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

ABSTRACT: 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.

SUBMITTER: Cox DG

PROVIDER: S-EPMC3733139 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

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

Human molecular genetics 20110902 23

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 g ...[more]

PMID: 21890493

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Project description:INTRODUCTION:More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS:We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS:The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)?=?0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC?=?0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC?=?0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS:Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

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

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

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