer patients could not be deduced from the results of this relatively small pilot study. More studies with larger numbers of patients are needed to clarify the relation between BRCA1 and BRCA2 gene mutations and the prediction of breast cancer in Egypt.

  8. The Quality of Genetic Counseling and Connected Factors as Evaluated by Male BRCA1/2 Mutation Carriers in Finland.

    Science.gov (United States)

    Kajula, Outi; Kääriäinen, Maria; Moilanen, Jukka S; Kyngäs, Helvi

    2016-06-01

    There is little written about the quality of genetic counseling for men with the BRCA1/2 mutation. The purpose of this study was to describe the quality of genetic counseling and connected factors according to Finnish male BRCA1/2 mutation carriers' (n = 35) perspectives and reasons for seeking genetic counseling. Data were collected from the Departments of Clinical Genetics at five Finnish university hospitals. The exploratory study design was conducted using a 51-item questionnaire based on a previously devised quality of counseling model and analyzed using non-parametric tests and principle content analysis. The satisfaction level with genetic counseling was high, especially with regard to the content of genetic counseling. The benefit of genetic counseling on the quality of life differed significantly (p education, affected the perceived quality of genetic counseling. The results of the study could be used to tailor genetic counseling for male BRCA1/2 mutation carriers. PMID:26416184

  9. Genetic Variation at 9p22.2 and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility....

  10. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ramus, Susan J; Kartsonaki, Christiana; Gayther, Simon A;

    2011-01-01

    Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-w...

  11. Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B;

    2015-01-01

    BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In ...

  12. Characteristics of BRCA1/2 Mutation-Positive Breast Cancers in Korea: A Comparison Study Based on Multicenter Data and the Korean Breast Cancer Registry

    OpenAIRE

    Yu, Jong-Han; Lee, Jong Won; Son, Byung Ho; Kim, Sung-Won; Park, Sue K.; Lee, Min Hyuk; Kim, Lee Su; Noh, Woo-Chul; Kim, Eun-Kyu; Yoon, Dae Sung; Lee, Jeeyeon; Jung, Jin Hyang; Jung, Sang Seol; Gong, Gyungyup; Ahn, Sei-Hyun

    2014-01-01

    Purpose Mutations in BRCA genes are the main cause of hereditary breast cancer in Korea. The aim of this study was to investigate the characteristics of breast cancers involving BRCA1 (BRCA1 group) and BRCA2 (BRCA2 group) mutations. Methods We retrospectively reviewed the medical records of patients with BRCA1 (BRCA1 group) or BRCA2 (BRCA2 group) mutation positive breast cancer from multiple centers and compared the data to that of the Korean Breast Cancer Society registry (registry group). R...

  13. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    International Nuclear Information System (INIS)

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  14. A Study on BRCA1/2 Mutations, Hormone Status and HER-2 Status in Korean Women with Early-onset Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Doo Ho; Jin, So Young; Lee, Dong Wha; Kim, Eun Seog; Kim, Yong Ho [Soonchunhyang University College of Medicine, Seoul (Korea, Republic of)

    2008-03-15

    Women with breast cancer diagnosed at an age of 40 years or younger have a greater prevalence of germline BRCA1 and BRCA2 mutations than the prevalence of women with breast cancer diagnosed at older ages. Several immunohistochemical characteristics have been identified in breast cancers from studies of Caucasian women with BRCA1/2 mutations having familial or early-onset breast cancers. The aim of this study is to determine whether early-onset breast cancer in BRCA1 or BRCA2 mutation carriers, who were not selected from a family history, could be distinguished by the use of immunohistochemical methods and could be distinguished from breast cancer in women of a similar age without a germline BRCA1 or BRCA2 mutation. We also analyzed the prognostic difference between BRCA1/2 related and BRCA1/2 non-related patients by the use of univariate and multivariate analysis. Breast cancer tissue specimens from Korean women with early-onset breast cancers were studied using a tumor tissue microarray. Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR) and HER-2, as well as the histology and grade of these specimens, were compared. The prognostic impact of immunohistochemical and histological factors as well as the BRCA1/2 mutation status was investigated separately. There were 14 cases and 16 deleterious BRCA1/2 mutations among 101 patients tested. A family history (4/14) and bilateral breast cancers (3/9) were high risk factors for BRCA1/2 mutations. BRCA1/2- associated cancers demonstrated more expression of ER-negative (19.4% versus 5.1%, p=0.038) and HER-2 negative than BRCA1/2 negative tumors, especially for tumors with BRCA1 tumors The BRCA1/2 mutation rate for patients with triple negative tumors (negative expression of ER, PR and HER-2) was 24.2%. Tumor size, nodal status, and HER-2 expression status were significantly associated with disease free survival, as determined by univariate and multivariate analysis, but the BRCA1/2 status was

  15. A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    Science.gov (United States)

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Shimon–Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E.J.; Oosterwijk, Jan C.; van Asperen, Christi J.; García, Encarna B. Gómez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnès; Berthet, Pascaline; Dreyfus, Hélène; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnès; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M; Southey, Melissa; Goldgar, David; Singer, Christian F; Maria, Muy-Kheng Tea; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas v. O.; Ejlertsen, Bent; Johannsson, Oskar Th.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C; Neuhausen, Susan L.

    2012-01-01

    Background We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03). Conclusion The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers. Impact These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. PMID:22729394

  16. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    International Nuclear Information System (INIS)

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  17. First description of an acinic cell carcinoma of the breast in a BRCA1 mutation carrier: a case report

    International Nuclear Information System (INIS)

    Acinic cell carcinoma (ACC) is a rare malignant epithelial neoplasm characterized by the presence of malignant tubular acinar exocrine gland structures. Diagnosis is generally made in salivary glands and in the pancreas. ACC of the breast has been reported in few cases only. Carriers of inherited mutations in the BRCA1 gene are prone to the development of breast cancer, mainly invasive ductal or medullary type carcinomas. We describe for the first time a BRCA1 mutation carrier with a diagnosis of ACC of the breast. The patient developed an invasive ductal carcinoma (IDC) at the age of 40 years and an ACC in the contralateral breast at 44 years. Immunohistochemical examination of the ACC revealed a triple negative status (i.e., negativity for estrogen receptor, progesterone receptor and HER2 protein) and positivity for p53. Using a combination of loss of heterozygosity (LOH) and sequencing analyses, the loss of the wild-type BRCA1 allele was detected in both the ACC and the IDC. In addition, two different somatic TP53 mutations, one in the ACC only and another one in the IDC only, were observed. Both the immunohistochemical and molecular features observed in the ACC are typical of BRCA1-associated breast cancers and suggest an involvement of the patient’s germline mutation in the disease. The occurrence of rare histological types of breast cancers, including malignant phyllodes tumor, atypical medullary carcinoma and metaplastic carcinoma, in BRCA1 mutation carriers has been already reported. Our findings further broaden the spectrum of BRCA1-associated breast malignancies

  18. Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Candido-dos-Reis, Francisco J; Song, Honglin; Goode, Ellen L; Cunningham, Julie M; Fridley, Brooke L; Larson, Melissa C; Alsop, Kathryn; Dicks, Ed; Harrington, Patricia; Ramus, Susan J; de Fazio, Anna; Mitchell, Gillian; Fereday, Sian; Bolton, Kelly L; Gourley, Charlie; Michie, Caroline; Karlan, Beth; Lester, Jenny; Walsh, Christine; Cass, Ilana; Olsson, Håkan; Gore, Martin; Benitez, Javier J; Garcia, Maria J; Andrulis, Irene; Mulligan, Anna Marie; Glendon, Gord; Blanco, Ignacio; Lazaro, Conxi; Whittemore, Alice S; McGuire, Valerie; Sieh, Weiva; Montagna, Marco; Alducci, Elisa; Sadetzki, Siegal; Chetrit, Angela; Kwong, Ava; Kjaer, Susanne K; Jensen, Allan; Høgdall, Estrid; Neuhausen, Susan; Nussbaum, Robert; Daly, Mary; Greene, Mark H; Mai, Phuong L; Loud, Jennifer T; Moysich, Kirsten; Toland, Amanda E; Lambrechts, Diether; Ellis, Steve; Frost, Debra; Brenton, James D; Tischkowitz, Marc; Easton, Douglas F; Antoniou, Antonis; Chenevix-Trench, Georgia; Gayther, Simon A; Bowtell, David; Pharoah, Paul D P

    2015-01-01

    PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4......,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using...... Fine and Gray model. RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming...

  19. Age and Geographical Distribution in Families with BRCA1/BRCA2 Mutations in the Slovak Republic

    Directory of Open Access Journals (Sweden)

    Ciernikova Sona

    2006-12-01

    Full Text Available Abstract Molecular diagnostics of hereditary breast and/or ovarian cancer is mainly based on detection of BRCA1 and BRCA2 germline mutations in suspected families. The aim of the study was to determine the frequency, age and geographical distribution in 130 Slovak hereditary breast and ovarian cancer (HBOC families diagnosed within the years 2000-2004. Mutation screening was performed by single-strand conformation polymorphism (SSCP, heteroduplex analysis (HDA and sequencing of PCR products showing an abnormal migration pattern. Twenty of 130 (15.6% HBOC suspected families were found to carry mutations in BRCA1 or BRCA2 genes. The glossary data from the National Cancer Registry of Slovakia (NCRS were compared with the results from HBOC suspected kindreds. Age distribution of breast cancer onset in our study group showed the highest proportion of onset in HBC families within the 5th decade of life, while NCRS reports at least a ten year later onset. These findings confirmed that cases of breast cancer under 50 years of age can be used as one of the principal criteria to assign a family as a hereditary breast and/or ovarian cancer kindred. In contrast with unselected ovarian cancer cases, about 75% of all HOC index cases were diagnosed between 40 and 49 years of age. To study the geographical distribution of hereditary breast and/or ovarian cancer, Slovakia was divided into three parts. The distribution of HBOC suspected families approximately follows this division, with an increasing number in the western area of the country.

  20. BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

    International Nuclear Information System (INIS)

    Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from BRCA1-mutation carriers. The genomic instability of BRCA1-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and BRCA1-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs. There are several known molecular features characteristic for BRCA1-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of TP53 mutations and 4) a high incidence of complex, protein-truncating TP53 mutations. We compared the frequency of TP53 mutations and the pattern and amount of genomic aberrations between BRCA1-mutated breast tumors, BLBCs and luminal breast tumors by TP53 gene sequencing and array-based comparative genomics hybridization (aCGH) analysis. We found that the high incidence of protein truncating TP53 mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors. Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with

  1. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : a national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R; Hooning, Maartje J; Oosterwijk, Jan C; Koppert, Linetta B; de Bock, Geertruida H; Ausems, Margreet G; van Asperen, Christi J; Aalfs, Cora M; Gómez Garcia, Encarna B; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screen

  2. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years : A national cohort study

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Vos, Janet R.; Hooning, Maartje J.; Oosterwijk, Jan C.; Koppert, Linetta B.; de Bock, Geertruida H.; Ausems, Margreet G.; van Asperen, Christi J.; Aalfs, Cora M.; Garcia, Encarna B. Gomez; Meijers-Heijboer, Hanne; Hoogerbrugge, Nicoline; Piek, Marianne; Seynaeve, Caroline; Verhoef, Cornelis; Rookus, Matti; Tilanus-Linthorst, Madeleine M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >= 60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom scre

  3. Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study

    NARCIS (Netherlands)

    Saadatmand, S.; Vos, J.R.; Hooning, M.J.; Oosterwijk, J.C.; Koppert, L.B.; Bock, G.H. de; Ausems, M.G.; Asperen, C.J. van; Aalfs, C.M.; Garcia, E.B.; Meijers-Heijboer, H.; Hoogerbrugge, N.; Piek, M.; Seynaeve, C.; Verhoef, C.; Rookus, M.; Tilanus-Linthorst, M.M.

    2014-01-01

    Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised >/=60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom s

  4. Recommendations for prevention in carriers of BRCA1 and BRCA2 mutations

    International Nuclear Information System (INIS)

    It is estimated that 5% -10% of all breast cancers in women are developed in the context of inherited susceptibility of dominant autosomal, where the BRCA1 and BRCA2 are the main known associated genes. The inheritance of a mutated allele of some of these genes confers a risk extremely high in the breast cancer. In fact, while in the general population in countries with high incidence of breast cancer such as Uruguay, the cumulative risk of developing the disease is around 10% -12%, in the carriers of a germ line mutation in BRCA1 / 2 such risk can reach 85%. Furthermore, they present an increased risk of developing other tumors, including ovarian cancer. The recommendations for monitoring / screening are based on expert opinion. In relation to breast cancer, the emphasis is on the early onset controls than the general population, which is based on the younger age presentation of the disease in genetically predisposed women. Recommendations for ovarian cancer consists of trans vaginal ultrasound and determination of serum levels of CA125 from 30-35 years. The suboptimal results obtained with the conventional monitoring methods emphasize the importance of incorporating more useful procedures. In these sense preliminary results show that mammary magnetic resonance imaging has higher sensitivity. Moreover, proteomics allowed development of promising techniques to improve the early diagnosis of ovarian cancer. Primary prevention options include mastectomy and prophylactic oophorectomy and chemo prevention. Difficulties in early detection of ovarian cancer and its high mortality justify consider prophylactic oophorectomy as a management option from 35 years and once completed the family. In the case of breast cancer, if while prophylactic mastectomy has proven very effective, is unacceptable for most patients. Monitoring to detect early and chemo prevention are important alternatives. In all cases, the management should be individualized based on the level of risk and

  5. Prevalence of BRCA1 and BRCA2 Germline Mutations in Breast Cancer Women of Multiple Ethnic Region in Northwest China

    NARCIS (Netherlands)

    Ou, Jianghua; Wu, Tao; Sijmons, Rolf; Ni, Duo; Xu, Wenting; Upur, Halmurat

    2013-01-01

    Purpose: The aim of this study is to further understand the status of BRCA1 and BRCA2 mutation among Chinese high-risk breast cancer patients in multiple-ethnic regions of China. Methods: A total of 79 blood samples of high-risk breast cancer patients from Xinjiang Uyghur autonomous region were anal

  6. Low incidence of germline mutation in BRCA1 Exon 11 among early-onset and familial Filipino breast cancer patients

    International Nuclear Information System (INIS)

    Breast cancer susceptibility gene, type 1 (BRCA1) has been thought to be responsible for about 45% of families with multiple breast carcinoma cases and for more than 80% of hereditary breast and ovarian cancer (HBOC) families. About 61-75% of the reported distinct alterations that result in truncated protein products have been found in exon 11 which comprises 61% (3427bp) of the coding sequence of BRCA1(5592bp). Protein truncation test (PTT) has become a popular method as an efficient means of screening mutations in a coding sequence that lead to a truncated protein product. In this study, 34 early-onset and/or familial breast cancer (FBC) patients were investigated. Twenty-six patients are early-onset B(o)C cases (diagnosed≤40 years old), 14 of which have familiality of the disease. Among the 8 patients that have been diagnosed above 40 years old, 7 have familial clustering. Through radioactive PTT analysis of the 34 BC cases in a 5-20% denaturing gradient polyacrylamide gel, we found only one mutation in exon 11 having a 29.7 kDa truncated protein product. Our results corroborate the findings of a recently reported study of unselected incident breast cancer cases in the Philippines where the prevalence of BRCA1 mutation is also low. This would, however, be the second documented mutation in BRCA1 exon 11 in a Filipino BC patient since 1998. (author)

  7. PGD for hereditary breast and ovarian cancer : the route to universal tests for BRCA1 and BRCA2 mutation carriers

    NARCIS (Netherlands)

    Drusedau, Marion; Dreesen, Jos C.; Derks-Smeets, Inge; Coonen, Edith; van Golde, Ron; van Echten-Arends, Jannie; Kastrop, Peter M. M.; Blok, Marinus J.; Gomez-Garcia, Encarna; Geraedts, Joep P.; Smeets, Hubert J.; de Die-Smulders, Christine E.; Paulussen, Aimee D.

    2013-01-01

    Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in

  8. Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC)

    NARCIS (Netherlands)

    Saadatmand, Sepideh; Obdeijn, Inge-Marie; Rutgers, Emiel J.; Oosterwijk, Jan C.; Tollenaar, Rob A.; Woldringh, Gwendolyn H.; Bergers, Elisabeth; Verhoef, Cornelis; Heijnsdijk, Eveline A.; Hooning, Maartje J.; de Koning, Harry J.; Tilanus-Linthorst, Madeleine M.

    2015-01-01

    Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1

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

    NARCIS (Netherlands)

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

    2012-01-01

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

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  11. Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations

    Science.gov (United States)

    Phillips, Kelly-Anne; Collins, Ian M.; Milne, Roger L.; McLachlan, Sue Anne; Friedlander, Michael; Hickey, Martha; Stern, Catharyn; Hopper, John L.; Fisher, Richard; Kannemeyer, Gordon; Picken, Sandra; Smith, Charmaine D.; Kelsey, Thomas W.; Anderson, Richard A.

    2016-01-01

    STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest. PMID:27094481

  12. Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families

    DEFF Research Database (Denmark)

    Gerdes, Anne-Marie; Cruger, D G; Thomassen, M; Kruse, T A

    2006-01-01

    To meet the increasing demand for BRCA1 and BRCA2 mutation analysis, a robust system for selecting families who have a higher chance of a mutation has become important. Several models have been developed to help predict which samples are more likely to be mutation positive than others. We have...... undertaken a complete BRCA1 and BRCA2 mutation analysis in 267 Danish families with high-risk family history. We found deleterious mutations in 28% (76) of the families, 68% (52) of those in BRCA1 and 32% (24) in BRCA2. We compared our results with two popular manual models developed to estimate the chance...

  13. Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers

    International Nuclear Information System (INIS)

    The MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1. Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology™ was used to determine the genotype at the MDM2 SNP309 locus. The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80). We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1

  14. Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers

    Directory of Open Access Journals (Sweden)

    Johnson Peter W

    2006-03-01

    Full Text Available Abstract Background The MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP in the MDM2 promoter (a T to G exchange at nucleotide 309 has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1. Methods Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology™ was used to determine the genotype at the MDM2 SNP309 locus. Results The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6% and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G. Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T individuals (72.7% vs. 75.6%, p = 1.00. Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80. Conclusion We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.

  15. Is there a correlation between the structure of hair and breast cancer or BRCA1/2 mutations?

    Science.gov (United States)

    Laaziri, Khalid; Sutton, M.; Ghadirian, P.; Scott, A. S.; Paradis, A.-J.; Tonin, P. N.; Foulkes, W. D.

    2002-05-01

    It has been suggested that the small angle x-ray scattering (SAXS) pattern of human hair can be used to diagnose breast cancer and possibly to identify BRCA1/2 mutation carriers, who are at significantly elevated risk for developing breast cancer. In particular, the presence of a diffuse ring in the SAXS pattern was said to be diagnostic of either breast cancer or an increased risk thereof. To test this hypothesis, we measured SAXS from the pubic hair of 56 subjects with known BRCA1/2 and breast cancer status. We found that there is no clear association between the pattern of SAXS seen in human pubic hair and the risk of breast cancer or the presence of BRCA1/2 mutations. The possible use of SAXS to diagnose cancer remains conjectural, but this and previous studies do not suggest that SAXS can be used as a reliable method of identifying either BRCA1/2 mutation carriers or women who have had breast cancer.

  16. Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations

    OpenAIRE

    Manchanda, R.; Burnell, M.; Loggenberg, K.; Desai, R.; Wardle, J.; Sanderson, S.C.; Gessler, S.; Side, L.; Balogun, N.; Kumar, A.(State University of New York at Buffalo, Buffalo, USA); Dorkins, H.; Wallis, Y; Chapman, C; Tomlinson, I; Taylor, R.

    2016-01-01

    BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier....

  17. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    DEFF Research Database (Denmark)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan;

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 ...

  18. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

    DEFF Research Database (Denmark)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel;

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between ...

  19. Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial

    OpenAIRE

    Manchanda, R.; Loggenberg, K.; Sanderson, S.; Burnell, M.; Wardle, J; Gessler, S.; Side, L.; Balogun, N.; Desai, R; Kumar, A.; Dorkins, H.; Wallis, Y; Chapman, C; Taylor, R.; Jacobs, C.

    2015-01-01

    Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population ...

  20. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation

    Indian Academy of Sciences (India)

    Kannan Vaidyanathan; Smita Lakhotia; H M Ravishankar; Umaira Tabassum; Geetashree Mukherjee; Kumaravel Somasundaram

    2009-09-01

    Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 genes. In addition, while BRCA1 mutations were found in all age groups, BRCA2 mutations were found only in the age group of ≤ 40 years. Of the BRCA1 mutations, there were three novel mutations (295delCA; 4213T → A; 5267T → G) and three mutations that have been reported earlier. Interestingly, 185delAG, a BRCA1 mutation which occurs at a very high frequency in Ashkenazi Jews, was found at a frequency of 16.4% (10/61). There was one novel mutation (4866insT) and one reported mutation in BRCA2. Thus, our study emphasizes the importance of mutation screening in familial breast and/or ovarian cancers, and the potential implications of these findings in genetic counselling and preventive therapy.

  1. On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

    DEFF Research Database (Denmark)

    Hamel, Nancy; Feng, Bing-Jian; Foretova, Lenka;

    2011-01-01

    The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245.......5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.European Journal of Human...

  2. On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations

    DEFF Research Database (Denmark)

    Hamel, Nancy; Feng, Bing-Jian; Foretova, Lenka;

    2011-01-01

    The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245.......5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice....

  3. Novel mutations in the BRCA1 and BRCA2 genes in Iranian women with early-onset breast cancer

    International Nuclear Information System (INIS)

    Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. So far, germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population. With the collaboration of two main centres for cancer in Iran, we obtained clinical information, family history and peripheral blood from 83 women under the age of 45 with early-onset breast cancer for scanning of germline mutations in the BRCA1 and BRCA2 genes. We analysed BRCA1 exons 11 and BRCA2 exons 10 and 11 by the protein truncation test, and BRCA1 exons 2, 3, 5, 13 and 20 and BRCA2 exons 9, 17, 18 and 23 with the single-strand conformation polymorphism assay on genomic DNA amplified by polymerase chain reaction. Ten sequence variants were identified: five frameshifts (putative mutations – four novel); three missense changes of unknown significance and two polymorphisms, one seen commonly in both Iranian and British populations. Identification of these novel mutations suggests that any given population should develop a mutation database for its programme of breast cancer screening. The pattern of mutations seen in the BRCA genes seems not to differ from other populations studied. Early-onset breast cancer (less than 45 years) and a limited family history is sufficient to justify mutation screening with a detection rate of over 25% in this group, whereas sporadic early-onset breast cancer (detection rate less than 5%) is unlikely to be cost-effective

  4. Use of Gene Expression Profiles of Peripheral Blood Lymphocytes to Distinguish BRCA1 Mutation Carriers in High Risk Breast Cancer Families

    Directory of Open Access Journals (Sweden)

    Marie-Laure Vuillaume

    2009-01-01

    Full Text Available Mutations in two major genes, BRCA1 and BRCA2, account for up to 30% of families with hereditary breast cancer. Unfortunately, in most families there is little to indicate which gene should be targeted first for mutation screening, which is labor intensive, time consuming and often prohibitively expensive. As BRCA1 is a tumor suppressor gene involved in various cellular processes, heterozygous mutations could deregulate dependent pathways, such as DNA damage response, and disturb transcriptional activity of genes involved in the downstream signaling cascade. We investigated gene expression profiling in peripheral blood lymphocytes to evaluate this strategy for distinguishing BRCA1 mutation carriers from non-carriers. RNA from whole blood samples of 15 BRCA1 mutation carriers and 15 non-carriers from BRCA1 or BRCA2 families were hybridized to Agilent Technologies Whole Human Genome OligoMicroarrays (4 × 44 K multiplex format containing 41,000 unique human genes and transcripts. Gene expression data were analyzed with Welch’s t-tests and submitted to hierarchical clustering (GeneSpring GX software, Agilent Technologies. Statistical analysis revealed a slight tendency for 133 genes to be differentially expressed between BRCA1 mutation carriers and non-carriers. However, hierarchical clustering of these genes did not accurately discriminate BRCA1 mutation carriers from non-carriers. Expression variation for these genes according to BRCA1 mutation status was weak. In summary, microarray profiling of untreated whole blood does not appear to be informative in identifying breast cancer risk due to BRCA1 mutation.

  5. Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer

    Directory of Open Access Journals (Sweden)

    Kast Karin

    2012-11-01

    Full Text Available Abstract Background Hereditary Breast and Ovarian Cancer Syndrome (HBOCS and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR genes MLH1, MSH2, MSH6 or PMS2 are very rare. Case presentation We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Conclusions Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.

  6. BRCA1 185delAG MUTATION CAN BE EASILY DETECTED BY AN ADAPTED ALLELE-SPECIFIC PCR

    Directory of Open Access Journals (Sweden)

    Anca Negura

    2012-03-01

    Full Text Available BRCA1 gene accounts for a majority of hereditary breast and ovarian cancers. Germinal deleteriousmutations within this gene are directly responsible for the disease, with a lifetime risk of cancer for mutations carriers ofabout 80%. While outbred and western populations usually show a heterogeneous profile of unique and familialmutations, in isolated and eastern European populations some recurrent mutations can be afforded the most responsibilityfor familial hereditary cases. In Ashkenazi Jewish and most Slavic eastern population, the BRCA1 185delAG is one of themost frequent mutations. Therefore, rapid screening by PCR-based methods can be useful in oncogenetic diagnosis. Herewe present implementation of an adapted allele-specific PCR for the detection of 185delAG, with wide applications indiagnosis and genotyping for large population groups.

  7. Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer

    International Nuclear Information System (INIS)

    Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare. We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes

  8. Detection of BRCA1 and BRCA2 gene mutation in Egyptian females with breast cancer and their relatives by PCR-SSCP method.

    Science.gov (United States)

    Fattouh, Mona; Ahmed, Hydi; Hafez, Elsayed El-Sayed

    2011-01-01

    Germline mutations in the BRCA1 or BRCA2 genes predispose their carriers to breast or/and ovarian cancers during their lifetime. This study was performed to identify germline mutations in BRCA1 and BRCA2 genes for the early detection of pre-symptomatic mutation carriers in Egyptian healthy females who were first-degree relatives of affected women from families with and without family history of breast cancer. Sixty-two patients (index cases) with invasive breast cancer belonging to sixty families and their asymptomatic female first-degree relatives (300 cases) were studied for germline mutations of BRCA1 and BRCA2 genes. Five mutations were detected in 52 families (86.7%) with inherited mutations in either BRCA1 or BRCA2. Sixty percent of these families had BRCA1 mutation and 26.7% had BRCA2 mutations. They were identified by using the combination of SSCP and heteroduplex analysis. All but one of the mutations were detected within the BRCA1 gene in addition to one mutation in the BRCA2 gene. PMID:23082475

  9. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Wang, Xianshu; Fredericksen, Zachary S;

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagn...

  10. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Wang, Xianshu; Fredericksen, Zachary S.; McGuffog, Lesley; Tarrell, Robert; Sinilnikova, Olga M.; Healey, Sue; Morrison, Jonathan; Kartsonaki, Christiana; Lesnick, Timothy; Ghoussaini, Maya; Barrowdale, Daniel; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Eccles, Diana; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Chu, Carol; Douglas, Fiona; Paterson, Joan; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Mazoyer, Sylvie; Giraud, Sophie; Lasset, Christine; Remenieras, Audrey; Caron, Olivier; Hardouin, Agnes; Berthet, Pascaline; Hogervorst, Frans B. L.; Rookus, Matti A.; Jager, Agnes; van den Ouweland, Ans; Hoogerbrugge, Nicoline; van der Luijt, Rob B.; Meijers-Heijboer, Hanne; Garcia, Encarna B. Gomez; Devilee, Peter; Vreeswijk, Maaike P. G.; Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Gorski, Bohdan; Cybulski, Cezary; Spurdle, Amanda B.; Holland, Helene; Goldgar, David E.; John, Esther M.; Hopper, John L.; Southey, Melissa; Buys, Saundra S.; Daly, Mary B.; Terry, Mary-Beth; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Preisler-Adams, Sabine; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy; Blum, Joanne L.; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Blank, Stephanie V.; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Kirchhoff, Tomas; Vijai, Joseph; Gaudet, Mia M.; Altshuler, David; Guiducci, Candace; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Ehrencrona, Hans; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Viel, Alessandra; Radice, Paolo; Caldes, Trinidad; de la Hoya, Miguel; Singer, Christian F.; Fink-Retter, Anneliese; Greene, Mark H.; Mai, Phuong L.; Loud, Jennifer T.; Guidugli, Lucia; Lindor, Noralane M.; Hansen, Thomas V. O.; Nielsen, Finn C.; Blanco, Ignacio; Lazaro, Conxi; Garber, Judy; Ramus, Susan J.; Gayther, Simon A.; Phelan, Catherine; Narod, Stephen; Szabo, Csilla I.; Benitez, Javier; Osorio, Ana; Nevanlinna, Heli; Heikkinen, Tuomas; Caligo, Maria A.; Beattie, Mary S.; Hamann, Ute; Godwin, Andrew K.; Montagna, Marco; Casella, Cinzia; Neuhausen, Susan L.; Karlan, Beth Y.; Tung, Nadine; Toland, Amanda E.; Weitzel, Jeffrey; Olopade, Olofunmilayo; Simard, Jacques; Soucy, Penny; Rubinstein, Wendy S.; Arason, Adalgeir; Rennert, Gad; Martin, Nicholas G.; Montgomery, Grant W.; Chang-Claude, Jenny; Flesch-Janys, Dieter; Brauch, Hiltrud; Severi, Gianluca; Baglietto, Laura; Cox, Angela; Cross, Simon S.; Miron, Penelope; Gerty, Sue M.; Tapper, William; Yannoukakos, Drakoulis; Fountzilas, George; Fasching, Peter A.; Beckmann, Matthias W.; Silva, Isabel dos Santos; Peto, Julian; Lambrechts, Diether; Paridaens, Robert; Ruediger, Thomas; Foersti, Asta; Winqvist, Robert; Pylkaes, Katri; Diasio, Robert B.; Lee, Adam M.; Eckel-Passow, Jeanette; Vachon, Celine; Blows, Fiona; Driver, Kristy; Dunning, Alison; Pharoah, Paul P. D.; Offit, Kenneth; Pankratz, V. Shane; Hakonarson, Hakon; Chenevix-Trench, Georgia; Easton, Douglas F.; Couch, Fergus J.

    2010-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosi

  11. Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

    Directory of Open Access Journals (Sweden)

    Metcalfe Kelly A

    2005-04-01

    Full Text Available Abstract Purpose To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups. Results Women with prior bilateral oophorectomy presented with smaller tumours on average compared to women without prior oophorectomy (mean size 1.50 cm vs. 1.95 cm; p = 0.01. Additionally, although not statistically significant, women with intact ovaries were more likely to have high-grade tumour (70% vs. 54%: p = 0.10 and to have positive lymph nodes (34% vs. 18%; p = 0.11 compared to women with prior bilateral oophorectomy. Conclusions Bilateral oophorectomy prior to breast cancer appears to favourably influence the biological presentation of breast cancer in BRCA1 and BRCA2 mutation carriers.

  12. [Gynecological Care and Prevention of Gynecological Malignancies in BRCA1 and BRCA2 Mutation Carriers].

    Science.gov (United States)

    Zikán, M

    2016-01-01

    This paper summarizes the current knowledge of gynecological care aspects in women with inherited predisposition to breast and ovarian cancer, i.e. BRCA1 and BRCA2 mutation carriers, and proposes guidelines for furher management of these women, addressing follow-up recommendations, prophylactic surgery indications and preimplantation genetic conseling. It evaluates cancer risk and severity of ovarian cancer in particular with regards to its high mortality resulting from aggressive biological behavior of the tumor and late detection rates. BRCA-positive women should be enrolled in prevention programs including carefull surveillance, prophylactic surgery or pre-implantation genetic counseling. Follow-up care consists of gynecological examination, expert oncogynecological ultrasound and tumor marker CA125 examination every six months. However, the most effective strategy for mortality reduction in ovarian cancer is prophylactic surgery--salpingo-oophorectomy (and hysterectomy). The optimal age for surgery is between 35 to 40 years. Prophylactic salpingo-oophorectomy performed in premenopausal women was proved to reduce the risk of ovarian as well as breast cancer. Symptoms of estrogen deficiency after prophylactic surgery can be suppressed by administration of hormone replacement therapy without increasing the risk of breast cancer. Preimplantation genetic diagnosis is an effective way to prevent the trans--mission of hereditary predisposition to the next generation. The management of patients with hereditary suspceptibility to ovarian cancer should be confined to specialized centres. PMID:26691939

  13. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    Energy Technology Data Exchange (ETDEWEB)

    Veltman, J.; Mann, R.; Blickman, J.G.; Boetes, C. [University Medical Center, 430 Department of Radiology, P.O. Box 9101, Nijmegen (Netherlands); Kok, T. [University Medical Center, Department of Radiology, Groningen (Netherlands); Obdeijn, I.M. [Erasmus Medical Center Daniel den Hoed Cancer Center, Department of Radiology, Rotterdam (Netherlands); Hoogerbrugge, N. [University Medical Center, Department of Human Genetics, Nijmegen (Netherlands)

    2008-05-15

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control group of 29 sporadic breast cancer cases. Detection rates on both modalities were evaluated. Tumors were analyzed on morphology, density (mammography), enhancement pattern and kinetics (MRI). Overall detection was significantly better with MRI than with mammography (55/58 vs 44/57, P = 0.021). On mammography, lesions in the BRCA-MC group were significantly more described as rounded (12//19 vs 3/13, P = 0.036) and with sharp margins (9/19 vs 1/13, P = 0.024). On MRI lesions in the BRCA-MC group were significantly more described as rounded (16/27 vs 7/28, P = 0.010), with sharp margins (20/27 vs 7/28, P < 0.001) and with rim enhancement (7/27 vs 1/28, P = 0.025). No significant difference was found for enhancement kinetics (P = 0.667). Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions, like a rounded shape or sharp margins. This applies for both mammography and MRI. However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy. (orig.)

