Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes

Timothy R. Rebbeck, Nandita Mitra, Susan M. Domchek, Fei Wan, Tara M. Friebel, Teo V. Tran, Christian F. Singer, Muy Kheng Maria Tea, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Carrie L. Snyder, Judy E. Garber, Antonis C. Antoniou, Susan Peock, D. Gareth Evans, Joan Paterson, M. John KennedyAlan Donaldson, Huw Dorkins, Douglas F. Easton, Wendy S. Rubinstein, Mary B. Daly, Claudine Isaacs, Heli Nevanlinna, Fergus J. Couch, Irene L. Andrulis, Eitan Freidman, Yael Laitman, Patricia A. Ganz, Gail E. Tomlinson, Susan L. Neuhausen, Steven A. Narod, Catherine M. Phelan, Roger Greenberg, Katherine L. Nathanson

    Research output: Contribution to journalArticlepeer-review

    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 (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (P FDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR <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. ©2011 AACR.
    Original languageEnglish
    Pages (from-to)5792-5805
    Number of pages13
    JournalCancer Research
    Volume71
    Issue number17
    DOIs
    Publication statusPublished - 1 Sep 2011

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