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Title: Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk
Author: Gaudet, Mia M.
Kuchenbaecker, Karoline B.
Vijai, Joseph
Klein, Robert J.
Kirchhoff, Tomas
McGuffog, Lesley
Barrowdale, Daniel
Dunning, Alison M.
Lee, Andrew
Dennis, Joe
Healey, Sue
Dicks, Ed
Soucy, Penny
Sinilnikova, Olga M.
Pankratz, Vernon S.
Wang, Xianshu
Eldridge, Ronald C.
Tessier, Daniel C.
Vincent, Daniel
Bacot, François
Hogervorst, Frans B. L.
Peock, Susan
Stoppa-Lyonnet, Dominique
Peterlongo, Paolo
Schmutzler, Rita Katharina
Nathanson, Katherine L.
Piedmonte, Marion
Singer, Christian F.
Thomassen, Mads
Hansen, Thomas V. O.
Neuhausen, Susan L.
Blanco Guillermo, Ignacio
Lázaro García, Conxi
Keywords: Càncer de mama
Cromosomes humans
Malalties hereditàries
Genoma humà
Breast cancer
Human chromosomes
Genetic diseases
Human genome
Issue Date: 27-Mar-2013
Publisher: Public Library of Science (PLoS)
Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
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It is part of: PLoS Genetics, 2013, vol. 9, num. 3, p. e1003173
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ISSN: 1553-7390
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

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