  14. Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

    International Nuclear Information System (INIS)

    The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control group of 29 sporadic breast cancer cases. Detection rates on both modalities were evaluated. Tumors were analyzed on morphology, density (mammography), enhancement pattern and kinetics (MRI). Overall detection was significantly better with MRI than with mammography (55/58 vs 44/57, P = 0.021). On mammography, lesions in the BRCA-MC group were significantly more described as rounded (12//19 vs 3/13, P = 0.036) and with sharp margins (9/19 vs 1/13, P 0.024). On MRI lesions in the BRCA-MC group were significantly more described as rounded (16/27 vs 7/28, P = 0.010), with sharp margins (20/27 vs 7/28, P < 0.001) and with rim enhancement (7/27 vs 1/28, P = 0.025). No significant difference was found for enhancement kinetics (P = 0.667). Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions, like a rounded shape or sharp margins. This applies for both mammography and MRI. However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy. (orig.)

  15. An international survey of surveillance schemes for unaffected BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Madorsky-Feldman, Dana; Sklair-Levy, Miri; Perri, Tamar; Laitman, Yael; Paluch-Shimon, Shani; Schmutzler, Rita; Rhiem, Kerstin; Lester, Jenny; Karlan, Beth Y; Singer, Christian F; Van Maerken, Tom; Claes, Kathleen; Brunet, Joan; Izquierdo, Angel; Teulé, Alex; Lee, Jong Won; Kim, Sung-Won; Arun, Banu; Jakubowska, Anna; Lubinski, Jan; Tucker, Katherine; Poplawski, Nicola K; Varesco, Liliana; Bonelli, Luigina Ada; Buys, Saundra S; Mitchell, Gillian; Tischkowitz, Marc; Gerdes, Anne-Marie; Seynaeve, Caroline; Robson, Mark; Kwong, Ava; Tung, Nadine; Tessa, Nalven; Domchek, Susan M; Godwin, Andrew K; Rantala, Johanna; Arver, Brita; Friedman, Eitan

    2016-06-01

    Female BRCA1/BRCA2 mutation carriers are at substantially increased risk for developing breast and/or ovarian cancer, and are offered enhanced surveillance including screening from a young age and risk-reducing surgery (RRS)-mastectomy (RRM) and/or salpingo-oophorectomy (RRSO). While there are established guidelines for early detection of breast cancer in high-risk women who have not undergone RRM, there are less developed guidelines after RRM. We evaluated the schemes offered before and after RRS in internationally diverse high-risk clinics. An e-mailed survey was distributed to high-risk clinics affiliated with CIMBA. Overall, 22 centers from 16 countries responded. Pre RRS surveillance schemes overwhelmingly included breast imaging (primarily MRI) from 18 to 30 years and clinical breast exam (CBE) at 6-12 month intervals. For ovarian cancer, all but 6 centers offered semiannual/annual gynecological exam, transvaginal ultrasound, and CA 125 measurements. Post RRM, most centers offered only annual CBE while 4 centers offered annual MRI, primarily for substantial residual breast tissue. After RRSO only 4 centers offered specific gynecological surveillance. Existing guidelines for breast/ovarian cancer detection in BRCA carriers are being applied pre RRS but are not globally harmonized, and most centers offer no specific surveillance post RRS. From this comprehensive multinational study it is clear that evidence-based, long-term prospective data on the most effective scheme for BRCA carriers post RRS is needed. PMID:27117159

  16. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A; Milne, R L; Pita, G;

    2009-01-01

    Background:In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.Methods:We have geno...

  17. Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

    DEFF Research Database (Denmark)

    Osorio, A.; Milne, R.L.; Pita, G.;

    2009-01-01

    BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have g...

  18. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...

  19. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    NARCIS (Netherlands)

    Mulligan, A.M.; Couch, F.J.; Barrowdale, D.; Domchek, S.M.; Eccles, D.; Nevanlinna, H.; Ramus, S.J.; Robson, M.; Sherman, M.; Spurdle, A.B.; Wappenschmidt, B.; Lee, A.; McGuffog, L.; Healey, S.; Sinilnikova, O.M.; Janavicius, R.; Hansen, T.V.; Nielsen, F.C.; Ejlertsen, B.; Osorio, A.; Munoz-Repeto, I.; Duran, M.; Godino, J.; Pertesi, M.; Benitez, J.; Peterlongo, P.; Manoukian, S.; Peissel, B.; Zaffaroni, D.; Cattaneo, E.; Bonanni, B.; Viel, A.; Pasini, B.; Papi, L.; Ottini, L.; Savarese, A.; Bernard, L.; Radice, P.; Hamann, U.; Verheus, M.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Nelen, M.R.; Kets, C.M.; Seynaeve, C.; Tilanus-Linthorst, M.M.; Luijt, R.B. van der; Os, T.V.; Rookus, M.; Frost, D.; Jones, J.L.; Evans, D.G.; Lalloo, F.; Eeles, R.; Izatt, L.; Adlard, J.; Davidson, R.; Cook, J.; Donaldson, A.; Dorkins, H.; Gregory, H.; Eason, J.; Houghton, C.; Barwell, J.; Side, L.E.; McCann, E.; Murray, A.; Peock, S.; Godwin, A.K.; Schmutzler, R.K.; Rhiem, K.; Engel, C.; Meindl, A.; Ruehl, I.; Arnold, N.; Niederacher, D.; Sutter, C.; Deissler, H.; Gadzicki, D.; Kast, K.; Preisler-Adams, S.; Varon-Mateeva, R.; Schoenbuchner, I.; Fiebig, B.; Heinritz, W.; Schafer, D.; Gevensleben, H.; Caux-Moncoutier, V.; Fassy-Colcombet, M.; Cornelis, F.; Mazoyer, S.; Leone, M.; Boutry-Kryza, N.; Hardouin, A.; Berthet, P.; Muller, D.; Fricker, J.P.; Mortemousque, I.; Pujol, P.

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes i

  20. Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland.

    Science.gov (United States)

    Gronwald, Jacek; Byrski, Tomasz; Huzarski, Tomasz; Cybulski, Cezary; Sun, Ping; Tulman, Anna; Narod, Steven A; Lubinski, Jan

    2006-01-01

    It has been estimated that the lifetime risk of breast cancer among women who inherit a BRCA1 or BRCA2 mutation is as high as 80%, and the risk estimates for ovarian cancer range from 15 to 40%. Several environmental and lifestyle factors are believed to contribute to the development of breast cancer in the general population and it is of interest to establish if these factors operate among mutation carriers as well. To evaluate the effects of age of menarche, parity, breast-feeding, oophorectomy and oral contraceptive use, as well as smoking and coffee consumption, on the risks of breast and ovarian cancer, we conducted a matched case-control study of Polish women with BRCA1 mutations. There were 348 breast cancer patients, 150 ovarian cancer patients and similar numbers of age-matched controls. BRCA1 carriers with late age of menarche, lower parity and long-term breast-feeding were less likely to develop breast cancer. Oral contraceptives protected against ovarian cancer. PMID:16261399

  1. Roles of DNA mutation in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumors.

    Science.gov (United States)

    Qiu, Hengbin; Lin, Deigui

    2016-07-01

    The Breast cancer 1, early onset gene (BRCA1) is known to be significantly associated with human familial breast cancer and is identified to play an important role in canine mammary tumors. Here, genetic variations in the coding region and DNA methylation in the 5' flanking region of BRCA1 in canine mammary tumor samples, 15 each of benign and malignant against 10 normal canine mammary tissue samples, were analyzed using the direct sequencing method. The results indicated two point mutations each in the coding region of canine BRCA1 in one benign mammary tumor sample (4702G >T and 4765G >T) and in one malignant canine mammary tumor sample (3619A >G and 4006G >A). No mutations were detected in the normal canine mammary tissue samples. The 4702G >T mutation was found to terminate further translation. The physical effect of the 4765G >T mutation was found to be the repalacement of the glutamate residue with glutamine. The physical effect of the 3619A >G mutation was found to be the replacement of the threonine residue with alanine, and that of mutation 4006G >A was the replacement of the valine residue with isoleucine in the BRCA1 protein. Bisulfite sequencing detected methylated CpG sites in one canine malignant mammary tumor sample. In conclusion, the present study elucidated the mutational status of the BRCA1 coding region and methylation status of the 5' flanking region of BRCA1 in canine mammary tumors. PMID:26888582

  2. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Directory of Open Access Journals (Sweden)

    Dirce Maria Carraro

    Full Text Available Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22% [7 in BRCA1 (13%, 4 in BRCA2 (7% and one in TP53 (2% gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes. Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.

  3. Comprehensive analysis of BRCA1, BRCA2 and TP53 germline mutation and tumor characterization: a portrait of early-onset breast cancer in Brazil.

    Science.gov (United States)

    Carraro, Dirce Maria; Koike Folgueira, Maria Aparecida Azevedo; Garcia Lisboa, Bianca Cristina; Ribeiro Olivieri, Eloisa Helena; Vitorino Krepischi, Ana Cristina; de Carvalho, Alex Fiorini; de Carvalho Mota, Louise Danielle; Puga, Renato David; do Socorro Maciel, Maria; Michelli, Rodrigo Augusto Depieri; de Lyra, Eduardo Carneiro; Grosso, Stana Helena Giorgi; Soares, Fernando Augusto; Achatz, Maria Isabel Alves de Souza Waddington; Brentani, Helena; Moreira-Filho, Carlos Alberto; Brentani, Maria Mitzi

    2013-01-01

    Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients. PMID:23469205

  4. Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

    DEFF Research Database (Denmark)

    Mulligan, Anna Marie; Couch, Fergus J; Barrowdale, Daniel;

    2011-01-01

    ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtype...... subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers....

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

    Science.gov (United States)

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

    2012-01-01

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

  6. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  7. Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

    Science.gov (United States)

    Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

    2016-01-01

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

  8. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Demsky, Rochelle; Neuhausen, Susan L; Kim-Sing, Charmaine; Tung, Nadine; Friedman, Susan; Senter, Leigha; Weitzel, Jeffrey; Karlan, Beth; Moller, Pal; Sun, Ping; Narod, Steven A

    2015-09-01

    The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA-associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41-0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48-0.79) and 50% (95% CI 0.29-0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40-0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22-0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79-0.96; p-trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81-1.19; p-trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03-1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations. PMID:25482078

  9. Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg is a pathogenic mutation.

    Directory of Open Access Journals (Sweden)

    Phillip J Whiley

    Full Text Available Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5. BRCA1:c.4484G> C(p.Arg1495Thr was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1, nine were likely not pathogenic (Class 2, and one was uncertain (Class 3.These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.

  10. Analysis of Founder Mutations in Rare Tumors Associated With Hereditary Breast/Ovarian Cancer Reveals a Novel Association of BRCA2 Mutations with Ampulla of Vater Carcinomas.

    Science.gov (United States)

    Pinto, Pedro; Peixoto, Ana; Santos, Catarina; Rocha, Patrícia; Pinto, Carla; Pinheiro, Manuela; Leça, Luís; Martins, Ana Teresa; Ferreira, Verónica; Bartosch, Carla; Teixeira, Manuel R

    2016-01-01

    BRCA1 and BRCA2 mutations are responsible for hereditary breast and ovarian cancer, but they also confer an increased risk for the development of rarer cancers associated with this syndrome, namely, cancer of the pancreas, male breast, peritoneum, and fallopian tube. The objective of this work was to quantify the contribution of the founder mutations BRCA2 c.156_157insAlu and BRCA1 c.3331_3334del for cancer etiology in unselected hospital-based cohorts of Portuguese patients diagnosed with these rarer cancers, by using a strategy that included testing of archival tumor tissue. A total of 102 male breast, 68 pancreatic and 33 peritoneal/fallopian tube carcinoma cases were included in the study. The BRCA2 c.156_157insAlu mutation was observed with a frequency of 7.8% in male breast cancers, 3.0% in peritoneal/fallopian tube cancers, and 1.6% in pancreatic cancers, with estimated total contributions of germline BRCA2 mutations of 14.3%, 5.5%, and 2.8%, respectively. No carriers of the BRCA1 c.3331_3334del mutation were identified. During our study, a patient with an ampulla of Vater carcinoma was incidentally found to carry the BRCA2 c.156_157insAlu mutation, so we decided to test a consecutive series of additional 15 ampullary carcinomas for BRCA1/BRCA2 mutations using a combination of direct founder mutation testing and full gene analysis with next generation sequencing. BRCA2 mutations were observed with a frequency of 14.3% in ampulla of Vater carcinomas. In conclusion, taking into account the implications for both the individuals and their family members, we recommend that patients with these neoplasias should be offered BRCA1/BRCA2 genetic testing and we here show that it is feasible to test for founder mutations in archival tumor tissue. Furthermore, we identified for the first time a high frequency of germline BRCA2 mutations in ampullary cancers. PMID:27532258

  11. Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?

    Science.gov (United States)

    Lener, Marcin R; Scott, Rodney J; Kluźniak, Wojciech; Baszuk, Piotr; Cybulski, Cezary; Wiechowska-Kozłowska, Anna; Huzarski, Tomasz; Byrski, Tomasz; Kładny, Józef; Pietrzak, Sandra; Soluch, Agnieszka; Jakubowska, Anna; Lubiński, Jan

    2016-08-01

    Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among PaCa patients and assessed their possible association with the risk of disease in Poland. In the study 383 PaCa patients and 4,000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G > A, del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1 gene. The Slavic NBS1 gene mutation (657delACAAA) was detected in 8 of 383 (2.09%) unselected cases compared with 22 of 4,000 (0.55%) controls (OR: 3.80, p = 0.002). The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0.52%) unselected cases of PaCa and in 8 (0.20%) of 4,000 controls (OR: 2.61, p = 0.49). For BRCA1, the three mutations combined were detected in 4 of 383 (1.04%) PaCa patients and in 17 of 4,000 (0.42%) controls (OR: 2.46, p = 0.20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR: 1.11, p = 0.72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa. PMID:27038244

  12. Genome instability in blood cells of a BRCA1+ breast cancer family

    International Nuclear Information System (INIS)

    BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells

  13. Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers

    Science.gov (United States)

    Blanco, Ignacio; Kuchenbaecker, Karoline; Cuadras, Daniel; Wang, Xianshu; Barrowdale, Daniel; de Garibay, Gorka Ruiz; Librado, Pablo; Sánchez-Gracia, Alejandro; Rozas, Julio; Bonifaci, Núria; McGuffog, Lesley; Pankratz, Vernon S.; Islam, Abul; Mateo, Francesca; Berenguer, Antoni; Petit, Anna; Català, Isabel; Brunet, Joan; Feliubadaló, Lidia; Tornero, Eva; Benítez, Javier; Osorio, Ana; Cajal, Teresa Ramón y; Nevanlinna, Heli; Aittomäki, Kristiina; Arun, Banu K.; Toland, Amanda E.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Greene, Mark H.; Mai, Phuong L.; Nussbaum, Robert L.; Andrulis, Irene L.; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Barkardottir, Rosa B.; Jakubowska, Anna; Lubinski, Jan; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Claes, Kathleen; Van Maerken, Tom; Díez, Orland; Hansen, Thomas V.; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; de la Hoya, Miguel; Caldés, Trinidad; Dunning, Alison M.; Oliver, Clare; Fineberg, Elena; Cook, Margaret; Peock, Susan; McCann, Emma; Murray, Alex; Jacobs, Chris; Pichert, Gabriella; Lalloo, Fiona; Chu, Carol; Dorkins, Huw; Paterson, Joan; Ong, Kai-Ren; Teixeira, Manuel R.; Hogervorst, Frans B. L.; van der Hout, Annemarie H.; Seynaeve, Caroline; van der Luijt, Rob B.; Ligtenberg, Marjolijn J. L.; Devilee, Peter; Wijnen, Juul T.; Rookus, Matti A.; Meijers-Heijboer, Hanne E. J.; Blok, Marinus J.; van den Ouweland, Ans M. W.; Aalfs, Cora M.; Rodriguez, Gustavo C.; Phillips, Kelly-Anne A.; Piedmonte, Marion; Nerenstone, Stacy R.; Bae-Jump, Victoria L.; O'Malley, David M.; Ratner, Elena S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Rhiem, Kerstin; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg J.; Niederacher, Dieter; Sutter, Christian; Wang-Gohrke, Shan; Steinemann, Doris; Preisler-Adams, Sabine; Kast, Karin; Varon-Mateeva, Raymonda; Gehrig, Andrea; Bojesen, Anders; Pedersen, Inge Sokilde; Sunde, Lone; Jensen, Uffe Birk; Thomassen, Mads; Kruse, Torben A.; Foretova, Lenka; Peterlongo, Paolo; Bernard, Loris; Peissel, Bernard; Scuvera, Giulietta; Manoukian, Siranoush; Radice, Paolo; Ottini, Laura; Montagna, Marco; Agata, Simona; Maugard, Christine; Simard, Jacques; Soucy, Penny; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Geschwantler-Kaulich, Daphne; Tea, Muy-Kheng; Pfeiler, Georg; John, Esther M.; Miron, Alex; Neuhausen, Susan L.; Terry, Mary Beth; Chung, Wendy K.; Daly, Mary B.; Goldgar, David E.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elisabeth J.; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Godwin, Andrew K.; Olah, Edith; Narod, Steven A.; Rennert, Gad; Paluch, Shani Shimon; Laitman, Yael; Friedman, Eitan; Liljegren, Annelie; Rantala, Johanna; Stenmark-Askmalm, Marie; Loman, Niklas; Imyanitov, Evgeny N.; Hamann, Ute; Spurdle, Amanda B.; Healey, Sue; Weitzel, Jeffrey N.; Herzog, Josef; Margileth, David; Gorrini, Chiara; Esteller, Manel; Gómez, Antonio; Sayols, Sergi; Vidal, Enrique; Heyn, Holger; Stoppa-Lyonnet, Dominique; Léoné, Melanie; Barjhoux, Laure; Fassy-Colcombet, Marion; de Pauw, Antoine; Lasset, Christine; Ferrer, Sandra Fert; Castera, Laurent; Berthet, Pascaline; Cornelis, François; Bignon, Yves-Jean; Damiola, Francesca; Mazoyer, Sylvie; Maxwell, Christopher A.; Vijai, Joseph; Robson, Mark; Kauff, Noah; Corines, Marina J.; Villano, Danylko; Cunningham, Julie; Lee, Adam; Lindor, Noralane; Lázaro, Conxi; Easton, Douglas F.; Offit, Kenneth; Chenevix-Trench, Georgia; Couch, Fergus J.; Antoniou, Antonis C.; Pujana, Miguel Angel

    2015-01-01

    While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID:25830658

  14. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ignacio Blanco

    Full Text Available While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR = 1.10, 95% confidence interval (CI 1.04-1.15, p = 1.9 x 10(-4 (false discovery rate (FDR-adjusted p = 0.043. Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045. Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05 for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

  15. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Spurdle, Amanda B; Sinilnikova, Olga M;

    2008-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide...... polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample...... of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0...

  16. Characterization of a novel large deletion and single point mutations in the BRCA1 gene in a Greek cohort of families with suspected hereditary breast cancer

    Directory of Open Access Journals (Sweden)

    Hadjisavvas Andreas

    2004-09-01

    Full Text Available Abstract Background Germline mutations in BRCA1 and BRCA2 predispose to breast and ovarian cancer. A multitude of mutations have been described and are found to be scattered throughout these two large genes. We describe analysis of BRCA1 in 25 individuals from 18 families from a Greek cohort. Methods The approach used is based on dHPLC mutation screening of the BRCA1 gene, followed by sequencing of fragments suspected to carry a mutation including intron – exon boundaries. In patients with a strong family history but for whom no mutations were detected, analysis was extended to exons 10 and 11 of the BRCA2 gene, followed by MLPA analysis for screening for large genomic rearrangements. Results A pathogenic mutation in BRCA1 was identified in 5/18 (27.7 % families, where four distinct mutations have been observed. Single base putative pathogenic mutations were identified by dHPLC and confirmed by sequence analysis in 4 families: 5382insC (in two families, G1738R, and 5586G > A (in one family each. In addition, 18 unclassified variants and silent polymorphisms were detected including a novel silent polymorphism in exon 11 of the BRCA1 gene. Finally, MLPA revealed deletion of exon 20 of the BRCA1 gene in one family, a deletion that encompasses 3.2 kb of the gene starting 21 bases into exon 20 and extending 3.2 kb into intron 20 and leads to skipping of the entire exon 20. The 3' breakpoint lies within an AluSp repeat but there are no recognizable repeat motifs at the 5' breakpoint implicating a mechanism different to Alu-mediated recombination, responsible for the majority of rearrangements in the BRCA1 gene. Conclusions We conclude that a combination of techniques capable of detecting both single base mutations and small insertions / deletions and large genomic rearrangements is necessary in order to accurately analyze the BRCA1 gene in patients at high risk of carrying a germline mutation as determined by their family history. Furthermore, our

  17. In their own words: treating very young BRCA1/2 mutation-positive women with care and caution.

    Directory of Open Access Journals (Sweden)

    Lindsey M Hoskins

    Full Text Available PURPOSE: Young women who have been identified as carrying a deleterious mutation in BRCA1 or BRCA2 face a unique set of challenges related to managing cancer risk during a demographically-dense stage of life. They may struggle with decision-making in the absence of clear age-specific guidelines for medical management and because they have not yet fully developed the capacity to make life-altering decisions confidently. This study sought a patient-centered perspective on the dilemmas faced by 18-24 year olds who completed BRCA1/2 gene mutation testing prior to their 25(th birthdays. PATIENTS AND METHOD: This study integrated qualitative data from three independent investigations of BRCA1/2-positive women recruited through cancer risk clinics, hospital-based research centers, and online organizations. All 32 participants were women aged 21-25 who tested positive for a BRCA1/2 gene mutation between 2 and 60 months prior to data collection. Investigators used techniques of grounded theory and interpretive description to conduct both within and cross-study analysis. RESULTS: Participants expressed needs for (1 greater clarity in recommendations for screening and prevention before age 25, especially with consideration of early and regular exposure to radiation associated with mammography or to hormones used in birth control, and (2 ongoing contact with providers to discuss risk management protocols as they become available. CONCLUSIONS: Health care needs during the young adult years evolve with the cognitive capacity to address abrupt and pressing change. Specific needs of women in this population include a desire to balance autonomous decision-making with supportive guidance, a need for clear, accurate and consistent medical recommendations. Optimally, these women are best cared for by a team of genetically-oriented providers as part of a sustained program of ongoing support, rather than seen in an episodic, crisis-driven fashion. A discussion of

  18. Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers.

    Science.gov (United States)

    Paluch-Shimon, Shani; Friedman, Eitan; Berger, Raanan; Papa, Moshe; Dadiani, Maya; Friedman, Neil; Shabtai, Moshe; Zippel, Dov; Gutman, Mordechai; Golan, Talia; Yosepovich, Ady; Catane, Raphael; Modiano, Tami; Kaufman, Bella

    2016-05-01

    The purpose of this study was to assess pathological complete response and whether it serves a surrogate for survival among patients receiving neo-adjuvant doxorubicin-cyclophosphamide followed by paclitaxel for triple-negative breast cancer with respect to BRCA1 mutation status. From a neo-adjuvant systemic therapy database of 588 breast cancer cases, 80 triple-negative cases who had undergone BRCA genotyping were identified. Logistic regression model was fitted to examine the association between BRCA1 status and pathological complete response. Survival outcomes were evaluated using Kaplan-Meier method, differences between study groups calculated by log-rank test. Thirty-four BRCA1 carriers and 43 non-carriers were identified. The BRCA1 carriers had pathological complete response rate of 68 % compared with 37 % among non-carriers, p = 0.01. Yet this did not translate into superior survival for BRCA1 carriers compared with non-carriers. No difference in relapse-free survival were noted among those with or without pathological complete response in BRCA1 carriers regardless of pathological complete response status (Log-rank p = 0.25), whereas in the non-carrier cohort, relapse-free survival was superior for those achieving pathological complete response (Log-rank p < 0.0001). Response to neo-adjuvant systemic therapy differed in BRCA1-associated triple-negative breast cancer compared with triple-negative non-carriers, with a higher rate of pathological complete response. However, compared with non-carrier triple-negative breast cancer, pathological complete response was not a surrogate for superior relapse-free survival in BRCA1 patients. Future studies using specific chemotherapy regimens may provide further improvements in outcomes. PMID:27113739

  19. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

    Directory of Open Access Journals (Sweden)

    Ana Osorio

    2014-04-01

    Full Text Available Single Nucleotide Polymorphisms (SNPs in genes involved in the DNA Base Excision Repair (BER pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase, and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2 gene (HR: 1.09, 95% CI (1.03-1.16, p = 2.7 × 10(-3 for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3. DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

  20. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue

    DEFF Research Database (Denmark)

    Petersen, Annabeth Høgh; Jørgensen, Mads Malik Aagaard; Nielsen, Henriette Roed;

    2016-01-01

    Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder...... mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild......1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE...

  1. Rapid detection of most frequent Slovenian germ-line mutations in BRCA1 gene using real-time PCR and melting curve analysis

    International Nuclear Information System (INIS)

    Background. Detection of inherited mutations in cancer susceptibility genes is of great importance in some types of cancers including the colorectal cancer (mutations of APC gene in familial adenomatous polyposis - FAP, mutations in mismatch repair genes in hereditary nonpolyposis colorectal cancer - HNPCC), malignant melanoma (mutations in CDKN2A and CDK4 genes) and breast cancer (mutations in BRCA1 and BRCA2 genes). Methods. This article presents the technical data for the detection of five mutations in BRCA1 gene in breast cancer patients and their relatives. The mutations - 1806C>T, 300T>G, 300T>A, 310G>A, 5382insC - were determined by the real-time PCR and the melting curve analysis. Results and conclusion. In comparison to direct sequencing, this method proved to be sensitive and rapid enough for the routine daily determination of mutations in DNA isolated from the peripheral blood. (author)

  2. Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry.

    Science.gov (United States)

    Graña, B; Fachal, L; Darder, E; Balmaña, J; Ramón Y Cajal, T; Blanco, I; Torres, A; Lázaro, C; Diez, O; Alonso, C; Santamariña, M; Velasco, A; Teulé, A; Lasa, A; Blanco, A; Izquierdo, A; Borràs, J; Gutiérrez-Enríquez, S; Vega, A; Brunet, J

    2011-07-01

    Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case-control study to determine the prevalence of 32 known ATM mutations causing A-T in Spanish population in 323 BRCA1/BRCA2 negative hereditary breast cancer (HBC) cases and 625 matched Spanish controls. For the detection of the 32 ATM mutations we used the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry technique. We identified one patient carrier of the c.8264_8268delATAAG ATM mutation. This mutation was not found in the 625 controls. These results suggest a low frequency of these 32 A-T causing mutations in the HBC cases in our population. Further case-control studies analyzing the entire coding and flanking sequences of the ATM gene are warranted in Spanish BC patients to know its implication in BC predisposition. PMID:21445571

  3. Mitochondrial localization, ELK-1 transcriptional regulation and Growth inhibitory functions of BRCA1, BRCA1a and BRCA1b proteins

    OpenAIRE

    Maniccia, Anna W.; Lewis, Catherine; BEGUM, NURJAHAN; Xu, Jingyao; Cui, Jianqi; Chipitsyna, Galina; AYSOLA, KARTIK; REDDY, VAISHALI; Bhat, Ganapathy; Fujimura, Yasuo; Henderson, Beric; Reddy, E. Shyam P; Rao, Veena N.

    2009-01-01

    BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compar...

  4. NGS-based BRCA1/2 mutation testing of high-grade serous ovarian cancer tissue: results and conclusions of the first international round robin trial.

    Science.gov (United States)

    Endris, Volker; Stenzinger, Albrecht; Pfarr, Nicole; Penzel, Roland; Möbs, Markus; Lenze, Dido; Darb-Esfahani, Silvia; Hummel, Michael; Sabine-Merkelbach-Bruse; Jung, Andreas; Lehmann, Ulrich; Kreipe, Hans; Kirchner, Thomas; Büttner, Reinhard; Jochum, Wolfram; Höfler, Gerald; Dietel, Manfred; Weichert, Wilko; Schirmacher, Peter

    2016-06-01

    With the approval of olaparib as monotherapy treatment in platinum-sensitive, relapsed high-grade serous ovarian cancer by the European Medical Agency (EMA), comprehensive genotyping of BRCA1 and BRCA2 in tumor tissue has become a mandatory pre-therapeutic test. This requires significant advances in routine tumor test methodologies due to the large size of both genes and the lack of mutational hot spots. Classical focused screening approaches, like Sanger sequencing, do not allow for a sensitive, rapid, and economic analysis of tumor tissue. Next-generation sequencing (NGS) approaches employing targeted panels for BRCA1/2 to interrogate formalin-fixed and paraffin-embedded tumor samples from either surgical resection or biopsy specimens can overcome these limitations. Although focused NGS methods have been implemented by few centers in routine molecular diagnostics for the analysis of some druggable oncogenic mutations, the reliable diagnostic testing of the entire coding regions of BRCA1 and BRCA2 was a new challenge requiring extensive technological improvement and quality management. Here, we describe the implementation and results of the first round robin trial for BRCA1/2 mutation testing in tumor tissue that was conducted in central Europe on May 2015, shortly after the approval and prior to the official release of olaparib. The high success rate of 81 % (21/26 test centers) demonstrates that BRCA1/2 multicenter mutation testing is well feasible in FFPE tumor tissue, extending to other tumor entities beyond ovarian cancer. The high number of test centers passing the trial demonstrates the success of the concerted efforts by German, Swiss, and Austrian pathology centers to ensure quality-controlled NGS-based testing and proves the potential of this technology in routine molecular pathology. On the basis of our results, we provide recommendations for predictive testing of tumor tissue for BRCA1/2 to clinical decision making in ovarian cancer patients. PMID

  5. Prevalence of BRCA1 and BRCA2 gene mutations in families with medium and high risk of breast and ovarian cancer in Brazil

    Directory of Open Access Journals (Sweden)

    V.F. Esteves

    2009-05-01

    Full Text Available Of all malignant neoplasias affecting women, breast cancer has the highest incidence rate in Brazil. The objective of the present study was to determine the frequency of genetic modifications in families with medium and high risk for breast and ovarian cancer from different regions of Brazil. An exploratory, descriptive study was carried out on the prevalence of the BRCA1 and BRCA2 mutations in case series of high-risk families for breast and/or ovarian cancer. After heredogram construction, a blood sample was taken and DNA extraction was performed in all index cases. The protein truncation test was used to screen for truncated mutations in exon 11 of the BRCA1 gene and in exons 10 and 11 of the BRCA2 gene. Of the 612 individuals submitted to genetic testing, 21 (3.4%, 19 women and 2 men, had mutations in the BRCA1 or BRCA2 genes. Of the 19 BRCA1 mutations found in the 18 participants, 7 consisted of ins6kb mutations, 4 were 5382insC, 3 were 2156delGinsCC, 2 were 185delAG, 1 was C1201G, 1 was C3522T, and 1 was 3450del4. With respect to the BRCA2 gene, 3 mutations were found: 5878del10, 5036delA and 4232insA (one case each. The prevalence of germline mutations in the BRCA1 and BRCA2 genes found in the present study was lower than reported by other studies on high-risk Brazilian populations. The inclusion of individuals with medium risk may have contributed to the lower prevalence observed.

  6. KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients.

    Science.gov (United States)

    Kang, Eunyoung; Park, Sue K; Lee, Jong Won; Kim, Zisun; Noh, Woo-Chul; Jung, Yongsik; Yang, Jung-Hyun; Jung, Sung Hoo; Kim, Sung-Won

    2016-05-01

    The widely used Western BRCA mutation prediction models underestimated the risk of having a BRCA mutation in Korean breast cancer patients. This study aimed to identify predictive factors for BRCA1/2 mutations and to develop a Korean BRCA risk calculator. The model was constructed by logistic regression model, and it was based on the Korean Hereditary Breast Cancer study, in which 1669 female patients were enrolled between May 2007 and December 2010. A separate data set of 402 patients, who were enrolled from Jan 2011 to August 2012, was used to test the performance of our model. In total, 264 (15.8%) and 67 (16.7%) BRCA mutation carriers were identified in the model and validation set, respectively. Multivariate analysis showed that age at breast cancer diagnosis, bilateral breast cancer, triple-negative breast cancer (TNBC) and the number of relatives with breast or ovarian cancer within third-degree relatives were independent predictors of the BRCA mutation among familial breast cancer patients. An age cancer, both breast and ovarian cancer and TNBC remained significant predictors in non-familial breast cancer cases. Our model was developed based on logistic regression models. The validation results showed no differences between the observed and expected carrier probabilities. This model will be a useful tool for providing genetic risk assessments in Korean populations. PMID:26763880

  7. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study

    DEFF Research Database (Denmark)

    Mitra, Anita V; Bancroft, Elizabeth K; Barbachano, Yolanda;

    2011-01-01

    Study Type - Diagnostic (validating cohort)
Level of Evidence 1b OBJECTIVES: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening ...

