Dataset Information

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

ABSTRACT: 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 frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.

SUBMITTER: Im KM

PROVIDER: S-EPMC3196382 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

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

Human genetics 20110520 5

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 frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift ...[more]

PMID: 21597964

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Project description:BackgroundTechnological 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.MethodsIn a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided.ResultsOne thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%.ConclusionCompared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn't adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.

Project description:BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: We observed no significant association of breast cancer risk with TP53 genetic variants based on BRCA1/2 mutation carrier status. Although the small sample size did not permit analysis of all possible haplotypes, we observed that BRCA2 mutation carriers harboring the Ins16minus-72Arg haplotype had a significantly younger mean age of diagnosis of breast cancer. These observations suggest that investigations in a larger French Canadian sample are warranted to further elucidate the effects of TP53 variants on age of diagnosis of breast cancer among BRCA1 and BRCA2 mutation carriers.

Project description:ImportanceAmong Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.ObjectiveTo determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer.Design, setting, and participantsIn this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017.Main outcomes and measuresGenomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel.ResultsOf the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not.Conclusions and relevanceComprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.

Dataset Information

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

Publications

Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

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