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Rebbeck TR, Mitra N, Domchek SM, Wan F, Friebel TM, Tran TV, Singer CF, Tea MK, Blum JL, Tung N, Olopade OI, Weitzel JN, Lynch HT, Snyder CL, Garber JE, Antoniou AC, Peock S, Evans DG, Paterson J, Kennedy MJ, Donaldson A, Dorkins H, Easton DF, Rubinstein WS, Daly MB, Isaacs C, Nevanlinna H, Couch FJ, Andrulis IL, Freidman E, Laitman Y, Ganz PA, Tomlinson GE, Neuhausen SL, Narod SA, Phelan CM, Greenberg R, Nathanson KL, Epidemiological Study BB
Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes
Cancer Research (2011) 71:5792-5805.
Abstract
Inherited BRCA1 mutations confer elevated 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 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations. Cancer Res; 71(17); 5792-805. (C)2011 AACR.
Note
Publication Date: 2011-09-01.
PMCID: PMC3170727
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