  8. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations : retrospective cohort study (GENE-RAD-RISK)

    NARCIS (Netherlands)

    Pijpe, Anouk; Andrieu, Nadine; Easton, Douglas F.; Kesminiene, Ausrele; Cardis, Elisabeth; Nogues, Catherine; Gauthier-Villars, Marion; Lasset, Christine; Fricker, Jean-Pierre; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Rosalind A.; Paterson, Joan; Manders, Peggy; van Asperen, Christi J.; Ausems, Margreet G. E. M.; Meijers-Heijboer, Hanne; Thierry-Chef, Isabelle; Hauptmann, Michael; Goldgar, David; Rookus, Matti A.; van Leeuwen, Flora E.

    2012-01-01

    Objective To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations. Design Retrospective cohort study (GENE-RAD-RISK). Setting Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands, Participants 1993 femal

  9. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    NARCIS (Netherlands)

    Holstege, H.; Van Beers, E.; Velds, A.; Liu, X.; Joosse, S.A.; Klarenbeek, S.; Schut, E.; Kerkhoven, R.; Klijn, C.N.; Wessels, L.F.A.; Nederlof, P.M.; Jonkers, J.

    2010-01-01

    Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor g

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

    NARCIS (Netherlands)

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

    2010-01-01

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

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  12. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

    NARCIS (Netherlands)

    Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Shani-Paluch-Shimon, [No Value; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Hakan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Ramony Cajal, Teresa; Stavropoulou, Alexandra V.; Benitez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; de Lange, Judith L.; Meijers-Heijboer, Hanne E. J.; Oosterwijk, Jan C.; van Asperen, Christi J.; Garcia, Encarna B. Gomez; Hoogerbrugge, Nicoline; Jager, Agnes; van der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Leone, Melanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; de Pauw, Antoine; Hardouin, Agnes; Berthet, Pascaline; Dreyfus, Helene; Ferrer, Sandra Fert; Collonge-Rame, Marie-Agnes; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Tea, Muy-Kheng Maria; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas V. O.; Ejlertsen, Bent; Johannsson, Oskar T.; Offit, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R.; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomaki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne-Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne-Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Neuhausen, Susan L.

    2012-01-01

    Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were assoc

  13. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Ding, Yuan C; McGuffog, Lesley; Healey, Sue;

    2012-01-01

    We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated wit...

  14. A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

    NARCIS (Netherlands)

    Y.C. Ding (Yuan); L. McGuffog (Lesley); S. Healey (Sue); E. Friedman (Eitan); Y. Laitman (Yael); S.-P. Shimon (Shani-Paluch); B. Kaufman (Bella); A. Liljegren (Annelie); A. Lindblom (Annika); H. Olsson; U. Kristoffersson (Ulf); M. Stenmark-Askmalm (M.); B. Melin (Beatrice); S.M. Domchek (Susan); K.L. Nathanson (Katherine); R. Rebbeck (Timothy); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); K. Durda (Katarzyna); J. Gronwald (Jacek); T. Huzarski (Tomasz); C. Cybulski (Cezary); T. Byrski (Tomasz); A. Osorio (Ana); T.R. Cajal; A. Stavropoulou (Alexandra); J. Benítez (Javier); U. Hamann (Ute); M.A. Rookus (Matti); C.M. Aalfs (Cora); J.L. de Lange (J.); E.J. Meijers-Heijboer (Hanne); J.C. Oosterwijk (Jan); C.J. van Asperen (Christi); E.B. Gómez García (Encarna); N. Hoogerbrugge (Nicoline); A. Jager (Agnes); R.B. van der Luijt (Rob); D.F. Easton (Douglas); S. Peock (Susan); D. Frost (Debra); S.D. Ellis (Steve); R. Platte (Radka); E. Fineberg (Elena); D.G. Evans (Gareth); F. Lalloo (Fiona); L. Izatt (Louise); R. Eeles (Rosalind); J.W. Adlard (Julian); R. Davidson (Rosemarie); D. Eccles (Diana); T.J. Cole (Trevor); J. Cook (Jackie); C. Brewer (Carole); M. Tischkowitz (Marc); A.K. Godwin (Andrew); S.S. Pathak; D. Stoppa-Lyonnet (Dominique); O. Sinilnikova (Olga); S. Mazoyer (Sylvie); L. Barjhoux (Laure); M. Léone (Mélanie); M. Gauthier-Villars (Marion); V. Caux-Moncoutier (Virginie); A. de Pauw (Antoine); A. Hardouin (Agnès); P. Berthet (Pascaline); H. Dreyfus (Hélène); S.F. Ferrer; M.-A. Collonge-Rame; J. Sokolowska (Johanna); S.S. Buys (Saundra); M.B. Daly (Mary); A. Miron (Alexander); M.-B. Terry (Mary-Beth); W. Chung (Wendy); E.M. John (Esther); M.C. Southey (Melissa); D. Goldgar (David); C.F. Singer (Christian); M.-K. Tea; D. Gschwantler-Kaulich (Daphne); A. Fink-Retter (Anneliese); T.V.O. Hansen (Thomas); B. Ejlertsen (Bent); O.T. Johannson (Oskar); K. Offit (Kenneth); K. Sarrel (Kara); M.M. Gaudet (Mia); J. Vijai (Joseph); M. Robson (Mark); M. Piedmonte (Marion); L. Andrews (Lesley); D.E. Cohn (David); L.R. DeMars (Leslie); P. DiSilvestro (Paul); G.C. Rodriguez (Gustavo); A.E. Toland (Amanda); M. Montagna (Marco); S. Agata (Simona); E.N. Imyanitov (Evgeny); C. Isaacs (Claudine); R. Janavicius (Ramunas); C. Lazaro (Conxi); I. Blanco (Ignacio); S.J. Ramus (Susan); L. Sucheston (Lara); B. Karlan; J. Gross (Jenny); P.A. Ganz (Patricia); M.S. Beattie (Mary); R.K. Schmutzler (Rita); B. Wapenschmidt (Barbara); A. Meindl (Alfons); N. Arnold (Norbert); D. Niederacher (Dieter); S. Preisler-Adams (Sabine); D. Gadzicki (Dorothea); R. Varon-Mateeva (Raymonda); H. Deissler (Helmut); P.A. Gehrig (Paola A.); C. Sutter (Christian); K. Kast (Karin); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); J. Simard (Jacques); A.B. Spurdle (Amanda); J. Beesley (Jonathan); X. Chen (Xiaoqing); G. Tomlinson (Gail); J.N. Weitzel (Jeffrey); J. Garber; O.I. Olopade (Olofunmilayo); W.S. Rubinstein (Wendy); N. Tung (Nadine); J.L. Blum (Joann); S. Narod (Steven); S. Brummel (Sean); D.L. Gillen (Daniel); N.M. Lindor (Noralane); Z. Fredericksen (Zachary); V.S. Pankratz (Shane); F.J. Couch (Fergus); P. Radice (Paolo); P. Peterlongo (Paolo); M.H. Greene (Mark); J.T. Loud (Jennifer); P.L. Mai (Phuong); I.L. Andrulis (Irene); G. Glendon (Gord); H. Ozcelik (Hilmi); A-M. Gerdes (Anne-Marie); M. Thomassen (Mads); U.B. Jensen; A.-B. Skytte (Anne-Bine); M.A. Caligo (Maria); A. Lee (Andrew); G. Chenevix-Trench (Georgia); A.C. Antoniou (Antonis); S.L. Neuhausen (Susan)

    2012-01-01

    textabstractBackground: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and

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

    NARCIS (Netherlands)

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

    2010-01-01

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

  16. A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers.

    NARCIS (Netherlands)

    Ding, Y.C.; McGuffog, L.; Healey, S.; Friedman, E.; Laitman, Y.; Paluch-Shimon, S.; Kaufman, B.; Liljegren, A.; Lindblom, A.; Olsson, H.; Kristoffersson, U.; Stenmark-Askmalm, M.; Melin, B.; Domchek, S.M.; Nathanson, K.L.; Rebbeck, T.R.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Gronwald, J.; Huzarski, T.; Cybulski, C.; Byrski, T.; Osorio, A.; Cajal, T.R.; Stavropoulou, A.V.; Benitez, J.; Hamann, U.; Rookus, M.; Aalfs, C.M.; Lange, J.L. de; Meijers-Heijboer, H.E.; Oosterwijk, J.C.; Asperen, C.J. van; Gomez Garcia, E.B.; Hoogerbrugge, N.; Jager, A.; Luijt, R.B. van der; Easton, D.F.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Izatt, L.; Eeles, R.; Adlard, J.; Davidson, R.; Eccles, D.; Cole, T.; Cook, J.; Brewer, C.; Tischkowitz, M.; Godwin, A.K.; Pathak, H.; Stoppa-Lyonnet, D.; Sinilnikova, O.M.; Mazoyer, S.; Barjhoux, L.; Leone, M.; Gauthier-Villars, M.; Caux-Moncoutier, V.; Pauw, A. de; Hardouin, A.; Berthet, P.; Dreyfus, H.; Ferrer, S.F.; Collonge-Rame, M.A.; Sokolowska, J.; Buys, S.; Daly, M.; Miron, A.; Terry, M.B.; Chung, W.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Tea, M.K.; Gschwantler-Kaulich, D.; Fink-Retter, A.; Hansen, T.V.; Ejlertsen, B.; Johannsson, O.T.; Offit, K.; Sarrel, K.; Gaudet, M.M.; Vijai, J.; Robson, M.; Piedmonte, M.R.; Andrews, L.; Cohn, D.; Demars, L.R.; Disilvestro, P.; Rodriguez, G.; Toland, A.E.; Montagna, M.; Agata, S.; Imyanitov, E.; Isaacs, C.; Janavicius, R.; Lazaro, C.; Blanco, I.; Ramus, S.J.; Sucheston, L.; Karlan, B.Y.; Gross, J.; Ganz, P.A.; Beattie, M.S.; Schmutzler, R.K.; Wappenschmidt, B.; Meindl, A.; Arnold, N.; Niederacher, D.; Preisler-Adams, S.; Gadzicki, D.; Varon-Mateeva, R.; Deissler, H.; Gehrig, A.; Sutter, C.; Kast, K.; Nevanlinna, H.; Aittomaki, K.; Simard, J.; Spurdle, A.B.; Beesley, J.; Chen, X.; Tomlinson, G.E.; Weitzel, J.; Garber, J.E.; Olopade, O.I.; Rubinstein, W.S.; Tung, N.; Blum, J.L.; Narod, S.A.; Brummel, S.; Gillen, D.L.; Lindor, N.; Fredericksen, Z.; Pankratz, V.S.; Couch, F.J.; Radice, P.; Peterlongo, P.; Greene, M.H.; Loud, J.T.; Mai, P.L.; Andrulis, I.L.; Glendon, G.; Ozcelik, H.; Gerdes, A.M.; Thomassen, M.; Jensen, U.B.; Skytte, A.B.; Caligo, M.A.; Lee, A.; Chenevix-Trench, G.; Antoniou, A.C.; Neuhausen, S.L.

    2012-01-01

    BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were assoc

  17. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline;

    2014-01-01

    Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of th...

  18. Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes

    OpenAIRE

    Rebbeck, Timothy R.; Mitra, Nandita; Domchek, Susan M.; Wan, Fei; Friebel, Tara M.; Tran, Teo V.; Singer, Christian F.; Tea, Muy-Kheng Maria; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie L.; Garber, Judy E.

    2011-01-01

    Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 ...

  19. BRCA1, Hormone, and Tissue-Specific Tumor Suppression

    Directory of Open Access Journals (Sweden)

    Yanfen Hu

    2009-01-01

    Full Text Available Germline mutations of BRCA1 predispose women to breast and ovarian cancers. Elucidating molecular mechanism of tissue- and gender-specific phenomena in BRCA1-related tumors is a key to our understanding of BRCA1 function in tumor suppression. This review summarizes studies in recent years on the link between BRCA1 and estrogen/progesterone signaling pathways, as well as discusses various models underscoring a triangle relationship among BRCA1, estrogen and genome instability.

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

    DEFF Research Database (Denmark)

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

    2013-01-01

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

  1. Medullary carcinoma of breast with a novel germline mutation 1123>g in 11 of brca1

    International Nuclear Information System (INIS)

    Breast cancer, the most common malignancy in females, has an estimated 5-10% hereditary predisposition BRCAI is a tumor suppressor gene and is known to be responsible for breast cancer and breast-ovarian cancers running in families. In breast caner patients, several mutations in BRCAI have been reported throughout the gene. This report describes identification of a mutation in BRCAI gene using protein truncation (PTT) assay in a patient with medullary carcinoma of breast who also had a family history of breast cancer. Following DNA sequencing, the mutation was confirmed as substituation of thymine at position 1123 with guanine of exon 11 (1123 T>G). This mutation can be added to the pool of known BRCAI mutations in Pakistani population, which will help in developing a local screening panel of BRCAI mutations. (author)

  2. Large genomic rearrangements of BRCA1 and BRCA2 among patients referred for genetic analysis in Galicia (NW Spain): delimitation and mechanism of three novel BRCA1 rearrangements.

    Science.gov (United States)

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGRs. Here we used multiplex ligation-dependent probe amplification (MLPA) to screen 651 Galician index cases (out of the 830 individuals referred for genetic analysis) without point mutations or small indels. We identified three different BRCA1 LGRs in four families. Two of them have been previously classified as pathogenic LGRs: the complete deletion of BRCA1 (identified in two unrelated families) and the deletion of exons 1 to 13. We also identified the duplication of exons 1 and 2 that is a LGR with unknown pathogenicity. Determination of the breakpoints of the BRCA1 LGRs using CNV/SNP arrays and sequencing identified them as NG_005905.2:g.70536_180359del, NG_005905.2:g.90012_97270dup, and NC_000017.10:g.41230935_41399840delinsAluSx1, respectively; previous observations of BRCA1 exon1-24del, exon1-2dup, and exon1-13del LGRs have not characterized them in such detail. All the BRCA1 LGRs arose from unequal homologous recombination events involving Alu elements. We also detected, by sequencing, one BRCA2 LGR, the Portuguese founder mutation c.156_157insAluYa5. The low frequency of BRCA1 LGRs within BRCA1 mutation carriers in Galicia (2.34%, 95% CI: 0.61-7.22) seems to differ from the Spanish population (9.93%, 95% CI: 6.76-14.27, P-value = 0.013) and from the rest of the Iberian population (9.76%, 95% CI: 6.69-13.94, P-value = 0.014). PMID:24686251

  3. Breast Cancer Susceptibility Gene1 (BRCA1

    Directory of Open Access Journals (Sweden)

    Wasiksiri, S.

    2002-07-01

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

  4. BRCA1 — EDRN Public Portal

    Science.gov (United States)

    BRCA1 is a nuclear phosphoprotein that functions as a tumor suppressor. BRCA1 combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). BRCA1 associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers.

  5. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    Science.gov (United States)

    Antoniou, Antonis C.; Sinilnikova, Olga M.; McGuffog, Lesley; Healey, Sue; Nevanlinna, Heli; Heikkinen, Tuomas; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Neuhausen, Susan L.; Ding, Yuan C.; Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary; Peterlongo, Paolo; Peissel, Bernard; Bonanni, Bernardo; Viel, Alessandra; Bernard, Loris; Radice, Paolo; Szabo, Csilla I.; Foretova, Lenka; Zikan, Michal; Claes, Kathleen; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Lejbkowicz, Flavio; Andrulis, Irene L.; Ozcelik, Hilmi; Glendon, Gord; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Caligo, Maria A.; Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Kaufman, Bella; Dagan, Efrat; Baruch, Ruth Gershoni; Friedman, Eitan; Harbst, Katja; Barbany-Bustinza, Gisela; Rantala, Johanna; Ehrencrona, Hans; Karlsson, Per; Domchek, Susan M.; Nathanson, Katherine L.; Osorio, Ana; Blanco, Ignacio; Lasa, Adriana; Benítez, Javier; Hamann, Ute; Hogervorst, Frans B.L.; Rookus, Matti A.; Collee, J. Margriet; Devilee, Peter; Ligtenberg, Marjolijn J.; van der Luijt, Rob B.; Aalfs, Cora M.; Waisfisz, Quinten; Wijnen, Juul; van Roozendaal, Cornelis E.P.; Peock, Susan; Cook, Margaret; Frost, Debra; Oliver, Clare; Platte, Radka; Evans, D. Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Davidson, Rosemarie; Chu, Carol; Eccles, Diana; Cole, Trevor; Hodgson, Shirley; Godwin, Andrew K.; Stoppa-Lyonnet, Dominique; Buecher, Bruno; Léoné, Mélanie; Bressac-de Paillerets, Brigitte; Remenieras, Audrey; Caron, Olivier; Lenoir, Gilbert M.; Sevenet, Nicolas; Longy, Michel; Ferrer, Sandra Fert; Prieur, Fabienne; Goldgar, David; Miron, Alexander; John, Esther M.; Buys, Saundra S.; Daly, Mary B.; Hopper, John L.; Terry, Mary Beth; Yassin, Yosuf; Gschwantler-Kaulich, Daphne; Staudigl, Christine; Hansen, Thomas v. O.; Barkardottir, Rosa Bjork; Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Offit, Kenneth; Piedmonte, Marion; Rodriguez, Gustavo C.; Wakeley, Katie; Boggess, John F.; Basil, Jack; Schwartz, Peter E.; Blank, Stephanie V.; Toland, Amanda E.; Montagna, Marco; Casella, Cinzia; Imyanitov, Evgeny N.; Allavena, Anna; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Niederacher, Dieter; Deißler, Helmut; Fiebig, Britta; Suttner, Christian; Schönbuchner, Ines; Gadzicki, Dorothea; Caldes, Trinidad; de la Hoya, Miguel; Pooley, Karen A.; Easton, Douglas F.; Chenevix-Trench, Georgia

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07–1.25, P-trend = 2.8 × 10−4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04–1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04–1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98–1.14) was consistent with odds ratio estimates derived from population-based case–control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not. PMID:19656774

  6. Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival

    Science.gov (United States)

    Biglia, Nicoletta; Sgandurra, Paola; Bounous, Valentina Elisabetta; Maggiorotto, Furio; Piva, Eleonora; Pivetta, Emanuele; Ponzone, Riccardo; Pasini, Barbara

    2016-01-01

    Objectives To compare clinical–pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC). Methods Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical–pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups. Results The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls. Conclusions At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed. PMID:27350785

  7. Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study.

    Science.gov (United States)

    Segev, Yakir; Rosen, Barry; Lubinski, Jan; Gronwald, Jacek; Lynch, Henry T; Moller, Pal; Kim-Sing, Charmaine; Ghadirian, Parviz; Karlan, Beth; Eng, Charis; Gilchrist, Dawna; Neuhausen, Susan L; Eisen, Andrea; Friedman, Eitan; Euhus, David; Ping, Sun; Narod, Steven A

    2015-09-01

    BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study. PMID:25838159

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

    Directory of Open Access Journals (Sweden)

    Fergus J Couch

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

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

    Science.gov (United States)

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

    2013-01-01

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

  10. Mammographic and sonomammographic patterns of breast cancer in women belonging to a genetically confirmed risk group with a detected BRCA1 gene mutation

    International Nuclear Information System (INIS)

    Carriers of the BRCA1 mutation have 50-80% increased risk of breast cancer. Therefore it is necessary to perform screening examinations regularly, more frequently than in the normal population. We suggest beginning mammography at 35 years of age, which significantly increases the chance of early detection of the cancer. A total of 293 women aged 20 - 60 years were analyzed. All the women were examined at the Hereditary Cancer Center. Mammography and sonomammography were performed on all patients. Mammograms of women who had undergone mastectomy were evaluated retrospectively. Benign-like changes, such as dense cysts or fibroadenomas, in the carrier group of the BRCA1 gene mutation were found in 40.5% of the women. Dynamic growth of the tumor was symptomatic. In the remaining group of women, morphology of the detected cancers revealed large, staging-dependent variability. On the basis of these findings we can conclude that cancer in women with the BRCA1 gene mutation can have a benign-like morphology, but with rapid tumor growth. Therefore all suspicious or atypical changes should be verified histopathologically. (author)

  11. Experience of BRCA1/2 mutation-negative young women from families with hereditary breast and ovarian cancer: a qualitative study

    OpenAIRE

    Macrae, Lynn; de Souza, Alicia Navarro; Loiselle, Carmen G.; Wong, Nora

    2013-01-01

    Background Little is known about the experience of young women who become aware of their parent’s BRCA1 or BRCA2 (BRCA) mutation status as adolescents or young adults. There is also currently a gap in the literature pertaining to those who are found to be negative for their familial mutation. We aimed to investigate the experience of these mutation-negative young women from hereditary breast and ovarian cancer (HBOC) families. Methods Using a semi-structured questionnaire we interviewed 8 wom...

  12. DCIS in BRCA1 and BRCA2 mutation carriers: prevalence, phenotype, and expression of oncodrivers C-MET and HER3

    OpenAIRE

    Yang, Rachel L.; Mick, Rosemarie; Lee, Kathreen; Holly L Graves; Nathanson, Katherine L.; Domchek, Susan M.; Kelz, Rachel R; Zhang, Paul J; Czerniecki, Brian J.

    2015-01-01

    Background Studies report conflicting evidence regarding the existence of a DCIS-associated premalignant pathway in BRCA mutation carriers. We aimed to examine the prevalence, phenotype, and expression of oncodrivers in pure DCIS (pDCIS) and invasive breast cancer with concurrent DCIS (IBC + DCIS) in mutation carriers. Methods A cohort of BRCA1 and BRCA2 mutation carriers >18 years old who underwent surgery for breast cancer at an academic hospital (1992–2011) and had pathology available for ...

  13. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers

    International Nuclear Information System (INIS)

    Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1Δ/Δ;p53Δ/Δ, Brca2Δ/Δ;p53Δ/Δ and p53Δ/Δ mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYC-associated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2Δ/Δ;p53Δ/Δ tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. The selection of the oncogenome during mouse and

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

    Science.gov (United States)

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

    2010-01-01

    The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers. PMID:21118973

  15. Analysis of BRIP1 Variants among Korean Patients with BRCA1/2 Mutation-Negative High-Risk Breast Cancer

    Science.gov (United States)

    Kim, Haeyoung; Cho, Dae-Yeon; Choi, Doo Ho; Jung, Gee Hue; Shin, Inkyung; Park, Won; Huh, Seung Jae; Nam, Seok Jin; Lee, Jeong Eon; Gil, Won Ho; Kim, Seok Won

    2016-01-01

    Purpose The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation. Materials and Methods Overall, 235 Korean patientswith BRCA1/2 mutation–negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT. Results A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1. Conclusion No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer. PMID:26790966

  16. The correlation of mammographic-and histologic patterns of breast cancers in BRCA1 gene mutation carriers, compared to age-matched sporadic controls

    Energy Technology Data Exchange (ETDEWEB)

    Kaas, R. [The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital, Department of Surgery, Amsterdam (Netherlands); Kroger, R.; Muller, S.H. [The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Radiology, Amsterdam (Netherlands); Peterse, J.L. [The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Pathology, Amsterdam (Netherlands); Hart, A.A.M. [The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital, Department of Radiotherapy, Amsterdam (Netherlands)

    2006-12-15

    Breast cancers in BRCA1 gene mutation carriers often have specific histologic features: grade III tumors with pushing margins. Our purpose was to compare the mammographic and histologic features of breast cancers in carriers with those in age-matched sporadic controls. The features of breast cancers in 27 BRCA1 carriers found during annual surveillance were compared to those in 107 age-matched sporadic controls. The carriers had no (classic) spiculated mammographic lesions, a high percentage of well-defined masses and hardly any masses with microcalcifications, whereas the controls had significantly fewer well-defined ones and only in 27% spiculated lesions on the mammogram. The well-defined mammographic tumors correlated in 83% of the carriers and in 70% of the controls with histologic circumscribed tumor margins. Spiculated mammographic lesions in the controls were in 90% grade I or II tumors. DCIS with or without infiltration was seen in 22% of the carriers and in 45% of the controls. In conclusion, breast cancers diagnosed in BRCA1 carriers do not have classic malignant mammographic features. A minority of the young sporadic controls show the classic malignant lesion on the mammogram. Both carriers and controls generally show a good correlation between their mammographic- and histologic tumor pattern. (orig.)

  17. The correlation of mammographic-and histologic patterns of breast cancers in BRCA1 gene mutation carriers, compared to age-matched sporadic controls

    International Nuclear Information System (INIS)

    Breast cancers in BRCA1 gene mutation carriers often have specific histologic features: grade III tumors with pushing margins. Our purpose was to compare the mammographic and histologic features of breast cancers in carriers with those in age-matched sporadic controls. The features of breast cancers in 27 BRCA1 carriers found during annual surveillance were compared to those in 107 age-matched sporadic controls. The carriers had no (classic) spiculated mammographic lesions, a high percentage of well-defined masses and hardly any masses with microcalcifications, whereas the controls had significantly fewer well-defined ones and only in 27% spiculated lesions on the mammogram. The well-defined mammographic tumors correlated in 83% of the carriers and in 70% of the controls with histologic circumscribed tumor margins. Spiculated mammographic lesions in the controls were in 90% grade I or II tumors. DCIS with or without infiltration was seen in 22% of the carriers and in 45% of the controls. In conclusion, breast cancers diagnosed in BRCA1 carriers do not have classic malignant mammographic features. A minority of the young sporadic controls show the classic malignant lesion on the mammogram. Both carriers and controls generally show a good correlation between their mammographic- and histologic tumor pattern. (orig.)

  18. The CYP1A2 genotype modifies the association between coffee consumption and breast cancer risk among BRCA1 mutation carriers.

    Science.gov (United States)

    Kotsopoulos, Joanne; Ghadirian, Parviz; El-Sohemy, Ahmed; Lynch, Henry T; Snyder, Carrie; Daly, Mary; Domchek, Susan; Randall, Susan; Karlan, Beth; Zhang, Phil; Zhang, Shiyu; Sun, Ping; Narod, Steven A

    2007-05-01

    We have recently reported that, among BRCA1 mutation carriers, the consumption of caffeinated coffee was associated with a significant reduction in breast cancer risk. Because the metabolism of caffeine is primarily by CYP1A2, we examined whether or not the CYP1A2 genotype modifies the association between a history of coffee consumption and the risk of breast cancer. A common A to C polymorphism in the CYP1A2 gene is associated with decreased enzyme inducibility and impaired caffeine metabolism. Information regarding coffee consumption habits and the CYP1A2 genotype was available for 411 BRCA1 mutation carriers (170 cases and 241 controls). We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer associated with the CYP1A2 genotype and a history of coffee consumption before age 35, adjusting for potential confounders. The CYP1A2 genotype did not affect breast cancer risk. Among women with at least one variant C allele (AC or CC), those who consumed coffee had a 64% reduction in breast cancer risk, compared with women who never consumed coffee (OR, 0.36; 95% CI, 0.18-0.73). A significant protective effect of coffee consumption was not observed among women with the CYP1A2 AA genotype (OR, 0.93; 95% CI, 0.49-1.77). Similar results were obtained when the analysis was restricted to caffeinated coffee. This study suggests that caffeine protects against breast cancer in women with a BRCA1 mutation and illustrates the importance of integrating individual genetic variability when assessing diet-disease associations. PMID:17507615

  19. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kartsonaki, Christiana; Sinilnikova, Olga M;

    2011-01-01

    independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk...... to a better understanding of the biology of tumour development in these women....

  20. 中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究%Breast cancer risk in BRCA1 and BRCA2 mutation carriers in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    杨晓晨; 胡震; 吴炅; 柳光宇; 沈镇宙; 邵志敏

    2015-01-01

    背景与目的:BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法:回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果:BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论:中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。%Background and purpose: BRCA1 and BRCA2 mutation carriers have a high lifetime risk of developing breast and ovarian cancer. Through genetic counseling, mutation carriers can take the appropriate measures to reduce such cancer risk. At present, almost all related studies were conducted in Caucasian, while, the studies in Chinese population were rare. This study aimed to investigate the risk of breast cancer in BRCA1 and BRCA2 mutation carriers in Chinese Han population. Methods:Twenty unrelated families with BRCA1 or BRCA2 mutations were re-viewed. Kaplan-Meier analyses were used to estimate the cumulative risks of unilateral breast cancer and contralateral breast cancer for female BRCA1 and BRCA2 mutation carriers. Results:Breast cancer risk to 70 years (penetrance) was 67

  1. Effect of chest X-rays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators' Group.

    OpenAIRE

    Nadine, Andrieu; Easton, Douglas; Chang-Claude, Jenny; Rookus, Matti; Brohet, Richard,; Cardis, Elisabeth; Antoniou, Antonis; Wagner, Teresa; Simard, Jacques; Evans, Gareth; Peock, Susan; Fricker, Jean-Pierre; Nogues, Catherine; Van'T Veer, Laura; Leeuwen, Flora

    2006-01-01

    PURPOSE: Women who carry germline mutations in the BRCA1 and BRCA2 genes are at greatly increased risk of breast cancer (BC). Numerous studies have shown that moderate to high doses of ionizing radiation are a risk factor for BC. Because of the role of the BRCA proteins in DNA repair, we hypothesized that BRCA carriers might be more sensitive to ionizing radiation than women in the general population. PATIENTS AND METHODS: A retrospective cohort study of 1,601 female BRCA1/2 carriers was perf...

  2. BRCA1: a movement toward cancer prevention

    Science.gov (United States)

    Alli, Elizabeth; Ford, James M

    2015-01-01

    Breast cancer susceptibility gene 1 (BRCA1) was first identified in 1994 and has since been shown to encode a tumor suppressor protein that maintains genetic stability through DNA damage response pathways. Carriers of mutations in BRCA1 are predisposed to breast and ovarian cancer; however, their cancers lack the targets for existing anticancer drugs. We describe a novel chemoprevention approach that uses DNA repair-activating agents to enhance the repair of oxidative DNA damage and, in turn, prevent tumorigenesis in the presence of mutant BRCA1. PMID:27308455

  3. Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, A.C.; Sinilnikova, O.M.; McGuffog, L.;

    2009-01-01

    Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9...... and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated...... their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit...

  4. Prospective Study of Breast Cancer Incidence in Women With a BRCA1 or BRCA2 Mutation Under Surveillance With and Without Magnetic Resonance Imaging

    Science.gov (United States)

    Warner, Ellen; Hill, Kimberley; Causer, Petrina; Plewes, Donald; Jong, Roberta; Yaffe, Martin; Foulkes, William D.; Ghadirian, Parviz; Lynch, Henry; Couch, Fergus; Wong, John; Wright, Frances; Sun, Ping; Narod, Steven A.

    2011-01-01

    Purpose The sensitivity of magnetic resonance imaging (MRI) for breast cancer screening exceeds that of mammography. If MRI screening reduces mortality in women with a BRCA1 or BRCA2 mutation, it is expected that the incidence of advanced-stage breast cancers should be reduced in women undergoing MRI screening compared with those undergoing conventional screening. Patients and Methods We followed 1,275 women with a BRCA1 or BRCA2 mutation for a mean of 3.2 years. In total, 445 women were enrolled in an MRI screening trial in Toronto, Ontario, Canada, and 830 were in the comparison group. The cumulative incidences of ductal carcinoma in situ (DCIS), early-stage, and late-stage breast cancers were estimated at 6 years in the cohorts. Results There were 41 cases of breast cancer in the MRI-screened cohort (9.2%) and 76 cases in the comparison group (9.2%). The cumulative incidence of DCIS or stage I breast cancer at 6 years was 13.8% (95% CI, 9.1% to 18.5%) in the MRI-screened cohort and 7.2% (95% CI, 4.5% to 9.9%) in the comparison group (P = .01). The cumulative incidence of stages II to IV breast cancers was 1.9% (95% CI, 0.2% to 3.7%) in the MRI-screened cohort and 6.6% (95% CI, 3.8% to 9.3%) in the comparison group (P = .02). The adjusted hazard ratio for the development of stages II to IV breast cancer associated with MRI screening was 0.30 (95% CI, 0.12 to 0.72; P = .008). Conclusion Annual surveillance with MRI is associated with a significant reduction in the incidence of advanced-stage breast cancer in BRCA1 and BRCA2 carriers. PMID:21444874

  5. A screen for germline mutations in the gene encoding CCCTC-binding factor (CTCF) in familial non-BRCA1/BRCA2 breast cancer

    International Nuclear Information System (INIS)

    The CCCTC-binding factor (CTCF), known as a versatile transcription factor and chromatin insulator and to be involved in X inactivation, has also been suggested to be a tumour suppressor on 16q. We investigated 153 patients with familial non-BRCA1/BRCA2 breast cancer for germline mutations in the CTCF gene. Mutation screening of CTCF was performed by denaturing high-performance liquid chromatography followed by cycle sequencing. We found two sequence variants, 240G→A in the 5' untranslated region and 1455C→T (S388S) in exon 4, in five familial breast cancer cases. Three of these five cases had both variants. Cases and controls showed the same prevalence for the two variants, which were found in linkage disequilibrium in most cases and controls. The present study suggests that germline mutations in CTCF are not important as a risk factor for breast cancer

  6. Reproductive Endocrinologists' Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers.

    Science.gov (United States)

    Goetsch, Allison L; Wicklund, Catherine; Clayman, Marla L; Woodruff, Teresa K

    2016-06-01

    Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists' (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies. PMID:26567039

  7. Structure-Function Of The Tumor Suppressor BRCA1

    Directory of Open Access Journals (Sweden)

    Serena L. Clark

    2012-04-01

    Full Text Available BRCA1, a multi-domain protein, is mutated in a large percentage of hereditary breast and ovarian cancers. BRCA1 is most often mutated in three domains or regions: the N-terminal RING domain, exons 11-13, and the BRCT domain. The BRCA1 RING domain mediates interactions between BRCA1 and other proteins and is responsible for the E3 ubiquitin ligase activity of BRCA1. BRCA1 ubiquitinates several proteins with various functions. The BRCA1 BRCT domain binds to phosphoproteins with specific sequences recognized by both BRCA1 and ATM/ATR kinases. Structural studies of the RING and BRCT domains have revealed the molecular basis by which cancer causing mutations impact the functions of BRCA1. While no structural data is available for the amino acids encoded by exons 11-13, multiple binding sites and functional domains exist in this region. Many mutations in exons 11-13 have deleterious effects on the function of these domains. In this mini-review, we examine the structure-function relationships of the BRCA1 protein and the relevance to cancer progression.

  8. No germline mutations in the histone acetyltransferase gene EP300 in BRCA1 and BRCA2 negative families with breast cancer and gastric, pancreatic, or colorectal cancer

    International Nuclear Information System (INIS)

    Mutations in BRCA1, BRCA2, ATM, TP53, CHK2 and PTEN account for many, but not all, multiple-case breast and ovarian cancer families. The histone acetyltransferase gene EP300 may function as a tumour suppressor gene because it is sometimes somatically mutated in breast, colorectal, gastric and pancreatic cancers, and is located on a region of chromosome 22 that frequently undergoes loss of heterozygosity in many cancer types. We hypothesized that germline mutations in EP300 may account for some breast cancer families that include cases of gastric, pancreatic and/or colorectal cancer. We screened the entire coding region of EP300 for mutations in the youngest affected members of 23 non-BRCA1/BRCA2 breast cancer families with at least one confirmed case of gastric, pancreatic and/or colorectal cancer. These families were ascertained in Australia through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. Denaturing HPLC analysis identified a heterozygous alteration at codon 211, specifically a GGC to AGC (glycine to serine) alteration, in two individuals. This conservative amino acid change was not within any known functional domains of EP300. The frequency of the Ser211 variant did not differ significanlty between a series of 352 breast cancer patients (4.0%) and 254 control individuals (2.8%; P = 0.5). The present study does not support a major role for EP300 mutations in breast and ovarian cancer families with a history of gastric, pancreatic and/or colorectal cancer

  9. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH, and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5, clear cell (n = 4, or low grade serous (n = 2 carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic, BRCA1 loss (epigenetic, and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  10. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  11. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  12. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    International Nuclear Information System (INIS)

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways

  13. Experiences of Women Who Underwent Predictive BRCA 1/2 Mutation Testing Before the Age of 30.

    Science.gov (United States)

    Brunstrom, Kate; Murray, Alexandra; McAllister, Marion

    2016-02-01

    This qualitative interview study focuses on the experiences of a sample of British female BRCA 1/2 carriers who had predictive testing before the age of 30, which is the minimum age for breast screening in the UK. Following appropriate informed consent procedures participants were recruited through the Cancer Genetics Service for Wales. Semi-structured interviews were conducted face-to-face with seven participants, transcribed in full and analyzed using thematic analysis. The motives for testing and perceived advantages described by participants were similar to those identified in previous studies with older participants, such as increased awareness and knowledge and feeling more in control. However some of the perceived disadvantages were specific to younger women, including feeling pressured to make important life decisions earlier than they would have liked, such as about family planning and risk reducing surgery. Participants also reported feeling abandoned or forgotten because of lack of ongoing clinical contact, or feeling "stuck waiting" for screening to begin. However, none felt that these disadvantages were a reason to regret having testing. Findings in this small study suggest that having BRCA 1/2 predictive testing can have positive outcomes for young women even though they may be unable to access interventions such as breast screening. However it may be helpful to encourage young women during pre-test counseling to explore the decisions and choices they may face. These young women could benefit from ongoing support and follow up and increased interaction with healthcare professionals. PMID:25983051

  14. Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

    International Nuclear Information System (INIS)

    Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous Δ11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated

  15. Mitochondrial localization, ELK-1 transcriptional regulation and Growth inhibitory functions of BRCA1, BRCA1a and BRCA1b proteins

    Science.gov (United States)

    Maniccia, Anna W; Lewis, Catherine; Begum, Nurjahan; Xu, Jingyao; Cui, Jianqi; Chipitsyna, Galina; Aysola, Kartik; Reddy, Vaishali; Bhat, Ganapathy; Fujimura, Yasuo; Henderson, Beric; Reddy, E. Shyam P.; Rao, Veena N.

    2009-01-01

    BRCA1 is a tumor suppressor gene that is mutated in families with breast and ovarian cancer. Several BRCA1 splice variants are found in different tissues, but their subcellular localization and functions are poorly understood at the moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis and function as a tumor suppressor of triple negative breast, ovarian and prostate cancers. In this study we have analyzed the function of BRCA1 isoforms (BRCA1a and BRCA1b) and compared them to the wild type BRCA1 protein using several criteria like studying expression in normal and tumor cells by RNase protection assays, sub cellular localization/fractionation by immunofluorescence microscopy and western blot analysis, transcription regulation of biological relevant proteins and growth suppression in breast cancer cells. We are demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 transcriptional activity and possess antiproliferative activity on breast cancer cells. These results suggest that the exon 9,10 and 11 sequences (aa 263 – 1365) which contain two nuclear localization signals, p53, Rb, c-Myc, γ- tubulin, Stat, Rad 51, Rad 50 binding domains, angiopoietin-1 repression domain are not absolutely required for mitochondrial localization and growth suppressor function of these proteins. Since mitochondrial dysfunction is a hallmark of cancer, we can speculate that the mitochondrial localization of BRCA1 proteins may be functionally significant in regulating both the mitochondrial DNA damage as well as apoptotic activity of BRCA1 proteins and mislocalization causes cancer. PMID:19170108

  16. High rate of mutations in the BRCA1, BRCA2, CHEK2, NBN, and BLM genes in Russian ovarian cancer patients

    Directory of Open Access Journals (Sweden)

    Ye. I. Bateneva

    2015-01-01

    Full Text Available Background. The early diagnosis of ovarian cancer (OC is an important problem in modern gynecological oncology due to significant detection rates for late-stage tumors. Intensive screening of patients from high-risk groups that include OC predisposition gene mutation carriers is indicated.Subjects and methods. An unselected group of 202 patients with OC and two control groups of blood donors: 591 healthy females; 1197 persons (including 591 females, 606 males were examined. Patients and healthy individuals who identified themselves as ethnic Russians and residents of the Russian Federation participated in the study. Whole peripheral blood samples were collected at the Clinical Subdivisions of the N.N. Blokhin Russian Cancer Research Center and at the Department of Transfusiology of the Acad. B.V. Petrovsky Russian Research Center of Surgery in 2012–2013. Informed consent was obtained from all the participants. DNA was extracted using a Prep-GS-Genetics reagent kit. Real-time polymerase chain reaction genotyping assay was carried out by melting-curve analysis employing an BRCA SNP genotyping kit(BRCA1 and BRCA2 gene mutations and original oligonucleotides (CHEK2, NBN, and BLM gene mutations. Thirteen population-specific mutations, including 7 (185delAG, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT, 300T>G, and 2080delA in the BRCA1 gene, 1 (6174delT in the BRCA2 gene, 3 (1100delC, IVS2+1G>A, and 470T>C in the CHEK2 gene, 1 (657delACAAA in the NBN gene, and 1 (1642C>T in the BLM gene, were genotyped. Polymerase chain reaction was performed using a DTprime real-time detection thermal cycler.Results and discussion. BRCA1 and BRCA2 gene mutations were detected in 46 (22.8 % patients with OC; the prevailing mutation in the BRCA1 gene was 5382insC (58.7 %. OC was diagnosed in 32.6 % of the patients aged 51 years or older. The rate of moderate-penetrance mutations (1100delC and IVS2+1G>A in the CHEK2 gene, 657del5 in the NBN gene, and 1642

  17. DNA damage induces p53-dependent BRCA1 nuclear export

    International Nuclear Information System (INIS)

    Full text: Carriers of BRCA1 mutations have an 85% risk of developing breast cancer by age 70. This risk is about 20-fold higher than the general population. BRCA1 functions in multiple DNA damage response pathways, and its functions are regulated by a variety of mechanisms including transcription control, phosphorylation, and protein-protein interactions. Given the critical role of BRCA1 in nucleus, its sub-cellular localization could be an important mechanism in regulating its function. Recent studies showed that BRCA1 is a nuclear-cytoplasmic shuttle protein. It is imported to the nucleus through a nuclear localization signal (NLS)-mediated importing receptor pathway, and exported to cytoplasm via a nuclear export signal (NES)-facilitated CRM1 pathway. However, little is known on how BRCA1 shuttling between the nucleus and cytoplasm is controlled, what cellular process(s) or environmental insult(s) triggers cell to import BRCA1 protein to nucleus and verse visa. In view of the fact that BRCA1 plays critical roles in several DNA damage response pathways, we hypothesized that ionizing radiation-induced DNA damage may affect BRCA1 shuttling. We found that ionizing radiation-induced DNA damage promotes BRCA1 nuclear export in human breast cancer cells through a CRM1-dependent mechanism. We further found that DNA damage-induced BRCA1 nuclear export is dependent on wild-type p53 function. These results suggest that p53-dependent BRCA1 nucleus export might be an alternative mechanism for BRCA1 functional regulation in cellular response to DNA damage. Interruption of BRCA1 shuttling in breast cancer cells that do not have functional p53 may compromise the precise regulation of BRCA1 function timely and spatially, resulting in aberrant DNA repair and increased genetic instability in surviving cells

  18. BRCA1 loses the ring but lords over resistance.

    Science.gov (United States)

    Powell, Simon N

    2016-08-01

    Germline breast cancer 1 (BRCA1) variants are associated with a high risk of breast and ovarian cancers. Many BRCA1-mediated cancers are initially responsive to platinum-based therapy; however, resistance commonly develops. The BRCA1185delAG mutation is common in the Ashkenazi Jewish population and has been thought to result in loss of function due to the introduction of a stop codon in the 5' region of the BRCA1 transcript. Two studies in this issue of the JCI reveal that the BRCA1185delAG mutation results in the production of BRCA1 that lacks the N-terminal really interesting new gene (RING) domain. RING-less BRCA1 was shown to directly mediate chemoresistance, while maintaining some homologous recombination function. These results provide important insight into BRCA1 function and indicate that other truncated proteins could arise through similar alterations in codon usage. PMID:27454288

  19. Incorporating information about pre-implantation genetic diagnosis into discussions about testing and risk-management for BRCA1/2 mutations: A qualitative study of patient preferences

    Science.gov (United States)

    Hurley, Karen; Rubin, Lisa; Werner-Lin, Allison; Sagi, Michal; Kemel, Yelena; Stern, Rikki; Phillips, Aliza; Cholst, Ina; Kauff, Noah; Offit, Kenneth

    2016-01-01

    Background Studies show that BRCA1/2 mutation carriers are interested in learning about reproductive options such as pre-implantation genetic diagnosis (PGD) to prevent passing their risk onto their children. However, attitudes vary widely, and the procedure raises complex ethical and psychosocial issues. This complexity, plus the highly technical nature of PGD, makes it difficult to integrate PGD information into genetic counseling sessions that already cover probabilistic, emotionally-charged risk information. Method Thirty-three reproductive age BRCA1/2 mutation carriers who had previously undergone genetic counseling viewed a tutorial about PGD and were interviewed about attitudes towards PGD, and preferences about how to include PGD information in genetic counseling. Results Most participants preferred to be briefly informed of availability of PGD information, and to receive written materials about PGD, but with the option of deferring detailed discussion if they already feel overloaded or perceive that PGD is not immediately relevant to their risk management and/or childbearing plans. For some, the stress of testing temporarily interfered with information processing, producing states of cognitive avoidance (“in a fog,” “tuning out”). Some preferred to discuss PGD with a physician with whom they had an ongoing relationship (e.g., OB/GYN, primary care provider, oncologist). Conclusions Providers offering cancer genetic testing can consider indicating availability of PGD information, while attending to patients’ level of interest and ability to absorb information. Research is needed to link patient responses to information overload to psychosocial outcomes (e.g., distress, decision quality). Continuing medical education is needed to support providers in facilitating informed decisions about PGD. PMID:22736296

  20. Risk of cancer other than breast or ovarian in Chinese Han women with BRCA1/2 mutations%中国汉族BRCA1/2突变的乳腺癌家系中其他肿瘤发病风险分析

    Institute of Scientific and Technical Information of China (English)

    刘静; 张娟; 欧阳涛; 李金峰; 王天峰; 范照青; 范铁; 林本耀; 解云涛

    2013-01-01

    Objective To investigate the risk of cancer other than breast or ovarian in Chinese Han women with family breast cancer who carried a BRCA1 or BRCA2 mutation.Methods Germline mutations in BRCA1/2 genes in the cohort of 465 Chinese Han patients with familial breast cancer were screened using a PCR-sequencing assay.The proportion of cancer other than breast or ovarian was compared in mutantion group and non mutation group.Results Among the 465 familial breast cancer patients,47 (10.1%) were BRCA1/2 mutation carriers and 418 (89.9%) were non-carriers.There was no significant difference in the total proportion of cancers other than breast or ovarian in the family between BRCA1/2 mutation carriers and non-carriers (27.7% ∶29.9%,x2 =0.10,P=0.75).But the tumor spectrum was different between the BRCA1/2 carriers and non-carriers.In the family of BRCA1/2 carriers,the most common cancers were gastric cancer,pancreatic cancer,and prostate cancer; while in the non-carriers,the most common cancers were lung cancer,gastric cancer,and esophageal cancer.The relative risk of gastric cancer,pancreatic cancer and prostate cancer was significantly higher in the families of BRCA1/2 mutation carriers than that of non-carriers (17%∶7.7%,odd ratio:2.47,95% CI:1.07-5.74,P =O.048).Conclusion This study suggests that the relative risk of gastric cancer,pancreatic cancer and prostate cancer in BRCA1/2 carriers is moderate higher than in non-carriers in Chinese Han women.%目的 研究携带BRCA1/2突变的中国汉族家族性乳腺癌家系中非乳腺癌和卵巢癌的其他肿瘤发病风险.方法 采用聚合酶链反应(PCR)-直接测序法检测465个汉族家族性乳腺癌家系中先证者的BRCA1/2基因胚系突变,比较突变组与非突变组有非乳腺癌和卵巢癌的其他肿瘤家族史的比例.结果 在465例汉族家族性乳腺癌先证者中,BRCA1/2突变者47例(10.1%),非突变者418例(89.9%).在BRCA1/2突变组和非突变组中,两者总

  1. Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers

    DEFF Research Database (Denmark)

    Jakubowska, A; Rozkrut, D; Antoniou, A;

    2012-01-01

    The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or...

  2. Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Couch, Fergus J; Gaudet, Mia M; Antoniou, Antonis C;

    2012-01-01

    Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mut...

  3. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    DEFF Research Database (Denmark)

    Antoniou, Antonis C; Kuchenbaecker, Karoline B; Soucy, Penny;

    2012-01-01

    Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 ...

  4. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, A.C.; Kuchenbaecker, K.B.; Soucy, P.; Beesley, J.; Chen, X.; McGuffog, L.; Lee, A.; Barrowdale, D.; Healey, S.; Sinilnikova, O.M.; Caligo, M.A.; Loman, N.; Harbst, K.; Lindblom, A.; Arver, B.; Rosenquist, R.; Karlsson, P.; Nathanson, K.; Domchek, S.; Rebbeck, T.; Jakubowska, A.; Lubinski, J.; Jaworska, K.; Durda, K.; Zlowowcka-Perlowska, E.; Osorio, A.; Duran, M.; Andres, R.; Benitez, J.; Hamann, U.; Hogervorst, F.B.; Os, T.A. van; Verhoef, S.; Meijers-Heijboer, H.E.; Wijnen, J.; Gomez Garcia, E.B.; Ligtenberg, M.J.L.; Kriege, M.; Collee, J.M.; Ausems, M.G.; Oosterwijk, J.C.; Peock, S.; Frost, D.; Ellis, S.D.; Platte, R.; Fineberg, E.; Evans, D.G.; Lalloo, F.; Jacobs, C.; Eeles, R.; Adlard, J.; Davidson, R.; Cole, T.; Cook, J.; Paterson, J.; Douglas, F.; Brewer, C.; Hodgson, S.; Morrison, P.J.; Walker, L.; Rogers, M.T.; Donaldson, A.; Dorkins, H.; Godwin, A.K.; Bove, B.; Stoppa-Lyonnet, D.; Houdayer, C.; Buecher, B.; Pauw, A. de; Mazoyer, S.; Calender, A.; Leone, M.; Bressac-de Paillerets, B.; Caron, O.; Sobol, H.; Frenay, M.; Prieur, F.; Ferrer, S.U.; Mortemousque, I.; Buys, S.; Daly, M.; Miron, A.; Terry, M.U.; Hopper, J.L.; John, E.M.; Southey, M.; Goldgar, D.; Singer, C.F.; Fink-Retter, A.; Tea, M.K.; Kaulich, D.U.; Hansen, T.V.; Nielsen, F.C.; Barkardottir, R.B.; Gaudet, M.; Kirchhoff, T.; Joseph, V.; Dutra-Clarke, A.; Offit, K.; Piedmonte, M., et al.

    2012-01-01

    INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  5. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

    NARCIS (Netherlands)

    Antoniou, Antonis C.; Kuchenbaecker, Karoline B.; Soucy, Penny; Beesley, Jonathan; Chen, Xiaoqing; McGuffog, Lesley; Lee, Andrew; Barrowdale, Daniel; Healey, Sue; Sinilnikova, Olga M.; Caligo, Maria A.; Loman, Niklas; Harbst, Katja; Lindblom, Annika; Arver, Brita; Rosenquist, Richard; Karlsson, Per; Nathanson, Kate; Domchek, Susan; Rebbeck, Tim; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Zlowowcka-Perlowska, Elzbieta; Osorio, Ana; Duran, Mercedes; Andres, Raquel; Benitez, Javier; Hamann, Ute; Hogervorst, Frans B.; van Os, Theo A.; Verhoef, Senno; Meijers-Heijboer, Hanne E. J.; Wijnen, Juul; Garcia, Encarna B. Gomez; Ligtenberg, Marjolijn J.; Kriege, Mieke; Collee, Margriet; Ausems, Margreet G. E. M.; Oosterwijk, Jan C.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Jacobs, Chris; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Cole, Trevor; Cook, Jackie; Paterson, Joan; Douglas, Fiona; Brewer, Carole; Hodgson, Shirley; Morrison, Patrick J.; Walker, Lisa; Rogers, Mark T.; Donaldson, Alan; Dorkins, Huw; Godwin, Andrew K.; Bove, Betsy; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Buecher, Bruno; de Pauw, Antoine; Mazoyer, Sylvie; Calender, Alain; Leone, Melanie; Bressac-de Paillerets, Brigitte; Caron, Olivier; Sobol, Hagay; Frenay, Marc; Prieur, Fabienne; Ferrer, Sandra Fert; Mortemousque, Isabelle; Buys, Saundra; Daly, Mary; Miron, Alexander; Terry, Mary Beth; Hopper, John L.; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Fink-Retter, Anneliese; Tea, Muy-Kheng; Kaulich, Daphne Geschwantler; Hansen, Thomas V. O.; Nielsen, Finn C.; Barkardottir, Rosa B.; Gaudet, Mia; Kirchhoff, Tomas; Joseph, Vijai; Dutra-Clarke, Ana; Offit, Kenneth; Piedmonte, Marion; Kirk, Judy; Cohn, David; Hurteau, Jean; Byron, John; Fiorica, James; Toland, Amanda E.; Montagna, Marco; Oliani, Cristina; Imyanitov, Evgeny; Isaacs, Claudine; Tihomirova, Laima; Blanco, Ignacio; Lazaro, Conxi; Teule, Alex; Del Valle, J.; Gayther, Simon A.; Odunsi, Kunle; Gross, Jenny; Karlan, Beth Y.; Olah, Edith; Teo, Soo-Hwang; Ganz, Patricia A.; Beattie, Mary S.; Dorfling, Cecelia M.; van Rensburg, Elizabeth Jansen; Diez, Orland; Kwong, Ava; Schmutzler, Rita K.; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Heidemann, Simone; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorothea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Fiebig, Britta; Schaefer, Dieter; Caldes, Trinidad; de la Hoya, Miguel; Nevanlinna, Heli; Muranen, Taru A.; Lesperance, Bernard; Spurdle, Amanda B.; Neuhausen, Susan L.; Ding, Yuan C.; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S.; Lindor, Noralane M.; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Bonanni, Bernardo; Bernard, Loris; Dolcetti, Riccardo; Papi, Laura; Ottini, Laura; Radice, Paolo; Greene, Mark H.; Loud, Jennifer T.; Andrulis, Irene L.; Ozcelik, Hilmi; Mulligan, Anna Marie; Glendon, Gord; Thomassen, Mads; Gerdes, Anne-Marie; Jensen, Uffe B.; Skytte, Anne-Bine; Kruse, Torben A.; Chenevix-Trench, Georgia; Couch, Fergus J.; Simard, Jacques; Easton, Douglas F.

    2012-01-01

    Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B),

  6. Glucocorticoid receptor repression mediated by BRCA1 inactivation in ovarian cancer

    International Nuclear Information System (INIS)

    BRCA mutations are the main known hereditary factor for ovarian cancer. Notably, emerging evidence indicates that the glucocorticoid receptor (GR) has drawn considerable interest in ovarian cancer development. However, dynamic cross-talk between BRCA1 and GR signaling pathways are poorly understood. The regulatory effects of BRCA on GR were assessed in 146 serous ovarian cancer patients (28 pairs of BRCA1-mutated or not, 23 pairs of BRCA2-mutated or not, and 22 pairs with hypermethylated BRCA1 promoter or not). BRCA1 promoter methylation was analyzed by bisulfite sequencing using primers flanking the core promoter region. Expression levels of BRCA1 and GR were assessed by immunohistochemistry and real-time PCR. Regression analysis was used to examine the possible relationship between BRCA1 and GR expression levels. The knockdown and overexpression of BRCA1 were achieved using a lentiviral vector in 293 T cells, SKOV3 ovarian cancer cells, and primary non-mutated and BRCA1-mutated ovarian cancer cells. GR expression levels were unchanged in non-BRCA1-mutated, non-BRCA2-mutated and BRCA2-mutated ovarian cancer compared to their normal tissues; BRCA1 repression (BRCA1 mutation or BRCA1 promoter hypermethylation) ovarian cancer showed decreased GR levels compared to normal tissue; there was a positive correlation between BRCA1 and GR expression in human ovarian cancer specimens; BRCA1 knockdown was effective at inhibiting GR expression, and overexpression of BRCA1 induces an increase in GR levels in ovarian cancer cells. These results suggest that GR may be a potential target for BRCA1 in ovarian cancer progression

  7. BRCA1 in the DNA damage response and at telomeres

    Directory of Open Access Journals (Sweden)

    Eliot Michael Rosen

    2013-06-01

    Full Text Available Abstract. Mutations of the breast and ovarian cancer susceptibility gene 1 (BRCA1 account for about 40-45% of hereditary breast cancer cases. Moreover, a significant fraction of sporadic (non-hereditary breast and ovarian cancers exhibit reduced or absent expression of the BRCA1 protein, suggesting an additional role for BRCA1 in sporadic cancers. BRCA1 follows the classic pattern of a highly penetrant Knudsen-type tumor suppressor gene in which one allele is inactivated through a germ-line mutation and the other is mutated or deleted within the tumor. BRCA1 is a multi-functional protein but it is not fully understood which function(s is (are most important for tumor suppression, nor is it clear why BRCA1 mutations confer a high risk for breast and ovarian cancers and not a broad spectrum of tumor types. Here, we will review BRCA1 functions in the DNA damage response (DDR, which are likely to contribute to tumor suppression. In the process, we will highlight some of the controversies and unresolved issues in the field. We will also describe a recently identified and under-investigated role for BRCA1 in the regulation of telomeres and the implications of this role in the DDR and cancer suppression.

  8. Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.

    Directory of Open Access Journals (Sweden)

    Sophie Blein

    Full Text Available Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.

  9. Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2

    Science.gov (United States)

    Blein, Sophie; Barjhoux, Laure; Damiola, Francesca; Dondon, Marie-Gabrielle; Eon-Marchais, Séverine; Marcou, Morgane; Caron, Olivier; Lortholary, Alain; Buecher, Bruno; Berthet, Pascaline; Noguès, Catherine; Lasset, Christine; Gauthier-Villars, Marion; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Andrieu, Nadine; Cox, David G.

    2015-01-01

    Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk. PMID:26406445

  10. Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry

    OpenAIRE

    2011-01-01

    Abstract Biallelic inactivation of ATM gene causes the rare autosomal recessive disorder Ataxia-telangiectasia (A-T). Female relatives of A-T patients have a two-fold higher risk of developing breast cancer (BC) compared with the general population. ATM mutation carrier identification is laborious and expensive, therefore, a more rapid and directed strategy for ATM mutation profiling is needed. We designed a case?control study to determine the prevalence of 32 known ATM mutations c...

  11. Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ' easy to apply ' probability models

    NARCIS (Netherlands)

    Bodmer, D.; Ligtenberg, M. J. L.; van der Hout, A. H.; Gloudemans, S.; Ansink, K.; Oosterwijk, J. C.; Hoogerbrugge, N.

    2006-01-01

    To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of

  12. Characterization of BRCA1 Protein Targeting, Dynamics, and Function at the Centrosome

    Science.gov (United States)

    Brodie, Kirsty M.; Henderson, Beric R.

    2012-01-01

    BRCA1 is a DNA damage response protein and functions in the nucleus to stimulate DNA repair and at the centrosome to inhibit centrosome overduplication in response to DNA damage. The loss or mutation of BRCA1 causes centrosome amplification and abnormal mitotic spindle assembly in breast cancer cells. The BRCA1-BARD1 heterodimer binds and ubiquitinates γ-tubulin to inhibit centrosome amplification and promote microtubule nucleation; however regulation of BRCA1 targeting and function at the centrosome is poorly understood. Here we show that both N and C termini of BRCA1 are required for its centrosomal localization and that BRCA1 moves to the centrosome independently of BARD1 and γ-tubulin. Mutations in the C-terminal phosphoprotein-binding BRCT domain of BRCA1 prevented localization to centrosomes. Photobleaching experiments identified dynamic (60%) and immobilized (40%) pools of ectopic BRCA1 at the centrosome, and these are regulated by the nuclear export receptor CRM1 (chromosome region maintenance 1) and BARD1. CRM1 mediates nuclear export of BRCA1, and mutation of the export sequence blocked BRCA1 regulation of centrosome amplification in irradiated cells. CRM1 binds to undimerized BRCA1 and is displaced by BARD1. Photobleaching assays implicate CRM1 in driving undimerized BRCA1 to the centrosome and revealed that when BRCA1 subsequently binds to BARD1, it is less well retained at centrosomes, suggesting a mechanism to accelerate BRCA1 release after formation of the active heterodimer. Moreover, Aurora A binding and phosphorylation of BRCA1 enhanced its centrosomal retention and regulation of centrosome amplification. Thus, CRM1, BARD1 and Aurora A promote the targeting and function of BRCA1 at centrosomes. PMID:22262852

  13. BRCA1 and Oxidative Stress

    Energy Technology Data Exchange (ETDEWEB)

    Yi, Yong Weon; Kang, Hyo Jin [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Bae, Insoo, E-mail: ib42@georgetown.edu [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Department of Radiation Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States)

    2014-04-03

    The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.

  14. BRCA1 and Oxidative Stress

    International Nuclear Information System (INIS)

    The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1’s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers

  15. "Social separation" among women under 40 years of age diagnosed with breast cancer and carrying a BRCA1 or BRCA2 mutation.

    Science.gov (United States)

    Kenen, Regina; Ardern-Jones, Audrey; Eeles, Rosalind

    2006-06-01

    We conducted an exploratory, qualitative study investigating experiences of women who had developed breast cancer under the age of 40 and who were identified as BRCA1 or BRCA2 mutation carriers. These germline mutation carriers face an increased lifetime risk of a second primary breast cancer and an increased risk for a primary ovarian cancer. Thirteen women who fit this criteria participated in three focus groups conducted at a major cancer center in the UK during Spring 2003. We asked broad, open-ended questions that allowed for a wide range of responses about their cancer and genetic testing experiences, physical and psycho-social concerns, family and partner reactions and their need for social support. The women expressed feelings of devastation, loneliness, feeling different and isolation, ambivalence about having to support family members, worries about partner's anxiety and depression, and anxiety about talking to family members, especially children. These feelings were stronger after the cancer diagnosis and compounded by the genetic test results that occurred at a later time. We also found that, at least temporarily, the women experienced what we call "social separation"--emotional distance from, or dissonance with groups they interact with or are part of, e.g., family and friends, frequently leading to a reduction in communication or a change in previously unstated, but accepted normal interaction. We concentrate on a few characteristics of social separation-feelings of aloneness, isolation and separation, use of silence and verbal discretion, the relationship between estrangement and kinship interaction and norm disruption, and are looking at social patterns of interpersonal relationships that may occur when risk and illness statuses are new and framing and feeling rules have not as yet been clearly developed due to a cultural lag. PMID:16724273

  16. BRCA1 tumor suppressor network: focusing on its tail

    Directory of Open Access Journals (Sweden)

    Wang Bin

    2012-02-01

    Full Text Available Abstract Germline mutations of the BRCA1 tumor suppressor gene are a major cause of familial breast and ovarian cancer. BRCA1 plays critical roles in the DNA damage response that regulates activities of multiple repair and checkpoint pathways for maintaining genome stability. The BRCT domains of BRCA1 constitute a phospho-peptide binding domain recognizing a phospho-SPxF motif (S, serine; P, proline; × varies; F, phenylalanine. The BRCT domains are frequently targeted by clinically important mutations and most of these mutations disrupt the binding surface of the BRCT domains to phosphorylated peptides. The BRCT domain and its capability to bind phosphorylated protein is required for the tumor suppressor function of BRCA1. Through its BRCT phospho-binding ability BRCA1 forms at least three mutually exclusive complexes by binding to phosphorylated proteins Abraxas, Bach1 and CTIP. The A, B and C complexes, at lease partially undertake BRCA1's role in mechanisms of cell cycle checkpoint and DNA repair that maintain genome stability, thus may play important roles in BRCA1's tumor suppressor function.

  17. Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

    Directory of Open Access Journals (Sweden)

    Romdhane Lilia

    2012-08-01

    Full Text Available Abstract Background Tunisia is a North African country of 10 million inhabitants. The native background population is Berber. However, throughout its history, Tunisia has been the site of invasions and migratory waves of allogenic populations and ethnic groups such as Phoenicians, Romans, Vandals, Arabs, Ottomans and French. Like neighbouring and Middle Eastern countries, the Tunisian population shows a relatively high rate of consanguinity and endogamy that favor expression of recessive genetic disorders at relatively high rates. Many factors could contribute to the recurrence of monogenic morbid trait expression. Among them, founder mutations that arise in one ancestral individual and diffuse through generations in isolated communities. Method We report here on founder mutations in the Tunisian population by a systematic review of all available data from PubMed, other sources of the scientific literature as well as unpublished data from our research laboratory. Results We identified two different classes of founder mutations. The first includes founder mutations so far reported only among Tunisians that are responsible for 30 genetic diseases. The second group represents founder haplotypes described in 51 inherited conditions that occur among Tunisians and are also shared with other North African and Middle Eastern countries. Several heavily disabilitating diseases are caused by recessive founder mutations. They include, among others, neuromuscular diseases such as congenital muscular dystrophy and spastic paraglegia and also severe genodermatoses such as dystrophic epidermolysis bullosa and xeroderma pigmentosa. Conclusion This report provides informations on founder mutations for 73 genetic diseases either specific to Tunisians or shared by other populations. Taking into account the relatively high number and frequency of genetic diseases in the region and the limited resources, screening for these founder mutations should provide a rapid

  18. BRCA1 and BRCA2 gene mutations in familial breast cancer%家族性乳腺癌家系成员乳腺癌易感基因突变的研究

    Institute of Scientific and Technical Information of China (English)

    李军改; 回天立; 李峥; 白杨; 马国明; 孙玉巧; 李春晓; 耿翠芝

    2012-01-01

    目的 研究河北省地区家族性乳腺癌家系中的患者及健康一级亲属乳腺癌易感基因1(BRCA1)和乳腺癌易感基因2(BRCA2)突变位点及携带情况.方法 研究对象为2002年6月至2008年5月河北医科大学第四医院接诊的乳腺癌患者及其亲属,分别来自12个独立的汉族家族性乳腺癌家系,该家系中有2个及2个以上一级或二级亲属乳腺癌患病史,研究病例包括13例患者及46例健康一级亲属,共59例样本.由外周血提取基因组DNA,采用聚合酶链反应-单链构象多态性分析(PCR-SSCP)和基因测序技术对国内外报告中常见的4个BRCA1/BRCA2突变热点区域(BRCA1:外显子2、11、20;BRCA2外显子11)进行检测.结果 发现1个BRCA1突变位点(4193insA)和1个BRCA2突变位点(5329insT),全部为移码突变;发现4个变异位点(BRCA1:4165T>A 、287G>C,BRCA2:6251G>T、5416C>A),4193insA、5329insT、287G>C携带者的家系中均有3例乳腺癌患者.结论 BRCA1(4193insA)、BRCA2(5329insT)以及BRCA1:4165T>A 、287G>C和BRCA2:6251G>T、5416C>A可能是河北省家族性乳腺癌相关性突变位点,其携带者家系中乳腺癌发病率明显升高,建议对其一级亲属密切随访或尽早进行手术或药物干预.%Objectiff To investigate mutations and the carrying of breast cancer susceptibility gene ( BRCA) 1 and BRCA2 among patients and their healthy first degree relatives in family constellation of breast cancer in Hebei province . Mtehods This study involved breast cancer patients treated in the Fourth Affiliated Hospital of Hebei Medical University from June, 2002to May, 2008 and their relative, including 59 samples (13 patients and 46 healthy first degree relatives from 12 independent families of Han Nationality in which 2 or more first or second degree relatives had breast cancer history . Four BRCA1/ BRCA2 mutation hot spots ( BRCA1; Exon2,11,20 ; BRCA2; Exonl 1) commonly reported in literature were detected by extracting DNA from

  19. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

    Science.gov (United States)

    Antoniou, Antonis C; Wang, Xianshu; Fredericksen, Zachary S; McGuffog, Lesley; Tarrell, Robert; Sinilnikova, Olga M; Healey, Sue; Morrison, Jonathan; Kartsonaki, Christiana; Lesnick, Timothy; Ghoussaini, Maya; Barrowdale, Daniel; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Eccles, Diana; Evans, D Gareth; Eeles, Ros; Izatt, Louise; Chu, Carol; Douglas, Fiona; Paterson, Joan; Stoppa-Lyonnet, Dominique; Houdayer, Claude; Mazoyer, Sylvie; Giraud, Sophie; Lasset, Christine; Remenieras, Audrey; Caron, Olivier; Hardouin, Agnès; Berthet, Pascaline; Hogervorst, Frans B L; Rookus, Matti A; Jager, Agnes; van den Ouweland, Ans; Hoogerbrugge, Nicoline; van der Luijt, Rob B; Meijers-Heijboer, Hanne; García, Encarna B Gómez; Devilee, Peter; Vreeswijk, Maaike P G; Lubinski, Jan; Jakubowska, Anna; Gronwald, Jacek; Huzarski, Tomasz; Byrski, Tomasz; Górski, Bohdan; Cybulski, Cezary; Spurdle, Amanda B; Holland, Helene; Goldgar, David E; John, Esther M; Hopper, John L; Southey, Melissa; Buys, Saundra S; Daly, Mary B; Terry, Mary-Beth; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Preisler-Adams, Sabine; Arnold, Norbert; Niederacher, Dieter; Sutter, Christian; Domchek, Susan M; Nathanson, Katherine L; Rebbeck, Timothy; Blum, Joanne L; Piedmonte, Marion; Rodriguez, Gustavo C; Wakeley, Katie; Boggess, John F; Basil, Jack; Blank, Stephanie V; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Milgrom, Roni; Andrulis, Irene L; Glendon, Gord; Ozcelik, Hilmi; Kirchhoff, Tomas; Vijai, Joseph; Gaudet, Mia M; Altshuler, David; Guiducci, Candace; Loman, Niklas; Harbst, Katja; Rantala, Johanna; Ehrencrona, Hans; Gerdes, Anne-Marie; Thomassen, Mads; Sunde, Lone; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Viel, Alessandra; Radice, Paolo; Caldes, Trinidad; de la Hoya, Miguel; Singer, Christian F; Fink-Retter, Anneliese; Greene, Mark H; Mai, Phuong L; Loud, Jennifer T; Guidugli, Lucia; Lindor, Noralane M; Hansen, Thomas V O; Nielsen, Finn C; Blanco, Ignacio; Lazaro, Conxi; Garber, Judy; Ramus, Susan J; Gayther, Simon A; Phelan, Catherine; Narod, Stephen; Szabo, Csilla I; Benitez, Javier; Osorio, Ana; Nevanlinna, Heli; Heikkinen, Tuomas; Caligo, Maria A; Beattie, Mary S; Hamann, Ute; Godwin, Andrew K; Montagna, Marco; Casella, Cinzia; Neuhausen, Susan L; Karlan, Beth Y; Tung, Nadine; Toland, Amanda E; Weitzel, Jeffrey; Olopade, Olofunmilayo; Simard, Jacques; Soucy, Penny; Rubinstein, Wendy S; Arason, Adalgeir; Rennert, Gad; Martin, Nicholas G; Montgomery, Grant W; Chang-Claude, Jenny; Flesch-Janys, Dieter; Brauch, Hiltrud; Severi, Gianluca; Baglietto, Laura; Cox, Angela; Cross, Simon S; Miron, Penelope; Gerty, Sue M; Tapper, William; Yannoukakos, Drakoulis; Fountzilas, George; Fasching, Peter A; Beckmann, Matthias W; Silva, Isabel dos Santos; Peto, Julian; Lambrechts, Diether; Paridaens, Robert; Rüdiger, Thomas; Försti, Asta; Winqvist, Robert; Pylkäs, Katri; Diasio, Robert B; Lee, Adam M; Eckel-Passow, Jeanette; Vachon, Celine; Blows, Fiona; Driver, Kristy; Dunning, Alison; Pharoah, Paul P D; Offit, Kenneth; Pankratz, V Shane; Hakonarson, Hakon; Chenevix-Trench, Georgia; Easton, Douglas F; Couch, Fergus J

    2011-01-01

    Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7). PMID:20852631

  20. Post-mortem testing; germline BRCA1/2 variant detection using archival FFPE non-tumor tissue. A new paradigm in genetic counseling.

    Science.gov (United States)

    Petersen, Annabeth Høgh; Aagaard, Mads Malik; Nielsen, Henriette Roed; Steffensen, Karina Dahl; Waldstrøm, Marianne; Bojesen, Anders

    2016-08-01

    Accurate estimation of cancer risk in HBOC families often requires BRCA1/2 testing, but this may be impossible in deceased family members. Previous, testing archival formalin-fixed, paraffin-embedded (FFPE) tissue for germline BRCA1/2 variants was unsuccessful, except for the Jewish founder mutations. A high-throughput method to systematically test for variants in all coding regions of BRCA1/2 in archival FFPE samples of non-tumor tissue is described, using HaloPlex target enrichment and next-generation sequencing. In a validation study, correct identification of variants or wild-type was possible in 25 out of 30 (83%) FFPE samples (age range 1-14 years), with a known variant status in BRCA1/2. No false positive was found. Unsuccessful identification was due to highly degraded DNA or presence of large intragenic deletions. In clinical use, a total of 201 FFPE samples (aged 0-43 years) were processed. Thirty-six samples were rejected because of highly degraded DNA or failed library preparation. Fifteen samples were investigated to search for a known variant. In the remaining 150 samples (aged 0-38 years), three variants known to affect function and one variant likely to affect function in BRCA1, six variants known to affect function and one variant likely to affect function in BRCA2, as well as four variants of unknown significance (VUS) in BRCA1 and three VUS in BRCA2 were discovered. It is now possible to test for germline BRCA1/2 variants in deceased persons, using archival FFPE samples from non-tumor tissue. Accurate genetic counseling is achievable in families where variant testing would otherwise be impossible. PMID:26733283

  1. Features of 152 families eligible for the investigation of mutations in BRCA1 / 2, evaluated Onco genetics unit Clinics Hospital

    International Nuclear Information System (INIS)

    the prevalence of BRCA2 mutations in familial breast cancer in our country, previously reported by our group. With respect to biological subtype although the number of patients analyzed is small, it is noteworthy the high proportion of He r2 positive patients, which justifies the study of the biological profile of a greater number of patients with a history compatible with Uruguayan hereditary predisposition

  2. Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies

    OpenAIRE

    Antoniou, A; Pharoah, P. D. P.; Narod, S.; Risch, H A; Eyfjord, J. E.; Hopper, J L; Loman, N.; Olsson, H; Johannsson, O.; Borg, Å.; Pasini, B; Radice, P.; Manoukian, S; Eccles, D M; N. Tang

    2003-01-01

    Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family his...

  3. Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

    Directory of Open Access Journals (Sweden)

    Foulkes William D

    2006-03-01

    harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent. Conclusion These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed.

  4. Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers

    Directory of Open Access Journals (Sweden)

    Bjørnslett Merete

    2012-10-01

    Full Text Available Abstract Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60 were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465. Results The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005. In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057. Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002. The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068. No such associations were found in BRCA2 related ovarian cancer. Conclusions Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.

  5. Phosphatidylinositol 3-kinase/Akt signaling enhances nuclear localization and transcriptional activity of BRCA1

    International Nuclear Information System (INIS)

    Signaling pathways involved in regulating nuclear-cytoplasmic distribution of BRCA1 have not been previously reported. Here, we provide evidence that heregulin β1-induced activation of the Akt pathway increases the nuclear content of BRCA1. First, treatment of T47D breast cancer cells with heregulin β1 results in a two-fold increase in nuclear BRCA1 as assessed by FACS analysis, immunoblotting and immunofluorescence. This heregulin-induced increase in nuclear BRCA1 is blocked by siRNA-mediated down-regulation of Akt. Second, mutation of threonine 509 in BRCA1, the site of Akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce BRCA1 nuclear accumulation. These data suggest that Akt-catalyzed phosphorylation of BRCA1 is required for the heregulin-regulated nuclear concentration of BRCA1. Because most functions ascribed to BRCA1 occur within the nucleus, we postulated that phosphorylation-dependent nuclear accumulation of BRCA1 would result in enhanced nuclear activity, specifically transcriptional activity, of BRCA1. This postulate is affirmed by our observation that the ability of BRCA1 to transactivate GADD45 promoter constructs was enhanced in T47D cells treated with heregulin β1. Furthermore, the heterologous expression of BRCA1 in HCC1937 human breast cancer cells, which have constitutively active Akt, also induces GADD45 promoter activity, whereas the expression of BRCA1 in which threonine 509 has been mutated to an alanine is able to only minimally induce promoter activity. These findings implicate Akt in upstream events leading to BRCA1 nuclear localization and function

  6. The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression

    Directory of Open Access Journals (Sweden)

    Andy Castillo

    2014-08-01

    Full Text Available Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT domains interact with multiple proteins and are required for BRCA1’s tumor-suppressor function. In this study, we demonstrated that Abraxas, a BRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair and maintain genome stability. Both homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence. The gene encoding Abraxas suffers from gene copy loss and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers, suggesting that mutation and loss of function of Abraxas may contribute to tumor development in human patients.

  7. Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling.

    Science.gov (United States)

    Beristain, E; Martínez-Bouzas, C; Guerra, I; Viguera, N; Moreno, J; Ibañez, E; Díez, J; Rodríguez, F; Mallabiabarrena, G; Luján, S; Gorostiaga, J; De Pablo, J L; Mendizabal, J L; Tejada, M I

    2007-12-01

    The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population. PMID:17262179

  8. Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India.

    Science.gov (United States)

    Bijarnia-Mahay, Sunita; Movva, Sireesha; Gupta, Neerja; Sharma, Deepak; Puri, Ratna D; Kotecha, Udhaya; Saxena, Renu; Kabra, Madhulika; Mohan, Neelam; Verma, Ishwar C

    2015-01-01

    Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding "common mutations" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India. PMID:25595217

  9. Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

    Directory of Open Access Journals (Sweden)

    Beech Cameron M

    2011-11-01

    Full Text Available Abstract Background Imerslund-Gräsbeck syndrome (IGS was described just over 50 years ago by Olga Imerslund and Ralph Gräsbeck and colleagues. IGS is caused by specific malabsorption of cobalamin (Cbl due to bi-allelic mutations in either the cubilin gene (CUBN or the human amnionless homolog (AMN. Mutations in the two genes are commonly seen in founder populations or in societies with a high degree of consanguineous marriages. One particular mutation in AMN, c.208-2A>G, causing an out-of-frame loss of exon 4 in the mRNA, is responsible for some 15% of IGS cases globally. We present evidence that this founder mutation causes a substantial percentage of cases among diverse ethnicities and that the mutation is as old as human civilization. Methods Partial genotyping indicated a founder event but its presence in diverse peoples of Arabic, Turkish, Jewish, and Hispanic ancestry suggested that the mutation might be recurrent. We therefore studied the flanking sequence spanning 3.5 Mb to elucidate the origin of the haplotype and estimate the age of the mutation using a Bayesian inference method based on observed linkage disequilibrium. Results The mutation's distribution, the size of the shared haplotype, and estimates of growth rate and carrier frequency indicated that the mutation was a single prehistoric event. Dating back to the ancient Middle East around 11,600 BC, the mutation predates the advent of writing, farming, and the monotheistic religions of the region. Conclusions This mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East. Thus, rare founder mutations may cause a substantial number of cases, even among diverse ethnicities not usually thought to be related.

  10. BRCA1/2 associated hereditary breast cancer

    Institute of Scientific and Technical Information of China (English)

    Li-song TENG; Yi ZHENG; Hao-hao WANG

    2008-01-01

    Breast cancer is one of the leading causes of death in women today. Some of the patients are hereditary, with a large proportion characterized by mutation in BRCA1 and/or BRCA2 genes. In this review, we provide an overview of these two genes,focusing on their relationship with hereditary breast cancers. BRCA1/2 associated hereditary breast cancers have unique features that differ from the general breast cancers, including alterations in cellular molecules, pathological bases, biological behavior, and a different prevention strategy. But the outcome of BRCA1/2 associated hereditary breast cancers still remains controversial;further studies are needed to elucidate the nature of BRCA1/2 associated hereditary breast cancers.

  11. Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers

    OpenAIRE

    Bjørnslett Merete; Knappskog Stian; Lønning Per; Dørum Anne

    2012-01-01

    Abstract Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results we...

  12. BRCA1 and Oxidative Stress

    OpenAIRE

    Yong Weon Yi; Hyo Jin Kang; Insoo Bae

    2014-01-01

    The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to tre...

  13. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families

    DEFF Research Database (Denmark)

    Hansen, Thomas van Overeem; Jønson, Lars; Albrechtsen, Anders;

    2010-01-01

    >A/c.130T>A (p.Cys44Ser) mutation in another Greenlandic individual with ovarian cancer. This patient share a 1-2 Mb genomic fragment, containing the BRCA1 gene, with four Danish families harbouring the same mutation, suggesting that the 249T>A/c.130T>A (p.Cys44Ser) mutation originates from a Danish...

  14. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer

    DEFF Research Database (Denmark)

    Hansen, Thomas V O; Jønson, Lars; Albrechtsen, Anders;

    2010-01-01

    >A/c.130T>A (p.Cys44Ser) mutation in another Greenlandic individual with ovarian cancer. This patient share a 1-2 Mb genomic fragment, containing the BRCA1 gene, with four Danish families harbouring the same mutation, suggesting that the 249T>A/c.130T>A (p.Cys44Ser) mutation originates from a Danish...

  15. BRCA1 Zinc RING Finger Domain Disruption Alters Caspase Response in Ovarian Surface Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Kruk Patricia A

    2002-07-01

    Full Text Available Abstract Background The frequently occurring 185delAG mutation occurs in the amino-terminal zinc RING domain of the breast and ovarian cancer susceptibility gene, BRCA1. We sought to determine differential cell viability and apoptotic response of human ovarian surface epithelial cells with and without the 185delAG mutation. Results BRCA1wt and BRCA1+ cells were treated with staurosporine. Cell proliferation assays showed BRCA1wt cells grew to a greater extent compared to BRCA1+ cells. Trypan blue exclusion assays confirmed this observation. Western immunoblot analysis revealed that caspase 3 levels were higher after staurosporine treatment in BRCA1+ cells than in wild type cells, while full length DNA Fragmentation Factor 45 levels were lower in BRCA1+ cells. While there was no significant difference in levels of excision repair cross complementing protein1 (ERCC1 with BRCA1 status, BRCA1+ cells demonstrated cleavage of polyribose ADP polymerase (PARP before wild type cells. Conclusions Disruption of the BRCA1 RING domain caused altered cell viability and caspase-dependent apoptotic response after chemotoxic stress.

  16. 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.

  17. Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation

    DEFF Research Database (Denmark)

    Therkildsen, Christina; Isinger-Ekstrand, Anna; Ladelund, Steen; Nissen, Anja; Rambech, Eva; Bernstein, Inge; Nilbert, Mef

    2012-01-01

    for extracolonic cancer (RR of 0.69 for endometrial cancer and 0.39 for all other extracolonic cancers). We also characterized expression of key Wnt-signaling proteins in colorectal cancers with the founder mutation. Aberrant staining affected β-catenin in 59 %, E-cadherin in 68 %, TCF-4 in 94 % and...

  18. Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark

    DEFF Research Database (Denmark)

    Thomassen, Mads; Gerdes, Anne-Marie; Cruger, Dorthe; Jensen, Peter K A; Kruse, Torben A

    2006-01-01

    Germline mutations in BRCA1 and BRCA2 predispose female carriers to breast and ovarian cancer. The majority of mutations identified are small deletions or insertions or are nonsense mutations. Large genomic rearrangements in BRCA1 are found with varying frequencies in different populations, but...... BRCA2 rearrangements have not been investigated thoroughly. The objective in this study was to determine the frequency of large genomic rearrangements in BRCA1 and BRCA2 in a large group of Danish families with increased risk of breast and ovarian cancer. A total of 617 families previously tested...... negative for mutations involving few bases were screened with multiplex ligation-dependent probe amplification (MLPA). Two deletions in BRCA1 were identified in three families; no large rearrangements were detected in BRCA2. The large deletions constitute 3.8% of the BRCA1 mutations identified, which is...

  19. The breast cancer susceptibility gene BRCA1: DNA repair and other functions

    International Nuclear Information System (INIS)

    BRCA1 is a tumour suppressor gene. Germline mutations in BRCA1 confer susceptibility to breast and ovarian cancer and levels of BRCA1 mRNA and/or protein are reduced in a significant proportion of sporadic breast tumours. The product of this gene is a large multifunctional nuclear phosphoprotein that has been implicated in the regulation of cell cycle progression, apoptosis, transcription and DNA repair. Thus BRCA1 is thought to function as a genomic caretaker, responding to DNA damage by halting cell-cycle progression and activating DNA repair or cell death pathways. Evidence of a role for BRCA1 in DNA repair includes the identification of a novel C-terminal amino acid sequence motif (BRCT) common to a broad range of DNA repair proteins, the observation that the BRCA1 protein interacts with a number of DNA repair proteins, including Rad50, and the demonstration of defective double-strand break repair by homologous recombination and genetic instability in BRCA1-deficient cells. Loss of BRCA1 contributes to breast tumourigenesis by inducing genomic instability. The consistent histological phenotype of BRCA1 tumours, including their high-grade, pushing margins and syncytial appearance, together with the results of differential-expression analyses, indicate that the mutations that accumulate in these tumours are far from random. At present however the pathway between BRCA1 loss and BRCA1-mediated tumour development is poorly understood. In an attempt to address this we have studied the cellular and molecular effects of disrupting BRCA1 function. Results from this analysis and our studies on the regulation of BRCA1 expression will be presented

  20. The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and Function at Multiple Subcellular Locations

    OpenAIRE

    Henderson, Beric R.

    2012-01-01

    Inherited mutations in the BRCA1 gene predispose to a higher risk of breast/ovarian cancer. The BRCA1 tumor suppressor is a 1863 amino acid protein with multiple protein interaction domains that facilitate its roles in regulating DNA repair and maintenance, cell cycle progression, transcription, and cell survival/apoptosis. BRCA1 was first identified as a nuclear phosphoprotein, but has since been shown to contain different transport sequences including nuclear export and nuclear localization...

  1. Prolactin inhibits a major tumor-suppressive function of wild type BRCA1.

    Science.gov (United States)

    Chen, Kuan-Hui Ethan; Walker, Ameae M

    2016-06-01

    Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21. PMID:26970274

  2. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

    Science.gov (United States)

    Scumaci, Domenica; Tammè, Laura; Fiumara, Claudia Vincenza; Pappaianni, Giusi; Concolino, Antonio; Leone, Emanuela; Faniello, Maria Concetta; Quaresima, Barbara; Ricevuto, Enrico; Costanzo, Francesco Saverio; Cuda, Giovanni

    2015-01-01

    Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC. Methods To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19), previously reported by our group, with the aim to identify specific signatures. Results The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker. Conclusions Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer. PMID:26061043

  3. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications.

    Directory of Open Access Journals (Sweden)

    Domenica Scumaci

    Full Text Available Breast cancer (BC is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC.To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19, previously reported by our group, with the aim to identify specific signatures.The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker.Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer.

  4. A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor negative and positive breast cancers

    Science.gov (United States)

    Weigelt, Britta; Wilkerson, Paul M; Manie, Elodie; Grigoriadis, Anita; A’Hern, Roger; van der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turaljic, Samra; Furney, Simon J; Marais, Richard; Rodruigues, Daniel-Nava; Flora, Adriana C; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R; Ellis, Ian O; Swanton, Charles; van Diest, Paul; Delattre, Olivier; Lord, Christopher J; Foulkes, William D; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S

    2016-01-01

    BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In >80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative, however up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterise the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations and somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (i.e. DAPK3, TMEM135 and GATA4). PMID:22362584

  5. Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements.

    Science.gov (United States)

    Gad, S; Aurias, A; Puget, N; Mairal, A; Schurra, C; Montagna, M; Pages, S; Caux, V; Mazoyer, S; Bensimon, A; Stoppa-Lyonnet, D

    2001-05-01

    Genetic linkage data have shown that alterations of the BRCA1 gene are responsible for the majority of hereditary breast and ovarian cancers. BRCA1 germline mutations, however, are found less frequently than expected. Mutation detection strategies, which are generally based on the polymerase chain reaction, therefore focus on point and small gene alterations. These approaches do not allow for the detection of large gene rearrangements, which also can be involved in BRCA1 alterations. Indeed, a few of them, spread over the entire BRCA1 gene, have been detected recently by Southern blotting or transcript analysis. We have developed an alternative strategy allowing a panoramic view of the BRCA1 gene, based on dynamic molecular combing and the design of a full four-color bar code of the BRCA1 region. The strategy was tested with the study of four large BRCA1 rearrangements previously reported. In addition, when screening a series of 10 breast and ovarian cancer families negatively tested for point mutation in BRCA1/2, we found an unreported 17-kb BRCA1 duplication encompassing exons 3 to 8. The detection of rearrangements as small as 2 to 6 kb with respect to the normal size of the studied fragment is achieved when the BRCA1 region is divided into 10 fragments. In addition, as the BRCA1 bar code is a morphologic approach, the direct observation of complex and likely underreported rearrangements, such as inversions and insertions, becomes possible. PMID:11284038

  6. Ancient founder mutation is responsible for Imerslund-Gräsbeck Syndrome among diverse ethnicities

    OpenAIRE

    Beech Cameron M; Liyanarachchi Sandya; Shah Nidhi P; Sturm Amy C; Sadiq May F; de la Chapelle Albert; Tanner Stephan M

    2011-01-01

    Abstract Background Imerslund-Gräsbeck syndrome (IGS) was described just over 50 years ago by Olga Imerslund and Ralph Gräsbeck and colleagues. IGS is caused by specific malabsorption of cobalamin (Cbl) due to bi-allelic mutations in either the cubilin gene (CUBN) or the human amnionless homolog (AMN). Mutations in the two genes are commonly seen in founder populations or in societies with a high degree of consanguineous marriages. One particular mutation in AMN, c.208-2A>G, causing an out-of...

  7. A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing

    DEFF Research Database (Denmark)

    Thomassen, Mads; Pedersen, Inge Søkilde; Vogel, Ida;

    2011-01-01

    Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G>A (c.7617+1G>A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally......, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most...

  8. BRCA1 and BRCA2 gene testing

    Science.gov (United States)

    The BRCA1 and BRCA2 gene test is a blood test that can tell you if you have a higher ... BRCA1 and BRCA2 are genes that suppress malignant tumors (cancer) in humans. When these genes change (become ...

  9. Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

    Science.gov (United States)

    Sarkozy, Anna; Windpassinger, Christian; Hudson, Judith; Dougan, Charlotte F; Lecky, Bryan; Hilton-Jones, David; Eagle, Michelle; Charlton, Richard; Barresi, Rita; Lochmüller, Hanns; Bushby, Kate; Straub, Volker

    2011-01-01

    Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery–Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases. PMID:21629301

  10. IMPLICATION DE CERTAINES MUTATIONS DANS LES GENES BRCA1 ET BRCA2 SUR LA PRÉDISPOSITION AU CANCER DU SEIN ET AU CANCER OVARIEN

    Directory of Open Access Journals (Sweden)

    Lucian Negura

    2007-08-01

    Full Text Available Le cancer du sein, ainsi que celui ovarien, est une maladie fréquente chez les femmes, ayant un traitement assez difficile et, malheureusement, de sérieuses répercutions sur le physique ; c’est pourquoi il s’avère essentiel que la maladie soit dépistée dès les phases précoces. La prédisposition génétique est responsable de 5% des cancers et de 25% des cas apparus avant l’age de 30 ans [Breast Cancer Linkage Consortium, 1997]. Nous présentons ici l’implication des gènes suppresseurs des tumeurs BRCA1 et BRCA2 sur cette prédisposition.

  11. Large Genomic Rearrangements of BRCA1 and BRCA2 among Patients Referred for Genetic Analysis in Galicia (NW Spain): Delimitation and Mechanism of Three Novel BRCA1 Rearrangements

    OpenAIRE

    Fachal, Laura; Blanco, Ana; Santamariña, Marta; Carracedo, Angel; Vega, Ana

    2014-01-01

    In the Iberian Peninsula, which includes mainly Spain and Portugal, large genomic rearrangements (LGRs) of BRCA1 and BRCA2 have respectively been found in up to 2.33% and 8.4% of families with hereditary breast and/or ovarian cancer (HBOC) that lack point mutations and small indels. In Galicia (Northwest Spain), the spectrum and frequency of BRCA1/BRCA2 point mutations differs from the rest of the Iberian populations. However, to date there are no Galician frequency reports of BRCA1/BRCA2 LGR...

  12. A Common Founder Mutation in the EDA-A1 Gene in X-Linked Hypodontia

    Science.gov (United States)

    Kurban, Mazen; Michailidis, Eleni; Wajid, Muhammad; Shimomura, Yutaka; Christiano, Angela M.

    2010-01-01

    Background X-linked recessive hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is a rare genodermatosis characterized clinically by developmental abnormalities affecting the teeth, hair and sweat glands. Mutations in the EDA-A1 gene have been associated with XLHED. Recently, mutations in the EDA-A1 gene have also been implicated in isolated X-linked recessive hypodontia (XLRH; OMIM 313500). Methods We analyzed the DNA from members of 3 unrelated Pakistani families with XLRH for mutations in the EDA-A1 gene through direct sequencing and performed haplotype analysis. Results We identified a common missense mutation in both families designated c.1091T→C (p.M364T). Haplotype analysis revealed that this is a founder mutation in the 3 families. Conclusion XLHED is a syndrome with variable clinical presentations that contain a spectrum of findings, including hypodontia. We suggest that XLRH should be grouped under XLHED as both share several phenotypic and genotypic similarities. PMID:20628232

  13. BRCA1 Protein Expression Level and CD44+ Phenotype in Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Saadat Molanae

    2011-01-01

    Full Text Available Objective: CD44+/CD24-/low breast cancer cells have tumour-initiating properties with stemcell-like features. Breast cancer gene 1 (BRCA1 is a tumour suppressor gene that playsa crucial role in DNA repair and maintenance of chromosome stability. The clinicopathologicalfeatures of breast cancer in BRCA1 mutation carriers suggest that BRCA1 mayfunction as a stem-cell regulator.Materials and Methods: In the present experimental study we examined the expressionand localization of the BRCA1 protein and investigated the prognostic value aswell as its relationship with the putative cancer stem cell (CSC marker (CD44 in 156tumour samples from a well-characterized series of unselected breast carcinomas usingimmunohistochemistry. Statistical analysis of the data was performed using SPSSsoftware version 16 (Chicago, IL, USA.Results: In breast tumours, the loss of nuclear expression was detected in 23 cases(15%, whereas cytoplasmic expression of BRCA1 was observed in 133 breast carcinomas(85%. Altered BRCA1 expression was significantly associated with high grade and poorprognosis breast tumours (p=0.006. We further established an inverse significant correlationbetween BRCA1 expression levels and CD44+ cancer cell phenotype (p=0.02Conclusion: Loss of BRCA1 expression is a marker of tumour aggressiveness andcorrelates with CD44+ tumour cell phenotype. Taken together, the present study supportsthe idea that the loss of BRCA1 results in persistent errors in DNA replication inbreast stem cells and provides targets for additional carcinogenic events.

  14. Regulation of BRCA1 expression and its relationship to sporadic breast cancer

    International Nuclear Information System (INIS)

    Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. In contrast, decreased expression of the BRCA1 gene has been shown to be common in sporadic tumours, and the magnitude of the decrease correlates with disease progression. BRCA1 expression is also tightly regulated during normal breast development. Determining how these developmental regulators of BRCA1 expression are co-opted during breast tumourigenesis could lead to a better understanding of sporadic breast cancer aetiology and the generation of novel therapeutic strategies aimed at preventing sporadic breast tumour progression

  15. A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer

    OpenAIRE

    Li, Da; Bi, Fang-Fang; Chen, Na-Na; Cao, Ji-Min; Sun, Wu-Ping; Zhou, Yi-Ming; Li, Chun-Yan; Yang, Qing

    2014-01-01

    BRCA mutations are the main known hereditary factor for breast cancer. Notably, poly (ADP-ribose) polymerase 1 (PARP1) expression status plays a critical role in breast cancer progression and the clinical development of PARP1 inhibitors to treat BRCA-mutated breast cancer has advanced rapidly. However, dynamic crosstalk between BRCA1 and PARP1 remains largely unknown. Here, we showed that: (i) BRCA1 inactivation events (mutation, promoter methylation, or knockdown) were accompanied by increas...

  16. Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing

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    Stattin Eva-Lena

    2012-10-01

    Full Text Available Abstract Background Long QT syndrome (LQTS is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort. Methods Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT. Results In total, a disease-causing mutation was identified in 103 of the 200 (52% index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%, whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. Conclusion In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the

  17. Screening of BRCA1 sequence variants within exon 11 by heteroduplex analysis

    Directory of Open Access Journals (Sweden)

    Anca Negura

    2012-10-01

    Full Text Available Germ-line mutations of either BRCA1 or BRCA2 represents the major hereditary risk to breast and ovariancancer. Screening for mutations in these genes is now standard practice in molecular diagnosis, opening the way tooncogenetic counselling and follow-up. Because mutations in both BRCA1 and BRCA2 are distributed throughout theloci, accepted clinical protocols involve screening their entire coding regions. Systematic Sanger sequencing is time andmoney consuming. Therefore, a lot of pre-screening techniques evolved over time in order to identify anomalousamplicons prior to sequencing. Because BRCA mutations are always heterozygous, heteroduplex analysis proved to be asuitable pre-screening step. We previously implemented mismatch specific endonuclease heteroduplex analysis forBRCA1 exon7. Here we show the utility of the same method for mutations and SNPs found in BRCA1 exon 11

  18. Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient

    International Nuclear Information System (INIS)

    Ovarian carcinoma is a common, and often deadly, gynecological cancer. Mutations in BRCA1 and BRCA2 genes are present in at least a fifth of patients. Uncovering other genes that become mutated subsequent to BRCA1/BRCA2 inactivation during cancer development will be helpful for more effective treatments. We performed exome sequencing on the blood, primary tumor, omental metastasis and recurrence following therapy with carboplatin and paclitaxel, from a patient carrying a BRCA1 S1841R mutation. We observed loss of heterozygosity in the BRCA1 mutation in the primary and subsequent tumors, and somatic mutations in the TP53 and NF1 genes were identified, suggesting their role along with BRCA1 driving the tumor development. Notably, we show that exome sequencing is effective in detecting large chromosomal rearrangements such as deletions and amplifications in cancer. We found that a large deletion was present in the three tumors in the regions containing BRCA1, TP53, and NF1 mutations, and an amplification in the regions containing MYC. We did not observe the emergence of any new mutations among tumors from diagnosis to relapse after chemotherapy, suggesting that mutations already present in the primary tumor contributed to metastases and chemotherapy resistance. Our findings suggest that exome sequencing of matched samples from one patient is a powerful method of detecting somatic mutations and prioritizing their potential role in the development of the disease

  19. BRCA1 Expression is an Important Biomarker for Chemosensitivity: Suppression of BRCA1 Increases the Apoptosis via Up-regulation of p53 and p21 During Cisplatin Treatment in Ovarian Cancer Cells

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    Ikuo Konishi

    2006-01-01

    Full Text Available BRCA1 is a tumor suppressor which plays a crucial role in the repair of DNA double-strand breaks, and its abnormality is responsible for hereditary ovarian cancer syndrome. It has recently been reported that reduced expression of BRCA1 is also common in sporadic ovarian carcinoma via its promoter hypermethylation, and that ovarian carcinoma patients negative for BRCA1 expression showed favorable prognosis. To address if BRCA1 expression plays a role in the chemotherapeutic response, we analyzed the effect of BRCA1 suppression on the sensitivity to cisplatin and paclitaxel in ovarian cancer cells. Specific siRNA for BRCA1 gene was transfected into 3 ovarian cancer cell lines with various p53 status. Reduced expression of BRCA1 by transfection of BRCA1-siRNA resulted in a 5.3-fold increase in sensitivity to cisplatin in p53-wild A2780 cells, but not in p53-mutated A2780/CDDP and p53-deleted SKOV3 cells. Regarding the sensitivity to paclitaxel, BRCA1 suppression caused no significant changes in all the 3 cell lines. For ionizing radiation sensitivity, BRCA1 suppression also showed a significant higher sensitivity in A2780 cells. Growth curve and cell cycle analyses showed no signifi cant differences between BRCA1-siRNA-transfected A2780 cells and control cells. However, cisplatin treatment under suppression of BRCA1 showed a significantly increased apoptosis along with up-regulation of p53 and p21 in A2780 cells. Accordingly, reduced expression of BRCA1 enhances the cisplatin sensitivity and apoptosis via up-regulation of p53 and p21, but does not affect the paclitaxel sensitivity. Expression of BRCA1 might be an important biomarker for cisplatin resistance in ovarian carcinoma.

  20. Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation

    International Nuclear Information System (INIS)

    BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status. Using image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups. In this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA

  1. Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families

    DEFF Research Database (Denmark)

    Hansen, Thomas v O; Jønson, Lars; Albrechtsen, Anders;

    2009-01-01

    BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0-36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian...

  2. The Prognostic Value of BRCA1 and PARP Expression in Epithelial Ovarian Carcinoma

    DEFF Research Database (Denmark)

    Hjortkjær, Mette; Waldstrøm, Marianne; Jakobsen, Anders;

    2016-01-01

    BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene...... tissue from 170 patients with EOC was stained immunohistochemically with BRCA1 and PARP antibodies. Semiquantitative analyses were performed to determine loss of, equivocal, and retained BRCA1 and high versus low PARP protein expression. These parameters were analyzed for relation with patient and...

  3. Are we ready for BRCA-1 screening? The medical, ethical, and legal implications

    International Nuclear Information System (INIS)

    Inherited breast cancers account for approximately 5 to 10% of all breast malignancies. One gene, BRCA-1, is believed to account for 40-45% of hereditary breast cancers. Women who carry a BRCA-1 mutation has a 85-90% life-time risk of developing breast cancer and a 45-50% risk of developing ovarian cancer. Using linkage analyses of families with early onset breast cancer, bilateral breast cancer, and/or ovarian cancer, BRCA-1 was localized to chromosome 17q21. BRCA-1 has now been isolated and cloned. With the discovery of this inherited mutation, issues of genetic screening are facing women and their health care providers. Currently, testing for the presence of a BRCA-1 mutation is confined to members of high-risk families participating in research protocols, however, commercially available diagnostic assays are being developed for wide-spread screening. Screening for BRCA-1 is likely an inevitable reality. Therefore, panel members will discuss the implications of genetic screening specifically as they relate to the BRCA-1 gene. In particular, we will focus upon the genetic counseling that should be offered prior to the decision to proceed with testing, as well as the clinical and social implications of a positive test for a BRCA-1 mutation. Privacy issues for patients who pursue testing such s what should and should not be written in the medical records will be discussed, and the status of legislative measures designed to minimize insurance discrimination for those who test positive will be presented. Finally, options for management of women who have inherited a BRCA-1 mutation will be discussed, including the controversial role of radiotherapy for women diagnosed with breast cancer

  4. A DNA Repair BRCA1 Estrogen Receptor and Targeted Therapy in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Adisorn Ratanaphan

    2012-11-01

    Full Text Available BRCA1 is a key mediator of DNA repair pathways and participates in the maintenance of the genomic integrity of cells. The control of DNA damage repair mechanisms by BRCA1 is of great interest since molecular defects in this pathway may reflect a predictive value in terms of a cell’s sensitivity to DNA damaging agents or anticancer drugs. BRCA1 has been found to exhibit a hormone-dependent pattern of expression in breast cells. Wild-type BRCA1 is required for the inhibition of the growth of breast tumor cells in response to the pure steroidal ERα antagonist fulvestrant. Also a loss of BRCA1-mediated transcriptional activation of ERα expression results in increased resistance to ERα antagonists. Platinum-based drugs, poly(ADP-ribose polymerase (PARP inhibitors, and their combination are currently included in chemotherapy regimens for breast cancer. Preclinical and clinical studies in a BRCA1-defective setting have recently indicated a rationale for the use of these compounds against hereditary breast cancers. Initial findings indicate that neoadjuvant use of cisplatin results in high rates of complete pathological response in patients with breast cancer who have BRCA1 mutations. Cisplatin produces a better response in triple-negative breast cancer (TNBC than in non-TNBC diseases in both the neoadjuvant and adjuvant settings. This implies that TNBC cells may harbor a dysfunctional BRCA1 repair pathway.

  5. Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

    Directory of Open Access Journals (Sweden)

    Kana Tanahashi

    Full Text Available Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH, and the 2 missense mutations c.736T>A (p.Cys246Ser and c.742C>A (p.His248Asn are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016, and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024. In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH.

  6. Characterization of a novel founder MSH6 mutation causing Lynch syndrome in the French Canadian population.

    Science.gov (United States)

    Castellsagué, E; Liu, J; Volenik, A; Giroux, S; Gagné, R; Maranda, B; Roussel-Jobin, A; Latreille, J; Laframboise, R; Palma, L; Kasprzak, L; Marcus, V A; Breguet, M; Nolet, S; El-Haffaf, Z; Australie, K; Gologan, A; Aleynikova, O; Oros-Klein, K; Greenwood, C; Mes-Masson, A M; Provencher, D; Tischkowitz, M; Chong, G; Rousseau, F; Foulkes, W D

    2015-06-01

    We identified an MSH6 mutation (c.10C>T, p.Gln4*) causing Lynch syndrome (LS) in 11 French Canadian (FC) families from the Canadian province of Quebec. We aimed to investigate the molecular and clinical implications of this mutation among FC carriers and to assess its putative founder origin. We studied 11 probands and 27 family members. Additionally 6433 newborns, 187 colorectal cancer (CRC) cases, 381 endometrial cancer (EC) cases and 179 additional controls, all of them from Quebec, were used. Found in approximately 1 of 400 newborns, the mutation is one of the most common LS mutations described. We have found that this mutation confers a greater risk for EC than for CRC, both in the 11 studied families and in the unselected cases: EC [odds ratio (OR) = 7.5, p < 0.0001] and CRC (OR = 2.2, p = 0.46). Haplotype analyses showed that the mutation arose in a common ancestor, probably around 430-656 years ago, coinciding with the arrival of the first French settlers. Application of the results of this study could significantly improve the molecular testing and clinical management of LS families in Quebec. PMID:25318681

  7. Founder effect of a prevalent phenylketonuria mutation in the Oriental population

    International Nuclear Information System (INIS)

    A missense mutation has been identified in the human phenylalanine hydroxylase Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that northern Mongoloids represented a founding population in Asia. The results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations

  8. Association of BLM and BRCA1 during Telomere Maintenance in ALT Cells.

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    Samir Acharya

    Full Text Available Fifteen percent of tumors utilize recombination-based alternative lengthening of telomeres (ALT to maintain telomeres. The mechanisms underlying ALT are unclear but involve several proteins involved in homologous recombination including the BLM helicase, mutated in Bloom's syndrome, and the BRCA1 tumor suppressor. Cells deficient in either BLM or BRCA1 have phenotypes consistent with telomere dysfunction. Although BLM associates with numerous DNA damage repair proteins including BRCA1 during DNA repair, the functional consequences of BLM-BRCA1 association in telomere maintenance are not completely understood. Our earlier work showed the involvement of BRCA1 in different mechanisms of ALT, and telomere shortening upon loss of BLM in ALT cells. In order to delineate their roles in telomere maintenance, we studied their association in telomere metabolism in cells using ALT. This work shows that BLM and BRCA1 co-localize with RAD50 at telomeres during S- and G2-phases of the cell cycle in immortalized human cells using ALT but not in cells using telomerase to maintain telomeres. Co-immunoprecipitation of BRCA1 and BLM is enhanced in ALT cells at G2. Furthermore, BRCA1 and BLM interact with RAD50 predominantly in S- and G2-phases, respectively. Biochemical assays demonstrate that full-length BRCA1 increases the unwinding rate of BLM three-fold in assays using a DNA substrate that models a forked structure composed of telomeric repeats. Our results suggest that BRCA1 participates in ALT through its interactions with RAD50 and BLM.

  9. Identification of BRCA1-deficient ovarian cancers

    DEFF Research Database (Denmark)

    Skytte, Anne-Bine; Waldstrøm, Marianne; Rasmussen, Anders Aamann;

    2011-01-01

    . Design. BRCA1-immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) and methylation analyses were performed on formalin-fixed, paraffin-embedded ovarian cancer tissue. Sample: 54 ovarian cancers; 15 BRCA1 cancers, 4 BRCA2 cancers, 10 cancers from patients with a family history but no...

  10. Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients

    Science.gov (United States)

    Li, Jiayuan; Peng, Zuxiang; Deng, Ling; Zhu, Xuehua; Sun, Yun; Lu, Xuesong; Shen, Fuxiao; Su, Xinying; Zhang, Liying; Gu, Yi; Zheng, Hong

    2016-01-01

    Background The prevalence of BRCA1/2 variants in Chinese breast cancer patients varies among studies. Germline or somatic BRCA1/2 mutations are associated with sensitivity to poly(ADP-ribose) polymerase-1 inhibitors and DNA-damaging agents. We aimed to investigate the distribution of both somatic and germline BRCA1/2 variants in unselected Chinese breast cancer patients, and explore their roles in tumor phenotype and disease prognosis. Methods 507 breast cancer patients, unselected for family history of breast cancer or age at diagnosis, were prospectively enrolled from West China Hospital between Feb. 2008 and Feb. 2014. BRCA1/2 variants in the exons/flanking regions were detected in fresh-frozen tumors using next-generation sequencing and confirmed by independent methods. Germline/somatic status was validated by Sanger sequencing in paired blood/normal tissue. Results BRCA1/2 pathogenic or likely pathogenic (P/LP) variants were detected in 50 patients (9.9%), including 40 germline carriers (18 in BRCA1, 22 in BRCA2), 9 patients with somatic variants (3 in BRCA1, 6 in BRCA2), and 1 patient with concurrent germline/somatic variants in BRCA2. The triple-negative (21.4%) and Luminal B (9.7%) subtypes had higher rates of BRCA1/2 variants. In patients with disease stage 0~II, presence of a germline or somatic BRCA1 P/LP variant increased the risk of relapse as compared to non-carriers [univariate hazard ratio (HR): 3.70, P = 0.04]. Germline BRCA1 P/LP variants, which were associated with aggressive tumor phenotypes, predicted worse disease-free survival in the subgroup of stage 0~II (HR: 4.52, P = 0.02) and N0 (HR: 5.4, P = 0.04) compared to non-carriers. Conclusion A high frequency of germline and somatic BRCA1/2 P/LP variants was detected in unselected Chinese breast cancer patients. Luminal B subtype should be considered as a high-risk population of BRCA1/2 mutation, in addition to triple-negative breast cancer. BRCA1 status was associated with aggressive tumor

  11. Worldwide distribution of PSEN1 Met146Leu mutation: A large variability for a founder mutation

    OpenAIRE

    Bruni, A C; Bernardi, L.; Colao, R; Rubino, E.; Smirne, N.; Frangipane, F.; Terni, B.; Curcio, S.A.M.; Mirabelli, M.; Clodomiro, A.; Di Lorenzo, R.; Maletta, R.; Anfossi, M.; Gallo, M.; Geracitano, S.

    2010-01-01

    Objective: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide.

  12. A founder mutation in Anoctamin 5 is a major cause of limb girdle muscular dystrophy

    Science.gov (United States)

    Muelas, Nuria; Köehler, Katrin; Huebner, Angela; Hudson, Gavin; Chinnery, Patrick F.; Barresi, Rita; Eagle, Michelle; Polvikoski, Tuomo; Bailey, Geraldine; Miller, James; Radunovic, Aleksander; Hughes, Paul J.; Roberts, Richard; Krause, Sabine; Walter, Maggie C.; Laval, Steven H.; Straub, Volker; Lochmüller, Hanns; Bushby, Kate

    2014-01-01

    The limb girdle muscular dystrophies (LGMDs) are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, LGMD2L and non-dysferlin Miyoshi muscular dystrophy (MMD3). We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic SNP and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised creatinine kinase (CK) values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20s to 50s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high CK and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult LGMD patients. PMID:21186264

  13. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    OpenAIRE

    Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A.

    2000-01-01

    Introduction: Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of...

  14. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M;

    2012-01-01

    Germline mutations in the tumor suppressor gene BRCA1 confer an estimated lifetime risk of 56-80% for breast cancer and 15-60% for ovarian cancer. Since the mid 1990s when BRCA1 was identified, genetic testing has revealed over 1,500 unique germline variants. However, for a significant number of...... these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

  15. Distinct functions of BRCA1 and BRCA2 in double-strand break repair

    International Nuclear Information System (INIS)

    Individuals carrying BRCA mutations are predisposed to breast cancer. The BRCA1 and BRCA2 proteins are required for homologous recombination and DNA break repair, leading to the suggestion that they act in concert. However, direct evidence of a stable BRCA1/BRCA2 complex has not been demonstrated. Rather, the two proteins have been found as constituents of discrete, but perhaps nonexclusive complexes that are critical for repair. We discuss the interaction of BRCA1 with the BACH1 and BARD1 proteins, and suggest that the pleiotropic nature of mutations in BRCA1 may be associated with defects in protein–protein interactions. In contrast, the role of BRCA2 in DNA repair may be more defined by its direct interaction with the RAD51 recombinase

  16. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy.

    Science.gov (United States)

    Toyota, Kentaro; Hashimoto, Taeko; Ogino, Daisuke; Matsunaga, Akira; Ito, Minoru; Masakane, Ikuto; Degawa, Noriyuki; Sato, Hiroshi; Shirai, Sayuri; Umetsu, Kazuo; Tamiya, Gen; Saito, Takao; Hayasaka, Kiyoshi

    2013-05-01

    Lipoprotein glomerulopathy (LPG) is a hereditary disease characterized by lipoprotein thrombi in the glomerulus, hyperlipoproteinemia, and a marked increase in serum apolipoprotein E (APOE). More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture. Recently, effective therapy with intensive lipid-lowering agents was established, and epidemiologic data are required for early diagnosis. We determined the haplotype structure of APOE-Sendai in 13 patients from 9 unrelated families with LPG, and found that the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect. We also studied the gene frequency of APOE-Sendai in 2023 control subjects and 418 patients receiving hemodialysis in Yamagata prefecture using the TaqMan method, but did not identify any subjects carrying the mutation, indicating that it is very rare in the general population even in the eastern part of Japan. In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance. The patients did not have a common haplotype of the counterpart APOE allele, and some patients had the same haplotype of the counterpart APOE allele as the asymptomatic carriers. These results suggest that the counterpart APOE allele is not likely associated with the onset of LPG. Further study is required to clarify the pathogenesis of LPG. PMID:23407349

  17. Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder?

    DEFF Research Database (Denmark)

    D'Alessandro, Mariella; Coats, Stephanie E; Morley, Susan M; Mackintosh, Lorna; Tessari, Gianpaolo; Turco, Alberto; Gerdes, Anne-Marie; Pichert, Gabriella; Whittaker, Sean; Brandrup, Flemming; Broesby-Olsen, Sigurd; Gomez-Lira, Macarena; Girolomoni, Giampiero; Maize, John C; Feldman, Ron J; Kato, Naoko; Koga, Yukiko; Ferguson-Smith, Malcolm A; Goudie, David R; Lane, E Birgitte

    2007-01-01

    Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith Disease, is a rare cancer-associated genodermatosis with an autosomal dominant inheritance. Affected patients suffer from recurrent skin lesions, which clinically and histologically resemble keratoacanthomas or well......-differentiated squamous cell carcinomas, but which, if left, undergo spontaneous regression, leaving pronounced scarring. The majority of MSSE cases previously described were of Scottish ancestry and all shared the same at-risk haplotype, suggesting that this disorder was caused by a founder mutation. The candidate locus...... clinical course of their skin lesions. Once confirmed that they were really affected by MSSE, we performed haplotype analysis on them and their families. The haplotypes for polymorphic markers segregating with MSSE in non-Scottish and Scottish families differ, suggesting that MSSE is not caused by a...

  18. Ovarian Cancer and BRCA1/2 Testing: Opportunities to improve clinical care and disease prevention

    Directory of Open Access Journals (Sweden)

    Katherine eKarakasis

    2016-05-01

    Full Text Available Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High grade serous ovarian cancer (HGSOC is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer, those at risk of developing cancer, but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many which are now being found to have BRCA1/2 involvement.

  19. Ovarian Cancer and BRCA1/2 Testing: Opportunities to Improve Clinical Care and Disease Prevention.

    Science.gov (United States)

    Karakasis, Katherine; Burnier, Julia V; Bowering, Valerie; Oza, Amit M; Lheureux, Stephanie

    2016-01-01

    Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities, where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much-needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer and those at risk of developing cancer but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many of which are now being found to have BRCA1/2 involvement. PMID:27242959

  20. Ovarian Cancer and BRCA1/2 Testing: Opportunities to Improve Clinical Care and Disease Prevention

    Science.gov (United States)

    Karakasis, Katherine; Burnier, Julia V.; Bowering, Valerie; Oza, Amit M.; Lheureux, Stephanie

    2016-01-01

    Without prevention or screening options available, ovarian cancer is the most lethal malignancy of the female reproductive tract. High-grade serous ovarian cancer (HGSOC) is the most common histologic subtype, and the role of germline BRCA1/2 mutation in predisposition and prognosis is established. Given the targeted treatment opportunities with PARP inhibitors, a predictive role for BRCA1/2 mutation has emerged. Despite recommendations to provide BRCA1/2 testing to all women with histologically confirmed HGSOC, uniform implementation remains challenging. The opportunity to review and revise genetic screening and testing practices will identify opportunities, where universal adoption of BRCA1/2 mutation testing will impact and improve treatment of women with ovarian cancer. Improving education and awareness of genetic testing for women with cancer, as well as the broader general community, will help focus much-needed attention on opportunities to advance prevention and screening programs in ovarian cancer. This is imperative not only for women with cancer and those at risk of developing cancer but also for their first-degree relatives. In addition, BRCA1/2 testing may have direct implications for patients with other types of cancers, many of which are now being found to have BRCA1/2 involvement.

  1. Mechanisms for ATM mediated downstream gene BRCA1 and RAD51 in signaling pathway of DNA injury repair

    International Nuclear Information System (INIS)

    In order to investigate mechanisms of ATM (Ataxia telangiectasia mutated) genes mediating phosphorylation of BRCA1 (breast cancer gene 1) and its downstream gene RAD51 (DNA damage repair protein 51) in signaling pathway of DNA injury repair, the authors applied immunocoprecipitated and Western blot to observe changes in the expressions of BRCA1 and RAD51 proteins in AT cells, ATM+-AT cells (AT cells transfected with ATM genes) and GM cells (originated from human skin fibroblast, GM 0639) and used as control, after 5, 10 and 20 Gy 60Co γ-ray irradiation at dose rate of 1.0 Gy/min. The irradiated AT cells were analyzed to study interactive action between ATM and BRCA1 protein, BRCA1 and RAD51 protein, and the effect of PI3K inhibitor on ATM phosphorylating, its downstream gene, by immunocoprecipitate and Western blot. No expression bands of BRCA1 were found in ATM+-AT and GM cells of the control. After the irradiation, the BRCA1 and RAD51 were both expressed in GM and ATM cells. The PI3K inhibitor Wortmannin could inhibit the expression of BRCA1 in the AT, ATM+-AT and GM cells. The BRCA1 and RAD proteins were both expressed in ATM+-AT cells and GM cells. Therefore, after the irradiation the phosphorylation of BRCA1 mediated by ATM could further interact with RAD51. This is a cascade in signaling pathway for DNA damage repair and genome stabilization. (authors)

  2. Risk of breast cancer among French-Canadian women, noncarriers of more frequent BRCA1/2 mutations and consumption of total energy, coffee, and alcohol.

    Science.gov (United States)

    Bissonauth, Vishnee; Shatenstein, Bryna; Fafard, Eve; Maugard, Christine; Robidoux, André; Narod, Steven; Ghadirian, Parviz

    2009-01-01

    Although the connection between diet, lifestyle and hormones suggests that nutritional and lifestyle factors may exert an influence in the etiology of breast cancer, it is not clear whether these factors operate in the same way in women without BRCA gene mutations. A nested case-control study was conducted in a cohort of French-Canadian women, with 560 members involving 280 nongene carriers of mutated BRCA gene affected by breast cancer and 280 nonaffected and nongene carriers of mutated BRCA gene. A validated semi-quantitative food frequency questionnaire was used to ascertain dietary intake, and a core questionnaire, to gather information on lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models. It was found that energy intake >2,057 Kcal/day was significantly and positively related to breast cancer risk (OR = 2.54; 95% CI: 1.67-3.84; p = 0.01). Women who drank more than eight cups of coffee per day had an increased risk of breast cancer: OR = 1.40 (95% CI: 1.09-2.24; p = 0.03). Subjects who drank >9 g of alcohol (ethanol) per day had an increased risk of breast cancer: OR = 1.55 (95% CI: 1.02-2.37; p = 0.04). In addition, a positive and significant association was noted between the consumption of beer, wine and spirits, and breast cancer risk. The ORs were 1.34 (95% CI: 1.28-2.11; p = 0.04) for more than two bottles of beer per week, OR = 1.16 (95% CI: 1.08-2.58; p = 0.05) for >10 oz of wine per week and OR = 1.09 (95% CI: 1.02-2.08; p = 0.05) for >6 oz of spirit per week, respectively. Intakes of other nutrients and dietary components were not significantly associated with nongene carrier breast cancer risk. This study provides evidence that total energy intake, coffee, and alcohol consumption may play a role in breast cancer risk. PMID:19775332

  3. Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population

    OpenAIRE

    van den Broek, Alexandra J.; de Ruiter, Karen; Van 't Veer, Laura J; Tollenaar, Rob A.E.M.; van Leeuwen, Flora E.; Verhoef, Senno; Schmidt, Marjanka K.

    2014-01-01

    In this study, we evaluated the diagnostic value of the Dutch Clinical Genetic Center (CGC) referral guidelines for BRCA1/2 mutation testing in 903 early breast cancer patients, unselected for family history, diagnosed in a cancer hospital before the age of 50 years in 1974–2002; most prevalent Dutch pathogenic BRCA1/2 mutations had been analyzed on coded DNA in a research setting. Forty-nine (5.4%) of the patients were proven to be BRCA1/2 mutation carriers. We found that 78% and 69% of BRCA...

  4. Missense polymorphisms in BRCA1 and BRCA2 and risk of breast and ovarian cancer

    DEFF Research Database (Denmark)

    Dombernowsky, Sarah Louise; Weischer, Maren; Freiberg, Jacob Johannes;

    2009-01-01

    PURPOSE: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as...... and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms....... their impact on risk of breast and ovarian cancer is unclear. EXPERIMENTAL DESIGN: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and...

  5. BRCA1 and BRCA2 protein expressions in an ovotestis of a 46, XX true hermaphrodite

    International Nuclear Information System (INIS)

    BRCA1 and BRCA2 breast cancer susceptibility genes encode proteins, the normal cellular functions of which are complex and multiple, and germ-line mutations in individuals predispose both to breast and to ovarian cancer. There is nevertheless substantial evidence linking BRCA1 and BRCA2 to homologous recombination and DNA repair, to transcriptional control and to tissue proliferation. There is controversy regarding the localization of BRCA1 and BRCA2 proteins to either nucleus or cytoplasm and whether the expression is present in premeiotic germ cells or can still be expressed in mitotic spermatogonia. We report herein an immunohistochemical study of BRCA1 and BRCA2 distribution in a rather unsual tissue (an ovotestis), which addresses this issue

  6. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

    Science.gov (United States)

    Tan-Sindhunata, M Brigita; Mathijssen, Inge B; Smit, Margriet; Baas, Frank; de Vries, Johanna I; van der Voorn, J Patrick; Kluijt, Irma; Hagen, Marleen A; Blom, Eveline W; Sistermans, Erik; Meijers-Heijboer, Hanne; Waisfisz, Quinten; Weiss, Marjan M; Groffen, Alexander J

    2015-09-01

    Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing. PMID:25537362

  7. The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and Function at Multiple Subcellular Locations

    Science.gov (United States)

    Henderson, Beric R.

    2012-01-01

    Inherited mutations in the BRCA1 gene predispose to a higher risk of breast/ovarian cancer. The BRCA1 tumor suppressor is a 1863 amino acid protein with multiple protein interaction domains that facilitate its roles in regulating DNA repair and maintenance, cell cycle progression, transcription, and cell survival/apoptosis. BRCA1 was first identified as a nuclear phosphoprotein, but has since been shown to contain different transport sequences including nuclear export and nuclear localization signals that enable it to shuttle between specific sites within the nucleus and cytoplasm, including DNA repair foci, centrosomes, and mitochondria. BRCA1 nuclear transport and ubiquitin E3 ligase enzymatic activity are tightly regulated by the BRCA1 dimeric binding partner BARD1 and further modulated by cancer mutations and diverse signaling pathways. This paper will focus on the transport, dynamics, and multiple intracellular destinations of BRCA1 with emphasis on how regulation of these events has impact on, and determines, a broad range of important cellular functions. PMID:24278741

  8. Critical role for BRCA1 expression as a marker of chemosensitivity response and prognosis.

    Science.gov (United States)

    De Luca, Paola; De Siervi, Adriana

    2016-01-01

    Chemotherapy is still the leader option for cancer treatment. Nevertheless some patients develop chemotherapy resistance. One major research goal is to identify the critical genes involved in chemotherapy response to predict the best therapy option for patients. Germline mutations in the BReast Cancer susceptibility gene (BRCA1) are associated to increased risk of developing breast, ovarian and other types of cancers. However, due to harmful BRCA1 gene mutations are relatively rare in the general population, nowadays most researchers focused on BRCA1 expression downregulation and/or epigenetic inactivation in sporadic tumors as a prognosis tool for chemotherapy response in patients. Chemotherapy response can be dramatically different depending on BRCA1 expression status, tumor type and drug. Hence, the chemotherapy response could be dissimilar in breast, ovarian, uterine, prostate, esophageal, gastric and lung cancers. Additionally, differential BRCA1 expression in sporadic tumors shows different response to DNA-damaging agents, mitotic inhibitors or PARP inhibitors. In this review we will examine the response to different chemotherapy agents in several cancer types depending on BRCA1 expression status. PMID:26709647

  9. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

    DEFF Research Database (Denmark)

    Peixoto, Ana; Santos, Catarina; Pinheiro, Manuela;

    2011-01-01

    total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four...... individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 +/- 215 years ago. We further demonstrate significant quantitative differences...

  10. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

    DEFF Research Database (Denmark)

    Peixoto, Ana; Santos, Catarina; Pinheiro, Manuela;

    2011-01-01

    total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four...... individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences...

  11. BRCA1 and BRCA2 Unclassified Variants and Missense Polymorphisms in Algerian Breast/Ovarian Cancer Families

    Directory of Open Access Journals (Sweden)

    Farid Cherbal

    2012-01-01

    Full Text Available Background: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs (variants with unknown clinical significance and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis.

  12. BRCA1 and miRNAs: An Emerging Therapeutic Target and Intervention Tool in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Mintu Pal*

    2013-01-01

    Full Text Available Reduced BRCA1 activity, either by germ-line mutations in inherited breast cancer or by epigenetic down-regulation in sporadic cancers,represents a key pathway in tumour development and progression. Although best known for its role in the maintenance of chromosome integrity, BRCA1 has recently been found to play a role in chromatin remodelling and transcriptional regulation, as well as in mammary epithelial stem cell differentiation or mammary stem cell fate decision. While BRCA1 potentially plays a significant role in both mammary tumour development and malignant progression, its function connection to tumor development is poorly understood. Recent studies have uncovered a new role of BRCA1 in the regulation of small (~19-25 nucleotides non-coding microRNA (miRNA expression in breast cancer cells. Several studies have also shown that aggressive breast cancers and breast cancer stem cells exhibit distinctive profiles of miRNA expression, suggesting that BRCA1 associated differential expression of miRNAs can regulate important cellular functions facilitating the maintenance of breast cancer stem cells and/or promoting breast cancer aggression. In this context, we will review recent progress in the understanding of the BRCA1 function, with emphasis on the implication of the development and progression of breast cancer via differential expression of miRNAs and discuss how these studies can improve our understanding of breast cancer pathogenesis. We will also discuss the perspectives of BRCA1 function through miRNAs and the role of miRNAs in regulating BRCA1 in breast cancer, more specifically tumor suppressor, miR-125 and oncogene, mir-155 as diagnostic and prognostic tools in clinical practice, and as new avenues for therapeutic interventions.

  13. Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach

    OpenAIRE

    Tischkowitz, Marc; Hamel, Nancy; Carvalho, Marcelo A.; Birrane, Gabriel; Soni, Aditi; van Beers, Erik H.; Joosse, Simon A; Wong, Nora; Novak, David; Quenneville, Louise A; Grist, Scott A.; kConFab,; Nederlof, Petra M; Goldgar, David E; Tavtigian, Sean V.

    2008-01-01

    A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1...

  14. Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study

    DEFF Research Database (Denmark)

    Brohet, Richard M; Goldgar, David E; Easton, Douglas F;

    2007-01-01

    oral contraceptive use and risk of breast cancer among BRCA1/2 carriers. PATIENTS AND METHODS In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis. Results We found an increased risk of...... breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full...... found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk...

  15. Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk

    OpenAIRE

    Pelletier, Cory; Speed, William C; Paranjape, Trupti; Keane, Katie; Blitzblau, Rachel; Hollestelle, Antoinette; Safavi, Kyan; Van Den Ouweland, Ans; Zelterman, Daniel; Slack, Frank J; Kidd, Kenneth K.; Weidhaas, Joanne B

    2011-01-01

    Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3′ untranslated region (3′UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in ...

  16. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christopher A Maxwell

    2011-11-01

    Full Text Available Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((wHR = 1.09 (95% CI 1.02-1.16, p(trend = 0.017; and n = 3,965, (wHR = 1.04 (95% CI 0.94-1.16, p(trend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

  17. Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes

    International Nuclear Information System (INIS)

    Epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. Using mice with conditional expression of Brca1, we inactivated Brca1 in the murine OSE and demonstrate that this inactivation results in the development of preneoplastic changes, such as hyperplasia, epithelial invaginations, and inclusion cysts, which arise earlier and are more numerous than in control ovaries. These changes resemble the premalignant lesions that have been reported in human prophylactic oophorectomy specimens from women with BRCA1 germline mutation. We also report that inactivation of Brca1 in primary cultures of murine OSE cells leads to a suppression of proliferation due to increased apoptosis that can be rescued by concomitant inactivation of p53. These observations, along with our finding that these cells display an increased sensitivity to the DNA-damaging agent cisplatin, indicate that loss of function of Brca1 in OSE cells impacts both cellular growth control and DNA-damage repair which results in altered cell behavior manifested as morphological changes in vivo that arise earlier and are more numerous than what can be attributed to ageing

  18. BRCA1 and BRCA2 sequence variations detected with next-generation sequencing in patients with premature ovarian insufficiency

    Science.gov (United States)

    Yılmaz, Nafiye Karakaş; Karagin, Peren Hatice; Terzi, Yunus Kasım; Kahyaoğlu, İnci; Yılmaz, Saynur; Erkaya, Salim; Şahin, Feride İffet

    2016-01-01

    Objective Although the association between BRCA1 and BRCA2 gene mutations and breast and ovarian cancer is known, there is insufficient data about premature ovarian insufficiency (POI). However, several studies have reported that there might be a relationship between POI and BRCA1 and BRCA2 gene mutation. Therefore, in the present study, we aimed to investigate the role of BRCA1 and BRCA2 gene mutations in the etiology of POI in a Turkish population. Material and Methods The cohort was classified into two groups: a study group, consisting of 56 individuals diagnosed with premature ovarian insufficiency (and who were younger than 40 years of age, had an antral follicle count 12 IU/I), and a control group, consisting of 45 fertile individuals. A total of 101 individuals were analyzed by next-generation sequencing to detect BRCA1 and BRCA2 gene mutations. Results We detected four new variations (p.T1246N and p.R1835Q in BRCA1 and p.I3312V and IVS-7T>A in BRCA2) that had not been reported before. Conclusion We did not find an association between the BRCA1 and BRCA2 gene mutations and premature ovarian insufficiency. However, larger, functional studies are needed to clarify the association.

  19. The Icelandic founder mutation BRCA2 999del5: analysis of expression

    International Nuclear Information System (INIS)

    A founder mutation in the BRCA2 gene (BRCA2 999del5) accounts for 7–8% of female breast cancers and for 40% of male breast cancers in Iceland. If expressed, the mutant gene would encode a protein consisting of the first 256 amino acids of the BRCA2 protein. The purpose of this study was to determine whether this mutant protein is produced in heterozygous individuals and, if so, what might be the functional consequences of mutant protein production. The presence of BRCA2 999del5 transcripts in fibroblasts from heterozygous individuals was assayed by cDNA synthesis and sequencing. The potential protein-coding portion of BRCA2 999del5 was cloned into the pIND(SP1)/V5-His vector and expressed in COS7 cells. The presence of the mutant protein in cell lysates from heterozygous fibroblasts and from COS7 cells was tested by a number of methods including immunoprecipitation, affinity purification with nickel-coated agarose beads, Western blotting and ELISA, using antibodies to the N-terminal end of BRCA2, antiserum specific for the 16 nonrelevant amino acids at the carboxyl end and antibodies to fusion partners of recombinant proteins. The frequency of the BRCA2 999del5 transcript in heterozygous fibroblasts was about one-fifth of the wild-type transcript; however, no mutant protein could be detected. Overexpression of BRCA2 999del5 mRNA in COS7 cells failed to produce a mutant protein unless degradation by proteasomes was blocked. Our results show that the protein product of BRCA2 999del5 is extremely unstable. Therefore, an increase in breast cancer risk in BRCA2 999del5 carriers is due to haploinsufficiency at the BRCA2 locus

  20. Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking.

    Science.gov (United States)

    Henderson, Beric R

    2005-09-01

    The subcellular location and function of many proteins are regulated by nuclear-cytoplasmic shuttling. BRCA1 and BARD1 provide an interesting model system for understanding the influence of protein dimerization on nuclear transport and localization. These proteins function predominantly in the nucleus to regulate cell cycle progression, DNA repair/recombination and gene transcription, and their export to the cytoplasm has been linked to apoptosis. Germ-line mutations in the BRCA1/BRCA2 and BARD1 genes predispose to risk of breast/ovarian cancer, and certain mutations impair protein function and nuclear accumulation. BRCA1 and BARD1 shuttle between the nucleus and cytoplasm; however heterodimerization masks the nuclear export signals located within each protein, causing nuclear retention of the BRCA1-BARD1 complex and potentially influencing its role in DNA repair, cell survival and regulation of centrosome duplication. This review discusses BRCA1, BRCA2 and BARD1 subcellular localization with emphasis on regulation of transport by protein dimerization and its functional implications. PMID:16108063

  1. Functional and structural analysis of C-terminal BRCA1 missense variants.

    Directory of Open Access Journals (Sweden)

    Francisco Quiles

    Full Text Available Germline inactivating mutations in BRCA1 and BRCA2 genes are responsible for Hereditary Breast and Ovarian Cancer Syndrome (HBOCS. Genetic testing of these genes is available, although approximately 15% of tests identify variants of uncertain significance (VUS. Classification of these variants into pathogenic or non-pathogenic type is an important challenge in genetic diagnosis and counseling. The aim of the present study is to functionally assess a set of 7 missense VUS (Q1409L, S1473P, E1586G, R1589H, Y1703S, W1718L and G1770V located in the C-terminal region of BRCA1 by combining in silico prediction tools and structural analysis with a transcription activation (TA assay. The in silico prediction programs gave discrepant results making its interpretation difficult. Structural analysis of the three variants located in the BRCT domains (Y1703S, W1718L and G1770V reveals significant alterations of BRCT structure. The TA assay shows that variants Y1703S, W1718L and G1770V dramatically compromise the transcriptional activity of BRCA1, while variants Q1409L, S1473P, E1586G and R1589H behave like wild-type BRCA1. In conclusion, our results suggest that variants Y1703S, W1718L and G1770V can be classified as likely pathogenic BRCA1 mutations.

  2. Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications

    OpenAIRE

    Domenica Scumaci; Laura Tammè; Claudia Vincenza Fiumara; Giusi Pappaianni; Antonio Concolino; Emanuela Leone; Maria Concetta Faniello; Barbara Quaresima; Enrico Ricevuto; Francesco Saverio Costanzo; Giovanni Cuda

    2015-01-01

    Background Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ-line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-po...

  3. BRCA1/BRCA2-deficient cells are sensitive to mitomycin C and tirapazamine

    International Nuclear Information System (INIS)

    Full text: BRCA1- and BRCA2- deficient cells have defective repair of double-strand breaks (DSBs) via homologous recombination (HR). The toxicity profiles of these cells is of interest in the treatment of breast and ovarian cancer arising in mutation carriers. We focused on Mitomycin C (MMC), which produces DNA interstrand crosslinks, and Tirapazamine (TPZ), which is activated by hypoxia, and inhibits DNA replication and topoisomerase II. BRCA1-deficient HCC1937 cells, derived from a breast cancer in a BRCA1 carrier, were compared to cells corrected with wild-type (wt) BRCA1. BRCA2-deficient Capan-1 cells, derived from a pancreatic cancer in a BRCA2 carrier, were compared to a wt BRCA2-corrected clone. Expressing the BRC4 peptide in MCF-7 cells disrupted the association of BRCA2 with Rad51, thereby inactivating the function of BRCA2. Clonogenic cell survival was measured in response to X-rays, MMC, and TPZ (under hypoxia). BRCA1- and BRCA2-deficient cells were moderately sensitive to X-rays, consistent with defective DSB repair. Sensitivity to MMC often reveals cells with a defect in HR, but also defines the phenotype of Fanconi anemia, which has no major HR defect. Both BRCA1 and BRCA2 deficiency resulted in marked MMC sensitivity. After 0.5μM MMC, survival was reduced >100-fold without wt BRCA1 and 10-fold in BRCA2-inactivated MCF-7 cells. Based on a screen of yeast mutants that showed HR-deficient yeast were sensitive to TPZ, TPZ hypersensitivity was also observed in BRCA1/2-deficient cells. After 5μM TPZ, wt BRCA1 survival was 0.3, whereas BRCA1-deficient survival was <0.001. Similarly, BRCA2-deficient Capan-1 cells showed a ∼100-fold increased sensitivity to TPZ. The marked sensitivity of BRCA-deficient cancer cells to MMC and TPZ has important implications for the optimum systemic therapy of these tumors in the clinic. The critical damage that leads to this marked sensitivity, and how it depends on HR, is the subject of ongoing studies

  4. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua;

    2014-01-01

    BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar...... and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. CONCLUSIONS: Our finding indicates involvement of hereditary factors in non-BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to...... underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer...

  5. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families : high cancer incidence at older age

    NARCIS (Netherlands)

    van der Kolk, Dorina M.; de Bock, Geertruida H.; Leegte, Beike K.; Schaapveld, Michael; Mourits, Marian J. E.; de Vries, J; van der Hout, Annemieke H.; Oosterwijk, Jan C.

    2010-01-01

    Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the ge

  6. BRCA1-Dependent Translational Regulation in Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Estelle Dacheux

    Full Text Available BRCA1 (Breast Cancer 1 has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair and protein ubiquitination. We previously demonstrated that BRCA1 interacts with PABP1 (Poly(A-Binding Protein 1 and that BRCA1 modulates protein synthesis through this interaction. To identify the mRNAs that are translationally regulated by BRCA1, we used a microarray analysis of polysome-bound mRNAs in BRCA1-depleted and non-depleted MCF7 cells. Our findings show that BRCA1 modifies the translational efficiency of approximately 7% of the mRNAs expressed in these cells. Further analysis revealed that several processes contributing to cell surveillance such as cell cycle arrest, cell death, cellular growth and proliferation, DNA repair and gene expression, are largely enriched for the mRNAs whose translation is impacted by BRCA1. The BRCA1-dependent translation of these species of mRNAs therefore uncovers a novel mechanism through which BRCA1 exerts its onco-suppressive role. In addition, the BRCA1-dependent translation of mRNAs participating in unexpected functions such as cellular movement, nucleic acid metabolism or protein trafficking is indicative of novel functions for BRCA1. Finally, this study contributes to the identification of several markers associated with BRCA1 deficiency and to the discovery of new potential anti-neoplastic therapeutic targets.

  7. BRCA1 status in Pakistani breast cancer patients with moderate family history

    International Nuclear Information System (INIS)

    Objective: To determine BRCA1 status in breast carcinoma patients of Pakistani origin. Study Design: Observational study. Place and Duration of Study: The Oncology Clinics of the Aga Khan University Hospital, Karachi, between May 2005 and December 2009. Methodology: Fifty three breast cancer patients based on clinical and laboratory diagnosis were recruited for this study. Moderate family history was defined as having a close relative (mother, daughter, sister) diagnosed with breast cancer under 45 years. Peripheral blood samples were collected from each patient in a 5 ml tube containing EDTA as anticoagulant. Subsequent to DNA extraction, mutational analysis of BRCA1 exons 2, 5, 6, 16, 20 and 22 was carried out using single strand conformation polymorphism (SSCP) assay while protein truncation test (PTT) was used to examine mutations in exon 11. All BRCA1 sequence variants were confirmed by DNA sequencing. Results: Twenty-three patients were diagnosed with early onset breast cancer, 30 patients had moderate family history. At the time of diagnosis, the median age of enrolled patients was 39 years (range 24-65 years). Out of 53 patients, analyzed by SSCP assay, mobility shift was detected in exon 6, 16 and 20 of three patients, whereas one patient was tested positive for mutation in exon 11 by PTT assays. All patients with BRCA1 mutations were further confirmed by DNA sequencing analysis. In exon 16 c.4837A > G was confirmed, which is a common polymorphism reported in several populations including Asians. Moreover, mutations in exon 6 (c.271T > G), exon 20 (c.5231 del G) and exon 11 (c.1123 T > G) were reported first time in the Pakistani population. Several BRCA1 mutations were observed in Pakistani breast cancer patients with moderate family history. Therefore, mutation-based genetic counselling for patients with moderate family history can facilitate management, if one first or second degree relative or early onset disease is apparent. (author)

  8. Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

    OpenAIRE

    Alvarez, Carolina; Aravena, Andrés; Tapia, Teresa; Rozenblum, Ester; Solís, Luisa; Corvalán, Alejandro; Camus, Mauricio; Alvarez, Manuel; Munroe, David; Maass, Alejandro; Carvallo, Pilar

    2016-01-01

    Background Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. M...

  9. BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans.

    Science.gov (United States)

    Boulton, Simon J; Martin, Julie S; Polanowska, Jolanta; Hill, David E; Gartner, Anton; Vidal, Marc

    2004-01-01

    Inherited germline mutations in the tumor suppressor gene BRCA1 predispose individuals to early onset breast and ovarian cancer. BRCA1 together with its structurally related partner BARD1 is required for homologous recombination and DNA double-strand break repair, but how they perform these functions remains elusive. As part of a comprehensive search for DNA repair genes in C. elegans, we identified a BARD1 ortholog. In protein interaction screens, Ce-BRD-1 was found to interact with components of the sumoylation pathway, the TACC domain protein TAC-1, and most importantly, a homolog of mammalian BRCA1. We show that animals depleted for either Ce-brc-1 or Ce-brd-1 display similar abnormalities, including a high incidence of males, elevated levels of p53-dependent germ cell death before and after irradiation, and impaired progeny survival and chromosome fragmentation after irradiation. Furthermore, depletion of ubc-9 and tac-1 leads to radiation sensitivity and a high incidence of males, respectively, potentially linking these genes to the C. elegans BRCA1 pathway. Our findings support a shared role for Ce-BRC-1 and Ce-BRD-1 in C. elegans DNA repair processes, and this role will permit studies of the BRCA1 pathway in an organism amenable to rapid genetic and biochemical analysis. PMID:14711411

  10. A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer

    Directory of Open Access Journals (Sweden)

    Llombart Pilar

    2011-10-01

    Full Text Available Abstract Background Germline mutations in either of the two tumor-suppressor genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast and ovarian cancer cases. Most of these mutations consist of deletions, insertions, nonsense mutations, and splice variants, however an increasing number of large genomic rearrangements have been identified in these genes. Methods We analysed BRCA1 and BRCA2 genes by direct sequencing and MLPA. We confirmed the results by an alternative MLPA kit and characterized the BRCA1 deletion by Array CGH. Results We describe the first case of a patient with no strong family history of the disease who developed early-onset bilateral breast cancer with a de novo complete BRCA1 gene deletion in the germinal line. The detected deletion started from the region surrounding the VAT1 locus to the beginning of NBR1 gene, including the RND2, ΨBRCA1, BRCA1 and NBR2 complete genes. Conclusion This finding supports the large genomic rearrangement screening of BRCA genes in young breast cancer patients without family history, as well as in hereditary breast and ovarian cancer families previously tested negative for other variations.

  11. Selecting for BRCA1 testing using a combination of homogeneous selection criteria and immunohistochemical characteristics of breast cancers

    International Nuclear Information System (INIS)

    BRCA1 gene-related tumours are more frequently estrogen receptor (ER) and progesterone receptor (PR) negative with a lower prevalence of human epidermal growth factor receptor 2 (HER2) overexpression or amplification. We evaluated the effectiveness of a combination of homogeneously selected criteria and immunohistochemical (IHC) characteristics of Familial Breast Cancers (FBCs) in detecting BRCA1 mutation carriers. Primary breast tumours from 93 FBC patients defined by specific eligibility criteria, based on personal and familial tumour history, were evaluated by Allred's method. The BRCA1 molecular analysis, including Multiplex Ligation-dependent Probe Amplification (MLPA), was considered as the gold standard assay. A total of 10 BRCA1 pathogenetic mutations was found. With the exclusion of the tumours characterized by double positive receptorial status and/or strong HER2 positivity (3+), we identified 22 patients, 10 of whom resulted as BRCA1 mutation carriers. The sensitivity, specificity, positive and negative predictive values were 100%, 83.3%, 45.4% and 100% respectively. Our findings suggest that the IHC analysis by Allred's method improves our ability to select patients for BRCA1 testing

  12. BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.

    Science.gov (United States)

    Schouten, Philip C; Gluz, Oleg; Harbeck, Nadia; Mohrmann, Svjetlana; Diallo-Danebrock, Raihana; Pelz, Enrico; Kruizinga, Janneke; Velds, Arno; Nieuwland, Marja; Kerkhoven, Ron M; Liedtke, Cornelia; Frick, Markus; Kates, Ronald; Linn, Sabine C; Nitz, Ulrike; Marme, Frederik

    2016-08-15

    BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide. PMID:26946057

  13. History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation.

    Science.gov (United States)

    Rhouma, Faten Ben; Messai, Habib; Hsouna, Sana; Halim, Nizar Ben; Cherif, Wafa; Fadhel, Sihem Ben; Tiar, Afaf; Nagara, Majdi; Azzouz, Hatem; Sfar, Mohamed-Tahar; Dridi, Marie-Françoise Ben; Tebib, Neji; Ayadi, Abdelkarim; Abdelhak, Sonia; Kefi, Rym

    2016-09-01

    Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients' ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history. PMID:26704523

  14. Sequence Variants of BRCA1 and BRCA2 Genes in Four Iranian Families with Breast and Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    F Keshavarzi

    2011-06-01

    Full Text Available "nBackground: BRCA1 and BRCA2 genes have been recognized to be responsible for 20-30% of hereditary breast can­cers and approximately 50% of familial breast and ovarian cancers. Therefore, the demand for BRCA1 and BRCA2 muta­tion screening is rapidly increasing as their identification will affect medical management of people at increased risk. Because of high costs involved in analysis of BRCA1 and 2 genes, contribution of different mutation types in BRCA1 and 2 and not knowing who should be tested has hampered wide spread use of molecular testing of high -risk fami­lies. There is a need to identify the genes and types of mutations involved in breast or ovarian cancers at different age of onsets and polymorphism and polymorphic variations in our population."nMethods: Twenty-seven patients with either early onset breast cancer (at age≤ 35 years or a personal and/or family his­tory of breast or ovarian cancer and 50 control subjects participated in this study. After collecting blood samples and extract­ing DNA, BRCA1 and BRCA2 genes were fully sequenced."nResults: Thirteen missense substitutions in BRCA1 and BRCA2 (9 and 4, respectively were revealed. Two nucleotide substitu­tions were novel (Gly1140Ser in BRCA1 and Glu1391Gly in BRCA2. The Glu1038Pro and Gly1140Ser were found in large series of breast and ovarian cancer and matched controls."nConclusion: Some nucleotide substitutions were seen only in single families and other in several. In other cases, muta­tions were seen in both BRCA1 and BRCA2 genes. Clinical significance of these mutations was evaluated comparing with normal controls.  

  15. Cellular responses of BRCA1-defective and triple-negative breast cancer cells and in vitro BRCA1 interactions induced by metallo-intercalator ruthenium(II) complexes containing chloro-substituted phenylazopyridine

    International Nuclear Information System (INIS)

    Triple-negative breast cancer (TNBC) is defined by the absence of expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Breast cancers with a BRCA1 mutation are also frequently triple-negative. Currently, there is a lack of effective therapies and known specific molecular targets for this aggressive breast cancer subtype. To address this concern, we have explored the cellular responses of BRCA1-defective and triple-negative breast cancer cells, and in vitro BRCA1 interactions induced by the ruthenium(II) complexes containing the bidentate ligand, 5-chloro-2-(phenylazo)pyridine. Triple-negative MDA-MB-231, BRCA1-defective HCC1937 and BRCA1-competent MCF-7 breast cancer cell lines were treated with ruthenium(II) complexes. The cytoxoxicity of ruthenium-induced breast cancer cells was evaluated by a real time cellular analyzer (RTCA). Cellular uptake of ruthenium complexes was determined by ICP-MS. Cell cycle progression and apoptosis were assessed using propidium iodide and Annexin V flow cytometry. The N-terminal BRCA1 RING protein was used for conformational and functional studies using circular dichroism and in vitro ubiquitination. HCC1937 cells were significantly more sensitive to the ruthenium complexes than the MDA-MB-231 and MCF-7 cells. Treatment demonstrated a higher degree of cytotoxicity than cisplatin against all three cell lines. Most ruthenium atoms were retained in the nuclear compartment, particularly in HCC1937 cells, after 24 h of incubation, and produced a significant block at the G2/M phase. An increased induction of apoptotic cells as well as an upregulation of p53 mRNA was observed in all tested breast cancer cells. It was of interest that BRCA1 mRNA and replication of BRCA1-defective cells were downregulated. Changes in the conformation and binding constants of ruthenium-BRCA1 adducts were observed, causing inactivation of the RING heterodimer BRCA1/BARD1-mediated E3 ubiquitin ligase activity

  16. Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

    Directory of Open Access Journals (Sweden)

    Song Hongshuo

    2012-10-01

    Full Text Available Abstract Background A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL on viral fitness in the context of the cognate transmitted/founder (T/F genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS method. Results The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K in Env and a reversion mutation in the Tat/Rev overlapping region. Conclusions These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

  17. What Black Women Know and Want to Know About Counseling and Testing for BRCA1/2.

    Science.gov (United States)

    Adams, Inez; Christopher, Juleen; Williams, Karen Patricia; Sheppard, Vanessa B

    2015-06-01

    Black women are just as likely to have hereditary breast cancer mutations as White women, yet their participation in genetic counseling and testing is substantially lower. This study sought to describe Black women's awareness and perceptions of BRCA1/2 testing and to identify barriers and motivators to seeking BRCA1/2 services. Fifty intercept interviews were conducted with Black women in public places (a professional women's basketball game, a grocery store, a faith-based community event, and the waiting area at a breast care clinic) in Washington, DC. More than half of the women (54%) were aware that genetic tests to determine risk for certain breast and ovarian cancers exist, but the majority (88%) had never heard of BRCA1/2, specifically. After hearing a description of BRCA1/2 genetic markers, 82% stated that they would agree to BRCA1/2 testing if it was offered to them. Perceived advantages of testing included cancer prevention and the ability to share information with family members. Perceived disadvantages included emotional distress associated with identification of the mutation and the potential misuse of results to deny healthcare or employment. Physician recommendation, self-care, and known family history were among the motivators for testing. Women listed possible media and venues for intervention. In spite of low rates of BRCA1/2 testing in the Black community, women in this sample were open to the idea. Interventions that address barriers and include cultural tailoring are necessary. PMID:25301325

  18. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    International Nuclear Information System (INIS)

    We tested the hypothesis that BRCA1 may play a role in the regulation of ovarian tumor cell death as well as the inhibition of ovarian cell proliferation. Introduction of BRCA1 antisense retroviral constructs into BG-1 estrogen-dependent ovarian adenocarcinoma cells resulted in reduced BRCA1 expression. BRCA1 antisense pooled populations and derived subclones were able to proliferate in monolayer culture without estrogen, whereas control cells began to die after 10 days of estrogen deprivation. In addition, both populations and subclones of BRCA1 antisense infected cells demonstrated a growth advantage in monolayer culture in the presence of estrogen and were able to proliferate in monolayer culture without estrogen, while control cells did not. Furthermore, clonal studies demonstrated that reduced levels of BRCA1 protein correlated with growth in soft agar and greater tumor formation in nude mice in the absence of estrogen. These data suggest that reduction of BRCA1 protein in BG-1 ovarian adenocarcinoma cells may have an effect on cell survival during estrogen deprivation both in vitro and in vivo. Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of the lack of mutations in sporadic tumors, it is possible that alterations in the function of BRCA1 may occur by mechanisms other than mutation, leading to an underestimation of risk when it is calculated solely on the basis of mutational analysis. Such alterations cannot be identified until the function and regulation of BRCA1 are better understood. The BRCA1 gene encodes a 220-kDa nuclear

  19. A Founder Large Deletion Mutation in Xeroderma Pigmentosum-Variant Form in Tunisia: Implication for Molecular Diagnosis and Therapy

    Directory of Open Access Journals (Sweden)

    Mariem Ben Rekaya

    2014-01-01

    Full Text Available Xeroderma pigmentosum Variant (XP-V form is characterized by a late onset of skin symptoms. Our aim is the clinical and genetic investigations of XP-V Tunisian patients in order to develop a simple tool for early diagnosis. We investigated 16 suspected XP patients belonging to ten consanguineous families. Analysis of the POLH gene was performed by linkage analysis, long range PCR, and sequencing. Genetic analysis showed linkage to the POLH gene with a founder haplotype in all affected patients. Long range PCR of exon 9 to exon 11 showed a 3926 bp deletion compared to control individuals. Sequence analysis demonstrates that this deletion has occurred between two Alu-Sq2 repetitive sequences in the same orientation, respectively, in introns 9 and 10. We suggest that this mutation POLH NG_009252.1: g.36847_40771del3925 is caused by an equal crossover event that occurred between two homologous chromosomes at meiosis. These results allowed us to develop a simple test based on a simple PCR in order to screen suspected XP-V patients. In Tunisia, the prevalence of XP-V group seems to be underestimated and clinical diagnosis is usually later. Cascade screening of this founder mutation by PCR in regions with high frequency of XP provides a rapid and cost-effective tool for early diagnosis of XP-V in Tunisia and North Africa.

  20. BRCA1 gene expression and promoter methylation patterns in early-onset breast cancers among A-bomb survivors

    International Nuclear Information System (INIS)

    Full text: Early-onset breast cancer is one of the most obviously radiogenic cancers among A-bomb survivors. Our initial hypothesis was that A-bomb radiation exposure might have enhanced the risk of early-onset breast cancer in initially heterozygous BRCA1 mutation carriers by mutationally inactivating the normal copy of the BRCA1 gene. To test this hypothesis, we began by examining the changes in BRCA1 expression immunohistochemically using the formalin-fixed, paraffin-embedded breast cancer tissues that had been stored at various hospitals in Hiroshima and Nagasaki for several decades. We then developed a highly-sensitive methylation-specific PCR method to test for hypermethylation of the BRCA1 gene promoter as a possible explanation for BRCA1 expression having been reduced in breast cancer cases. The breast cancer tissues studied so far were from a group of A-bomb survivors who were <45 years of age at diagnosis (31cases), and from a non-exposed group who were also <45 (21 cases). Our observations indicate that BRCA1 protein expression levels were reduced by ∼90% in many tumor tissues from both groups. Review of these reduced cases indicated that methylation silencing of the BRCA1 gene promoter was present in 40-50% of both exposed and unexposed cases. By contrast, fully unmethylated BRCA1 promoter sequences were present in as few as 15-20% of cases in the non-exposed group and 30-35% in the exposed group. Clearly we need to examine many more of the 700 samples that we aim to collect before we will be able to draw any conclusions about the possible role of methylation silencing in the development of early-onset breast cancers among A-bomb survivors

  1. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

    International Nuclear Information System (INIS)

    Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility

  2. BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study.

    Science.gov (United States)

    Høberg-Vetti, Hildegunn; Bjorvatn, Cathrine; Fiane, Bent E; Aas, Turid; Woie, Kathrine; Espelid, Helge; Rusken, Tone; Eikesdal, Hans Petter; Listøl, Wenche; Haavind, Marianne T; Knappskog, Per M; Haukanes, Bjørn Ivar; Steen, Vidar M; Hoogerbrugge, Nicoline

    2016-06-01

    Germline BRCA1/2 testing of breast and ovarian cancer patients is growing rapidly as the result affects both treatment and cancer prevention in patients and relatives. Through the DNA-BONus study we offered BRCA1/2 testing and familial risk assessment to all new patients with breast (N=893) or ovarian (N=122) cancer diagnosed between September 2012 and April 2015, irrespective of family history or age, and without prior face-to-face genetic counselling. BRCA1/2 testing was accepted by 405 (45.4%) and 83 (68.0%) of the patients with breast or ovarian cancer, respectively. A pathogenic BRCA1/2 variant was found in 7 (1.7%) of the breast cancer patients and 19 (22.3%) of the ovarian cancer patients. In retrospect, all BRCA1/2 mutation carriers appeared to fulfill current criteria for BRCA1/2 testing. Hospital Anxiety and Depression Scale (HADS) scores showed that the mean levels of anxiety and depression were comparable to those reported for breast and gynecological cancer patients in general, with a significant drop in anxiety symptoms during a 6-month follow-up period, during which the test result was forwarded to the patients. These results show that BRCA1/2 testing is well accepted in newly diagnosed breast and ovarian cancer patients. Current test criteria based on age and family history are sufficient to identify most BRCA1/2 mutation carriers among breast cancer patients. We recommend germline BRCA1/2 testing in all patients with epithelial ovarian cancer because of the high prevalence of pathogenic BRCA1/2 variants. PMID:26350514

  3. Pathogenicity of the BRCA1 Missense Variant M1775K is Determined by the Disruption of the BRCT Phosphopeptide-Binding Pocket: a Multi-Modal Approach

    Energy Technology Data Exchange (ETDEWEB)

    Tischkowitz,M.; Hamel, N.; Carvalho, M.; Birrane, G.; Soni, A.; van Beers, E.; Joosse, S.; Wong, N.; Novak, D.; et al

    2008-01-01

    A number of germ-line mutations in the BRCA1 gene confer susceptibility to breast and ovarian cancer. However, it remains difficult to determine whether many single amino-acid (missense) changes in the BRCA1 protein that are frequently detected in the clinical setting are pathologic or not. Here, we used a combination of functional, crystallographic, biophysical, molecular and evolutionary techniques, and classical genetic segregation analysis to demonstrate that the BRCA1 missense variant M1775K is pathogenic. Functional assays in yeast and mammalian cells showed that the BRCA1 BRCT domains carrying the amino-acid change M1775K displayed markedly reduced transcriptional activity, indicating that this variant represents a deleterious mutation. Importantly, the M1775K mutation disrupted the phosphopeptide-binding pocket of the BRCA1 BRCT domains, thereby inhibiting the BRCA1 interaction with the proteins BRIP1 and CtIP, which are involved in DNA damage-induced checkpoint control. These results indicate that the integrity of the BRCT phosphopeptide-binding pocket is critical for the tumor suppression function of BRCA1. Moreover, this study demonstrates that multiple lines of evidence obtained from a combination of functional, structural, molecular and evolutionary techniques, and classical genetic segregation analysis are required to confirm the pathogenicity of rare variants of disease-susceptibility genes and obtain important insights into the underlying pathogenetic mechanisms.

  4. BRCA1-mediated repression of select X chromosome genes

    Directory of Open Access Journals (Sweden)

    Ropers H Hilger

    2004-09-01

    Full Text Available Abstract Recently BRCA1 has been implicated in the regulation of gene expression from the X chromosome. In this study the influence of BRCA1 on expression of X chromosome genes was investigated. Complementary DNA microarrays were used to compare the expression levels of X chromosome genes in 18 BRCA1-associated ovarian cancers to those of the 13 "BRCA1-like" and 14 "BRCA2-like" sporadic tumors (as defined by previously reported expression profiling. Significance was determined using parametric statistics with P

  5. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    Directory of Open Access Journals (Sweden)

    Sólyom Szilvia

    2008-05-01

    Full Text Available Abstract Background BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Methods Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. Results We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13 in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. Conclusion In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility.

  6. Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

    International Nuclear Information System (INIS)

    BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility

  7. Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor.

    Science.gov (United States)

    Karpati, Mazal; Gazit, Ephraim; Goldman, Boleslaw; Frisch, Amos; Colombo, Roberto; Peleg, Leah

    2004-02-01

    The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the world's pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G749T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C1351G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known "Jewish" mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known "non-Jewish" mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C1351G and G749T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor (theta) between the markers and mutated loci, and the population growth correction, we deduced that G749T occurred in a founder ancestor 44.8 +/- 14.2 generations (g) ago [95% confidence interval (CI) 17.0-72.6 g] and C1351G arose 80.4 +/- 35.9 g ago (95% CI 44.5-116.3 g). Thus, the estimated dates for introduction of mutations are: 626 +/- 426 A.D. (200-1052 A.D.) for G749T and 442 +/- 1077 B.C. (1519 B.C. to 635 A.D.) for C1351G. PMID:14648242

  8. A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families

    Directory of Open Access Journals (Sweden)

    Escámez María-José

    2010-09-01

    Full Text Available Abstract Background Recessive Dystrophic Epidermolysis Bullosa (RDEB is a genodermatosis caused by more than 500 different mutations in the COL7A1 gene and characterized by blistering of the skin following a minimal friction or mechanical trauma. The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation. Methods Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs throughout the COL7A1 gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin. Results Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation. Conclusion Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (CCGCTCAAA_6527insC, thus suggesting the presence of a common ancestor.

  9. Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population

    NARCIS (Netherlands)

    Verbeek, DS; van de Warrenburg, BPC; Hennekam, FAM; Dooijes, D; Ippel, PF; Verschuuren-Bemelmans, CC; Kremer, HPH; Sinke, RJ

    2005-01-01

    Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort (approxim

  10. Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage.

    Science.gov (United States)

    Sau, Andrea; Lau, Rosanna; Cabrita, Miguel A; Nolan, Emma; Crooks, Peter A; Visvader, Jane E; Pratt, M A Christine

    2016-07-01

    Human BRCA1 mutation carriers and BRCA1-deficient mouse mammary glands contain an abnormal population of mammary luminal progenitors that can form 3D colonies in a hormone-independent manner. The intrinsic cellular regulatory defect in these presumptive breast cancer precursors is not known. We have discovered that nuclear factor kappaB (NF-κB) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-κB, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKKα. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1(-/-) mouse mammary. In vivo, NF-κB inhibition prevented recovery of Brca1(-/-) hormone-independent colony-forming cells. The majority of human BRCA1(mut/+) mammary glands showed marked lobular expression of nuclear NF-κB. We conclude that the aberrant proliferative capacity of Brca1(-/-) luminal progenitor cells is linked to the replication-associated DNA damage response, where proliferation of mammary progenitors is perpetuated by damage-induced, autologous NF-κB signaling. PMID:27292187

  11. High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic

    Directory of Open Access Journals (Sweden)

    Kuklova Jitka

    2007-06-01

    Full Text Available Abstract Background Alterations in the highly penetrant cancer susceptibility gene BRCA1 are responsible for the majority of hereditary breast and/or ovarian cancers. However, the number of detected germline mutations has been lower than expected based upon genetic linkage data. Undetected deleterious mutations in the BRCA1 gene in some high-risk families could be due to the presence of intragenic rearrangements as deletions, duplications or insertions spanning whole exons. Standard PCR-based screening methods are mainly focused on detecting point mutations and small insertions/deletions, but large rearrangements might escape detection. The purpose of this study was to determine the type and frequency of large genomic rearrangements in the BRCA1 gene in hereditary breast and ovarian cancer cases in the Czech Republic. Methods Multiplex ligation-dependent probe amplification (MLPA was used to examine BRCA1 rearrangements in 172 unrelated patients with hereditary breast and/or ovarian cancer syndrome without finding deleterious mutation after complete screening of whole coding regions of BRCA1/2 genes. Positive MLPA results were confirmed and located by long-range PCR. The breakpoints of detected rearrangements were characterized by sequencing. Results Six different large deletions in the BRCA1 gene were identified in 10 out of 172 unrelated high-risk patients: exons 1A/1B and 2 deletion; partial deletion of exon 11 and exon 12; exons 18 and 19 deletion; exon 20 deletion; exons 21 and 22 deletion; and deletion of exons 5 to 14. The breakpoint junctions were localized and further characterized. Destabilization and global unfolding of the mutated BRCT domains explain the molecular and genetic defects associated with the exon 20 in-frame deletion and the exon 21 and 22 in-frame deletion, respectively. Conclusion Using MLPA, mutations were detected in 6% of high-risk patients previously designated as BRCA1/2 mutation-negative. The breakpoints of five

  12. BRCA1基因多态性与宫颈癌发生关系的研究%Study on the polymorphism of breast cancer susceptibility gene 1 (BRCA1) and risk of cervical cancer

    Institute of Scientific and Technical Information of China (English)

    李利玲

    2011-01-01

    Objective; To study the polymorphism of breast cancer susceptibility gene 1 ( BRCA1) and the correlation with cervical cancer. Methods; A population based case -control study was conducted in 68 healthy controls and 71 cervical cancer patients. The BRCA1 Pro871 Leu polymorphism was detected by PCR - restriction fragment length polymorphism ( PCR - RFLP). Results; For the BRCA1 871 C>T polymorphism, individuals with C/T, C/C, C/T + T/T genotype significantly decreased the risk of developing cervical cancer compared with those harboring CyC genotype (C/T: OR (95% CI) =0.29 (0.13-0.68), T/T: OR (95% CI) = 0.29 (0.12-0.69), C/T + T/T; OR (95%CI) =0.29 (0.14-0.61). Conclusion: This study confirms the close relationship between BRCA1 polymorphism and cervical cancer. Mutation of BRCA1 Pro871Leu is a protective factor of inhibiting generation of cervical cancer.%目的 探讨人乳腺癌易感基因1(BRCA1)基因多态性与宫颈癌发生的关系.方法 采用病例对照研究,运用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)法检测71例宫颈癌患者和68例健康人BRCA1 871 C>T单核苷酸多态性,比较上述各组基因型和等位基因频率分布有无差异.结果 BRCA1 871T/T,C/T,C/T+T/T基因型相对于C/C基因型显著降低了宫颈癌发生的风险(C/T:OR(95%CI)=0.29(0.13-0.68),T/T:OR(95%CI)=0.29(0.12-0.69),C/T+T/T:OR(95%CI)=0.29(0.14-0.61);结论BRCA1基因突变与宫颈癌密切相关,BRCA1 871C>T降低了宫颈癌发生的风险.

  13. Evidence for a Chk2-BRCA1-BRCA2 pathway in controlling homologous recombination

    International Nuclear Information System (INIS)

    The BRCA2 protein is thought to play a role as a supportive protein for the assembly of Rad51 filaments at the sites of DNA damage or stalled DNA replication, and thereby facilitates the process of homologous recombination (HR). We provide direct evidence that the interaction of BRCA2 and Rad51, via the BRC repeat motifs of BRCA2, is the key to its function in HR. Furthermore, the BRCA2's role to facilitate HR is dependent on a replicating DNA template, closely linking the process of HR to DNA replication. To date, no other role for BRCA2 has been elucidated in-vivo. BRCA1, by contrast, has a complex series of functions including a supportive role in HR, a possible role in non-homologous recombination (NHR), transcriptional co-activation and E3 ubiquitin ligase activity. The protein undergoes extensive post-translational modification, principally by phosphorylation, in both S-phase and in response to DNA damage. We show that ATM-dependent modifications of BRCA1 are important for S-phase and G2/M checkpoints, but have no direct impact on DNA repair. However, a chk2 dependent modification of BRCA1 at serine-988, appears critical for the promotion of Rad51-dependent HR and the inhibition of Mre11/Rad50/NBS1- dependent repair. Direct modification of chk2 kinase activity, by over-expression of a kinase-dead chk2, results in an identical phenotype as seen with the S988A mutation of BRCA1. Taken together, these results suggest that a chk2-BRCA1-BRCA2 dependent pathway promotes error-free HR, suppresses error-prone NHR and thereby maintains genomic stability

  14. POTENTIAL OF MARINE DERIVED COMPOUNDS AGAINST BREAST CANCER (BRCA1): AN IN-SILICO DOCKING STUDY

    OpenAIRE

    Senthilraja P; Senthil Vinoth K; Sindhuraj M; Prakash M

    2012-01-01

    The present study focused on molecular computational analysis to identify the potential compounds, derived from marine organisms (algae, sponges and fungi), which can block the mutated gene (BRCA1) responsible for the breast cancer. Seven compounds were tested against the carcinogenic protein. The 3D crystal structure of the protein (ID: 2IOK) was retrieved from protein data bank (PDB) and the protein binding sites of the test compounds were identified. The results revealed that among seven c...

  15. Structural Basis of BACH1 Phosphopeptide Recognition by BRCA1 Tandem BRCT Domains

    OpenAIRE

    Botuyan, Maria Victoria E.; Nominé, Yves; Yu, Xiaochun; Juranic, Nenad; Macura, Slobodan; Chen, Junjie; Mer, Georges

    2004-01-01

    BRCT tandem domains, found in many proteins involved in DNA damage checkpoint and DNA repair pathways, were recently shown to be phosphopeptide binding motifs. Using solution nuclear magnetic resonance (NMR) spectroscopy and mutational analysis, we have characterized the interaction of BRCA1-BRCT domains with a phosphoserine-containing peptide derived from the DNA repair helicase BACH1. We show that a phenylalanine in the +3 position from the phosphoserine of BACH1 is bound to a conserved hyd...

  16. A Personalized Approach to Parkinson’s Disease Patients Based on Founder Mutation Analysis

    Science.gov (United States)

    Giladi, Nir; Mirelman, Anat; Thaler, Avner; Orr-Urtreger, Avi

    2016-01-01

    While the phenotype of Parkinson disease (PD) is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables, including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient’s quality of life.

  17. A Personalized Approach to Parkinson's Disease Patients Based on Founder Mutation Analysis.

    Science.gov (United States)

    Giladi, Nir; Mirelman, Anat; Thaler, Avner; Orr-Urtreger, Avi

    2016-01-01

    While the phenotype of Parkinson disease (PD) is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables, including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient's quality of life. PMID:27242656

  18. A Personalized Approach to Parkinson's disease patients based on founder mutation analysis

    Directory of Open Access Journals (Sweden)

    Nir eGiladi

    2016-05-01

    Full Text Available While the phenotype of Parkinson disease (PD is heterogeneous, treatment approaches are mostly uniform. Personalized medicine aims to treat diseases with targeted therapies based on cumulative variables including genotype. We believe that sufficient evidence has accumulated to warrant the initiation of personalized medicine in PD based on subjects genotype and provide examples for our reasoning from observations of GBA and LRRK2 mutations carriers. While PD patients who carry the G2019S mutation in the LRRK2 gene seem to develop relatively mild disease with more frequent postural instability gait disturbance phenotype, carriers of mutations in the GBA gene tend to have an early onset, rapidly deteriorating disease, with more pronounced cognitive and autonomic impairments. These characteristics have significant implications for treatment and outcome and should be addressed from an early stage in the attempt to improve the patient's quality of life.

  19. Genetic evaluation of BRCA1-A complex genes with triple-negative breast cancer susceptibility in Chinese women

    Science.gov (United States)

    Zheng, Yi-Zi; Qiao, Feng; Yao, Ling; Cao, Zhi-Gang; Ye, Fu-Gui; Wu, Jiong; Hu, Xin; Wang, Bin; Shao, Zhi-Ming

    2016-01-01

    Background The tumor suppressor BRCA1 plays a pivotal role in maintaining genomic stability and tumor suppression. The BRCA1-A complex is required for recruitment of BRCA1 to DNA damage sites, DNA repair and cell cycle checkpoint control. Since germline mutations of BRCA1 often lead to breast tumors that are triple-negative breast cancer (TNBC) type, we aimed to investigate whether genetic deficiency in genes of the BRCA1-A complex is associated with risk to TNBC development. Results We found that rs7250266 in the promoter region of NBA1 confers a decreased risk to TNBC development, but not to non-TNBC susceptibility. In addition, the haplotypes containing two polymorphisms rs7250266 and rs2278256 are associated with a lower chance of TNBC development specifically. Our studies also showed that the protective alleles of rs7250266 (C > G) and rs2278256 (T > C) down-regulate promoter activity of NBA1 in mammary epithelial cells. Methods We investigated associations between the BRCA1-A complex genes and TNBC developing risk in first case-control study of Chinese Han Women population including 414 patients with TNBC and 354 cancer-free controls. We detected 37 common variants in ABRAXAS, RAP80, BRE, BRCC36 and NBA1/MERIT40 genes encoding the BRCA1-A complex and evaluated their genetic susceptibility to the risk of TNBC. An additional cohort with 652 other types of breast cancer (non-TNBC) cases and 890 controls was used to investigate the associations between TNBC-specific SNPs genotype and non-TNBCs susceptibility. Conclusions Genetic variants in NBA1 may be an important genetic determinant of TNBC susceptibility. Further investigation and validation of these SNPs in larger cohorts may facilitate in predication and prevention of TNBC and in counseling individuals for risk of TNBC development. PMID:26848770

  20. Prostate screening uptake in Australian BRCA1 and BRCA2 carriers

    Directory of Open Access Journals (Sweden)

    McKinley Joanne M

    2007-09-01

    Full Text Available Abstract Men who carry mutations in BRCA1 or BRCA2 are at increased risk for prostate cancer. However the efficacy of prostate screening in this setting is uncertain and limited data exists on the uptake of prostate screening by mutation carriers. This study prospectively evaluated uptake of prostate cancer screening in a multi-institutional cohort of mutation carriers. Subjects were unaffected male BRCA1 and BRCA2 mutation carriers, aged 40–69 years, enrolled in the Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab and who had completed a mailed, self-report follow-up questionnaire 3 yearly after study entry. Of the 75 male carriers in this study, only 26 (35% had elected to receive their mutation result. Overall, 51 (68% did not recall having received a recommendation to have prostate screening because of their family history, but 41 (55% had undergone a prostate specific antigen (PSA test and 32 (43% a digital rectal examination (DRE in the previous 3 years. Those who were aware of their mutation result were more likely to have received a recommendation for prostate screening (43 vs. 6%, p = 0.0001, and to have had a PSA test (77 vs. 43%, p = 0.005 and a DRE (69 vs. 29%, p = 0.001 in the previous 3 years. The majority of unaffected males enrolled in kConFab with a BRCA1/2 mutation have not sought out their mutation result. However, of those aware of their positive mutation status, most have undergone at least one round of prostate screening in the previous 3 years.

  1. Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

    KAUST Repository

    Haywood, Annika F M

    2012-11-15

    AimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.

  2. A prospective investigation of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene carriers

    OpenAIRE

    O'Sullivan, Jacintha

    2013-01-01

    Background Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this ...

  3. Discovery of cell-permeable inhibitors that target the BRCT domain of BRCA1 protein by using a small-molecule microarray.

    Science.gov (United States)

    Na, Zhenkun; Pan, Sijun; Uttamchandani, Mahesh; Yao, Shao Q

    2014-08-01

    BRCTs are phosphoserine-binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain-containing, tumor-suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50% of hereditary breast cancers. Cell-permeable, small-molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray-based platforms, we have discovered the first cell-permeable protein-protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)2 domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation-induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small-molecule inhibitor of poly-ADP-ribose polymerase) and Etoposide (a small-molecule inhibitor of topoisomerase II). Unlike previously reported peptide-based PPI inhibitors of BRCA1, our compounds are small-molecule-like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP-related pathways in DNA damage and repair response, and in cancer therapy. PMID:24961672

  4. A founder mutation in Anoctamin 5 is a major cause of limb girdle muscular dystrophy

    OpenAIRE

    Hicks, Debbie; Sarkozy, Anna; Muelas, Nuria; Köehler, Katrin; Huebner, Angela; Hudson, Gavin; Chinnery, Patrick F.; Barresi, Rita; Eagle, Michelle; Polvikoski, Tuomo; Bailey, Geraldine; Miller, James; Radunovic, Aleksander; Hughes, Paul J.; Roberts, Richard

    2011-01-01

    The limb girdle muscular dystrophies (LGMDs) are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, LGMD2L and non-dysferlin Miyoshi muscular dystrophy (MMD3). We screened a candidate group of 64 patients from 59 British and German kindreds and found the...

  5. Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

    OpenAIRE

    Tan-Sindhunata, M Brigita; Mathijssen, Inge B; Smit, Margriet; Baas, Frank; de Vries, Johanna I; van der Voorn, J. Patrick; Kluijt, Irma; Hagen, Marleen A; Blom, Eveline W; Sistermans, Erik; Meijers-Heijboer, Hanne; Waisfisz, Quinten; Weiss, Marjan M.; Groffen, Alexander J.

    2014-01-01

    Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mappi...

  6. High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.

    Science.gov (United States)

    Gorodnova, Tatiana V; Sokolenko, Anna P; Ivantsov, Alexandr O; Iyevleva, Aglaya G; Suspitsin, Evgeny N; Aleksakhina, Svetlana N; Yanus, Grigory A; Togo, Alexandr V; Maximov, Sergey Ya; Imyanitov, Evgeny N

    2015-12-28

    Preoperative therapy provides an advantage for clinical drug assessment, as it involves yet untreated patients and facilitates access to the post-treatment biological material. Testing for Slavic founder BRCA mutations was performed for 225 ovarian cancer (OC) patients, who were treated by platinum-based neoadjuvant therapy. 34 BRCA1 and 1 BRCA2 mutation carriers were identified. Complete clinical response was documented in 12/35 (34%) mutation carriers and 8/190 (4%) non-carriers (P = 0.000002). Histopathologic response was observed in 16/35 (46%) women with the germ-line mutation versus 42/169 (25%) patients with the wild-type genotype (P = 0.02). Somatic loss of heterozygosity (LOH) for the remaining wild-type BRCA1 allele was detected only in 7/24 (29%) post-neoadjuvant therapy residual tumor tissues as compared to 9/11 (82%) BRCA1-associated OC, which were not exposed to systemic treatment before the surgery (P = 0.009). Furthermore, comparison of pre- and post-treatment tumor material obtained from the same patients revealed restoration of BRCA1 heterozygosity in 2 out of 3 sample pairs presenting with LOH at diagnosis. The obtained data confirm high sensitivity of BRCA-driven OC to platinating agents and provide evidence for a rapid selection of tumor cell clones without LOH during the course of therapy. PMID:26342406

  7. Removal of Ovaries and Fallopian Tubes Cuts Cancer Risk for BRCA1/2 Carriers | Division of Cancer Prevention

    Science.gov (United States)

    Surgery that removes the ovaries and fallopian tubes, called salpingo-oophorectomy, is one of the most effective ways to decrease a woman's risk of breast and gynecologic cancer if she carries aBRCA1 or BRCA2 gene mutation. However, the true degree of risk reduction has not been precisely defined. |

  8. A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects

    Science.gov (United States)

    Schaffner, Adam; Fedick, Anastasia; Kaye, Lauren E.; Liao, Jun; Yachelevich, Naomi; Chu, Mary-Lynn; Boles, Richard G.; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A.; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-01-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. PMID:27120463

  9. Preliminary crystallographic studies of BRCA1 BRCT-ABRAXAS complex.

    Science.gov (United States)

    Badgujar, Dilip C; Sawant, Ulka; Yadav, Lumbini; Hosur, M V; Varma, Ashok K

    2013-12-01

    The BRCA1 holoenzyme complex plays an important role in DNA damage repair. ABRAXAS is a newly discovered component of this complex and its C-terminal region directly binds to the BRCA1 BRCT domain. Single crystals of the BRCA1 BRCT-ABRAXAS complex grown by co-crystallization belonged to space group P4(1)2(1)2, with unit-cell parameters a = b = 187.18, c = 85.31 Å. Diffraction data were collected on the BM-14 beamline at the ESRF. Molecular-replacement calculations using Phaser led to three molecules in the asymmetric unit and a high solvent content of 76%. PMID:24316840

  10. Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer

    International Nuclear Information System (INIS)

    Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer. We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls). One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02–1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women. We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear

  11. The pathology of familial breast cancer: The pre-BRCA1/BRCA2 era - historical perspectives

    International Nuclear Information System (INIS)

    A proportion of breast carcinomas develop as a result of a genetic predispostion to the disease. Prior to cloning of the BRCA1 and BRCA2 genes a limited number of studies were carried out to identify specific histopathological characteristics of hereditary breast cancer. These studies are the subject of this review. The main finding was the association of the (atypical) medullary type of breast cancer with a family history; the most important caveat being that medullary breast cancer is found more frequently in young patients. In view of the frequent bilateral occurrence of lobular cancer, this histologic type is also likely to be associated with a predisposing genetic defect. Future investigations will have to test this hypothesis. In addition to mutations in the BRCA1 and BRCA2 genes, there are as yet unidentified genetic defects predisposing to breast cancer development, and histopathology may well help in identifying these genes in the future

  12. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers

    International Nuclear Information System (INIS)

    The present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this 'BRCA pathway' due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias. Literature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products. Deleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers. An important function of the BRCA pathway is to prevent a subgroup of human leukemias and lymphomas that may

  13.  Poly(ADP-ribose polymerase (PARP inhibitors in BRCA1/2 cancer therapy

    Directory of Open Access Journals (Sweden)

    Katarzyna Kluzek

    2012-06-01

    Full Text Available  A majority of currently used anticancer drugs belong to a group of chemical agents that damage DNA. The efficiency of the treatment is limited by effective DNA repair systems functioning in cancer cells. Many chemotherapeutic compounds cause strong systemic toxicity. Therefore, there is still a need for new anticancer agents which are less toxic for nontransformed cells and selectively kill cancer cells. One of the most promising molecular targets in cancer therapy is poly(ADP-ribose polymerases (PARP. PARP play an essential role in repairing DNA strand breaks. Small molecule inhibitors of these enzymes have been developed and have proved to be extremely toxic for cancer cells that lack the functional BRCA1 and BRCA2 proteins that are involved in homologous recombination, a complex repair mechanism of DNA double strand breaks. Mutations in BRCA1/2 genes are associated with genetically inherited breast and ovarian cancers. Therefore PARP inhibitors may prove to be very effective and selective in the treatment of these cancer types. This review is focused on the function of BRCA1/2 proteins and poly(ADP-ribose polymerases in DNA repair systems, especially in the homologous recombination process. A short history of the studies that led to synthesis of high specificity small molecule PARP inhibitors is also presented, as well as the results of clinical trials concerning the most effective PARP inhibitors in view of their potential application in oncological treatment, particularly breast cancers.

  14. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members

    DEFF Research Database (Denmark)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco;

    2012-01-01

    laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood...... was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different...... analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c...

  15. Functional characterization of BRCA1 gene variants by mini-gene splicing assay

    DEFF Research Database (Denmark)

    Steffensen, Ane Y; Dandanell, Mette; Jønson, Lars;

    2014-01-01

    are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13...... BRCA1 variants of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213-1G>A, c.670+1delG, c.4185+1G......Mutational screening of the breast cancer susceptibility gene BRCA1 leads to the identification of numerous pathogenic variants such as frameshift and nonsense variants, as well as large genomic rearrangements. The screening moreover identifies a large number of variants, for example, missense...

  16. BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?

    Directory of Open Access Journals (Sweden)

    Tagliaferri Pierosandro

    2009-10-01

    Full Text Available Abstract Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients.

  17. The Occurrence and Contribution of Germline BRCA1/2 Sequence Alterations in Iranian Patients With Breast Cancer

    Directory of Open Access Journals (Sweden)

    Zeinali S

    2011-12-01

    Full Text Available Background: Breast cancer is the most common form of hereditary cancer worldwide and is an important cause of morbidity and mortality. Approximately 5-10% of breast and ovarian cancers are due to the highly penetrating germline mutations in cancer predisposing genes. Two genes, BRCA1 and BRCA2, account for at least half of these cases. The demand for BRCA1 and BRCA2 mutation screening is rapidly increasing as their identification will affect the medical management of people at increased risk for the disease. Therefore, the aim of this study was to investigate BRCA1/2 mutations in 100 high risk Iranian families.Methods: One hundred families who met the minimal risk factors for breast/ovarian cancer were screened among the families referred to Kawsar Human Genetics Research Center for the diseases in 2009-2011. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened for by direct sequencing and MLPA in both patients and the controls.Results: In the present study, we could detect the following novel mutations: p.Gly1140Ser, p.Ile26Val, p.Leu1418X, p.Glu23Gln, p.Leu3X, p.Asn1403His, p.Asn1403Asp, p.Lys581X, p.Pro938Arg, p.Thr77Arg, p.Leu6Val, p.Arg7Cys, p.Leu15Ile, p.Ser177Thr, IVS7+83(-TT, IVS8 -70(-CATT, IVS2+9(G>C, IVS1-20(G>A, IVS1-8(A>G, p.Met1Ile, IVS2+24(A>G, IVS5-8 (A>G, IVS2(35-39TTcctatGAT, IVS13+9 G>C in BRCA1 and p.Glu1391Gly, p. Val1852Ile, IVS6-70(T>G, 1994-1995 (InsA in BRCA2.Conclusion: Ten mutations seemed to be pathogenic and the disease-causing mutations were seen in 16% of the families. In addition, from the total number of substitutions and reassortments (42, 80% related to BRCA1 and 20% to mutations in BRCA2 genes.

  18. Predictive Factors for BRCA1 and BRCA2 Genetic Testing in an Asian Clinic-Based Population.

    Directory of Open Access Journals (Sweden)

    Edward S Y Wong

    Full Text Available The National Comprehensive Cancer Network (NCCN has proposed guidelines for the genetic testing of the BRCA1 and BRCA2 genes, based on studies in western populations. This current study assessed potential predictive factors for BRCA mutation probability, in an Asian population.A total of 359 breast cancer patients, who presented with either a family history (FH of breast and/or ovarian cancer or early onset breast cancer, were accrued at the National Cancer Center Singapore (NCCS. The relationships between clinico-pathological features and mutational status were calculated using the Chi-squared test and binary logistic regression analysis.Of 359 patients, 45 (12.5% had deleterious or damaging missense mutations in BRCA1 and/or BRCA2. BRCA1 mutations were more likely to be found in ER-negative than ER-positive breast cancer patients (P=0.01. Moreover, ER-negative patients with BRCA mutations were diagnosed at an earlier age (40 vs. 48 years, P=0.008. Similarly, triple-negative breast cancer (TNBC patients were more likely to have BRCA1 mutations (P=0.001 and that these patients were diagnosed at a relatively younger age than non-TNBC patients (38 vs. 46 years, P=0.028. Our analysis has confirmed that ER-negative status, TNBC status and a FH of hereditary breast and ovarian cancer (HBOC are strong factors predicting the likelihood of having BRCA mutations.Our study provides evidence that TNBC or ER-negative patients may benefit from BRCA genetic testing, particularly younger patients (<40 years or those with a strong FH of HBOC, in Asian patients.

  19. Radiation-induced effects of ATM gene on expressions of BRCA1 and RAD51 detected by laser scanning confocal microscopy

    International Nuclear Information System (INIS)

    Objective: To investigate the expressions of BRCA1 and RAD51 proteins in GM, ATM+- AT, and AT cells before and after irradiation by 60Co γ-rays. Methods: The localizations and expressions of BRCA1 and RAD51 proteins in GM, ATM+-AT, AT cells were detected by immunofluorescence staining and laser scanning confocal microscopy after 0 and 10 Gy 60Co γ-ray irradiation. Quantitative analysis was also processed on these proteins. Results: Before irradiation with γ-rays, few expression of RAD51 or BRCA1 protein and no colocalization was observed in GM, ATM+-AT, AT cells, and lowest expression in AT cells. Being irradiated with 10 Gy 60Co γ-rays, the expressions of BRCA1 and RAD51 proteins were increased in GM, ATM+-AT, and AT cells. Colocalized expressions in GM, ATM+-AT cells were observed, but no such expression in AT cells. The expressions of BRCA1 and RAD51 proteins in GM, ATM+-AT cells statistically significantly differed from those in AT cells (P+-AT cells was also statistically significant (P+-AT cells could activate its down stream genes, BRCA1 and RAD51, and could enhance the expressions of and interactions between these two proteins. All these changes are helpful for cell repair following radiation injury. The expressions of BRCA1 and RAD51 proteins were lower in normal GM cells transfected with extrinsic ATM than that in GM cells because the extrinsic ATM gene could not completely compensate the function, partial phosphorylation of down stream gene BRCA1, of intrinsic ATM mutative gene. (authors)

  20. Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report

    Directory of Open Access Journals (Sweden)

    Ayesha Farooq

    2011-01-01

    Mutational screening of the exons in all the samples of our study group did not reveal any pathogenic mutation. These results along with the results of the previous Pakistani studies for both BRCA1 and BRCA2 genes were summed up to prepare a Pakistani database. Percentage involvement of these genes was estimated. Nine percent of these cancers show alterations in BRCA1 gene while 3 percent have shown BRCA2 variants. The remaining 88 percent of breast and ovarian cancers can be attributed to the involvement of other genes.

  1. No evidence of increased breast cancer risk for proven noncarriers from BRCA1 and BRCA2 families

    DEFF Research Database (Denmark)

    Nielsen, Henriette Roed; Petersen, Janne; Krogh, Lotte; Nilbert, Mef; Skytte, Anne-Bine

    2016-01-01

    In families screened for mutations in the BRCA1 or BRCA2 genes and found to have a segregating mutation the breast cancer risk for women shown not to carry the family-specific mutation might be at above "average" risk. We assessed the risk of breast cancer in a clinic based cohort of 725 female...... proven noncarriers in 239 BRCA1 and BRCA2 families compared with birth-matched controls from the Danish Civil Registration System. Prospective analysis showed no significantly increased risk for breast cancer in noncarriers with a hazard ratio of 0.67 [95 % confidence interval (CI) 0.32-1.42, p = 0.......29] for all family members who tested negative and 0.87 (95 % CI 0.38-1.97, p = 0.73) for non-carries who were first-degree relatives of mutation carriers. Proven noncarriers from BRCA1 and BRCA2 families have no markedly increased risk for breast cancer compared to the general population, and our data do...

  2. Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP Beta promoter by an NRF-1-containing complex

    Directory of Open Access Journals (Sweden)

    MacDonald Gwen

    2011-05-01

    Full Text Available Abstract Background BRCA1 has recently been identified as a potential regulator of mammary stem/progenitor cell differentiation, and this function may explain the high prevalence of breast cancer in BRCA1 mutation carriers, as well as the downregulation of BRCA1 in a large proportion of sporadic breast cancers. That is, loss of BRCA1 function results in blocked differentiation with expansion of the mammary stem/progenitor cells. Because BRCA1 also maintains genomic integrity, its loss could produce a pool of genetically unstable stem/progenitor cells that are prime targets for further transforming events. Thus, elucidating the regulatory mechanisms of BRCA1 expression is important to our understanding of normal and malignant breast differentiation. Results Loss of BRCA1 expression in the ErbB2-amplified SK-BR-3 cell line was found to be the result of loss of activity of the ets transcription factor GABP, a previously characterized regulator of BRCA1 transcription. The expression of the non-DNA binding GABPβ subunit was shown to be deficient, while the DNA binding subunit, GABPα was rendered unstable by the absence of GABPβ. Deletion analysis of the GABPβ proximal promoter identified a potential NRF-1 binding site as being critical for expression. Supershift analysis, the binding of recombinant protein and chromatin immunoprecipitation confirmed the role of NRF-1 in regulating the expression of GABPβ. The siRNA knockdown of NRF-1 resulted in decreased GABPβ and BRCA1 expression in MCF-7 cells indicating that they form a transcriptional network. NRF-1 levels and activity did not differ between SK-BR-3 and MCF-7 cells, however the NRF-1 containing complex on the GABPβ promoter differed between the two lines and appears to be the result of altered coactivator binding. Conclusions Both NRF-1 and GABP have been linked to the regulation of nuclear-encoded mitochondrial proteins, and the results of this study suggest their expression is

  3. "Ring-fencing" BRCA1 tumor suppressor activity.

    Science.gov (United States)

    Patel, Ketan J; Crossan, Gerry P; Hodskinson, Michael R G

    2011-12-13

    BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis. PMID:22172717

  4. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members.

    Science.gov (United States)

    Thomassen, Mads; Blanco, Ana; Montagna, Marco; Hansen, Thomas V O; Pedersen, Inge S; Gutiérrez-Enríquez, Sara; Menéndez, Mireia; Fachal, Laura; Santamariña, Marta; Steffensen, Ane Y; Jønson, Lars; Agata, Simona; Whiley, Phillip; Tognazzo, Silvia; Tornero, Eva; Jensen, Uffe B; Balmaña, Judith; Kruse, Torben A; Goldgar, David E; Lázaro, Conxi; Diez, Orland; Spurdle, Amanda B; Vega, Ana

    2012-04-01

    Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of

  5. Communicating BRCA1/2 genetic test results within the family: a qualitative analysis.

    Science.gov (United States)

    Dancyger, Caroline; Wiseman, Mel; Jacobs, Chris; Smith, Jonathan A; Wallace, Melissa; Michie, Susan

    2011-08-01

    Genetic testing for BRCA1/2 mutations associated with hereditary breast and ovarian cancer reveals significant risk information about one's chances of developing cancer. It is important to study communication processes in families where members are undergoing genetic testing because the information received is crucial not just to the individual concerned but also to other members of the biological family. This study investigates family communication of BRCA1/2 test results from both the informants' and recipients' perspectives. A total of 10 female patients and 22 of their relatives were interviewed. Patients' and their relatives described feelings of responsibility for sharing genetic information within the family to enable others to reduce their risks of developing cancer. However, there were limits to an individuals' responsibility once key family members had been informed, who then had to take responsibility for continuing dissemination of information. Whilst there was an implicit responsibility to inform the family of a mutation, information was edited or withheld in the best interest of relatives, dependent upon their perceived emotional readiness, resilience and current life stage and circumstances. The pre-existing family culture and the impact previous cancer diagnoses had upon the family also influenced the process of communication. Findings are discussed in relation to extant literature and implications for clinical practice are considered. PMID:21797732

  6. Novel sequence variants and a high frequency of recurrent polymorphisms in BRCA1 gene in Sri Lankan breast cancer patients and at risk individuals

    Directory of Open Access Journals (Sweden)

    Angunawala Preethika

    2008-07-01

    Full Text Available Abstract Background Breast Cancer is the most commonly diagnosed cancer among Sri Lankan women. Germline mutations in the susceptibility genes BRCA1 and BRCA2 in hereditary breast/ovarian cancer, though low in prevalence, are highly penetrant and show geographical variations. There have been only a few reports from Asia on mutations in BRCA1/2 genes and none from Sri Lanka. Methods A total of 130 patients with (N = 66 and without (N = 64 a family history of breast cancer, 70 unaffected individuals with a family history of breast cancer and 40 control subjects were analysed for BRCA1 mutations. All but exon 11 were screened by single strand conformation analysis (SSCP and heteroduplex analysis. PCR products which showed abnormal patterns in SSCP were sequenced. Exon 11 was directly sequenced. Results Nineteen sequence variants were found in BRCA1 gene. Two novel deleterious frame-shift mutations; c.3086delT/exon11 (in one patient and c.5404delG/exon21 (in one patient and two of her family members were identified. A possibly pathogenic novel missense mutation (c.856T>G/exon 11 and three novel intronic variants (IVS7+36C>T, IVS7+41C>T, IVS7+49del15 were characterised. Ten previously reported common polymorphisms and three previously reported intronic variants were also observed. Conclusion After screening of 66 patients with family history and 64 sporadic breast cancer patients, 2 deleterious mutations (c.3086delT and c.5404delG in two families were identified and two more possibly pathogenic mutations (c.856T>G and IVS17-2A>T in two families were identified. Data base BRCA1 - Gene Bank: Accession # U14680 Version # 14680.1

  7. Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? Rotterdam/Leiden Genetics Working Group

    NARCIS (Netherlands)

    L.N. Lodder; P. Devilee (Peter); M.F. Niermeijer (Martinus); C.J. Cornelisse (Cees); P.G. Frets; R.W. Trijsburg (Wim); E.J. Meijers-Heijboer (Hanne); J.G.M. Klijn (Jan); H.J. Duivenvoorden (Hugo); A. Tibben (Arend); A. Wagner (Anja); C.A. van der Meer

    1999-01-01

    textabstractPresymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87

  8. Breast Cancer Risk Perceptions among Relatives of Women with Uninformative Negative BRCA1/2 Test Results: The Moderating Effect of the Amount of Shared Information

    OpenAIRE

    Himes, Deborah O.; Clayton, Margaret F.; Gary W. Donaldson; Ellington, Lee; Buys, Saundra S.; Kinney, Anita Y.

    2015-01-01

    The most common result of BRCA1/2 mutation testing when performed in a family without a previously identified mutation is an uninformative negative test result. Women in these families may have an increased risk for breast cancer because of mutations in non-BRCA breast cancer predisposition genes, including moderate- or low-risk genes, or shared environmental factors. Genetic counselors often encourage counselees to share information with family members, however it is unclear how much informa...

  9. Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.

    Science.gov (United States)

    Trego, Kelly S; Groesser, Torsten; Davalos, Albert R; Parplys, Ann C; Zhao, Weixing; Nelson, Michael R; Hlaing, Ayesu; Shih, Brian; Rydberg, Björn; Pluth, Janice M; Tsai, Miaw-Sheue; Hoeijmakers, Jan H J; Sung, Patrick; Wiese, Claudia; Campisi, Judith; Cooper, Priscilla K

    2016-02-18

    XPG is a structure-specific endonuclease required for nucleotide excision repair, and incision-defective XPG mutations cause the skin cancer-prone syndrome xeroderma pigmentosum. Truncating mutations instead cause the neurodevelopmental progeroid disorder Cockayne syndrome, but little is known about how XPG loss results in this devastating disease. We identify XPG as a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR). XPG depletion causes DNA double-strand breaks, chromosomal abnormalities, cell-cycle delays, defective HRR, inability to overcome replication fork stalling, and replication stress. XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation. Upstream in HRR, XPG interacts directly with BRCA1. Its depletion causes BRCA1 hyper-phosphorylation and persistent chromatin binding. These unexpected findings establish XPG as an HRR protein with important roles in genome stability and suggest how XPG defects produce severe clinical consequences including cancer and accelerated aging. PMID:26833090

  10. c-Myc activates BRCA1 gene expression through distal prom