Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

• Type of Material: Article
• Authors: Mia M. Gaudet, Emory University; Karoline B. Kuchenbaecker, University of Cambridge; Joseph Vijai, Memorial Sloan Kettering Cancer Center; Robert J. Klein, Memorial Sloan Kettering Cancer Center; Tomas Kirchhoff, New York University; Lesley McGuffog, University of Cambridge; Daniel Barrowdale, University of Cambridge; Alison M. Dunning, University of Cambridge; Andrew Lee, University of Cambridge; Joe Dennis, University of Cambridge; Sue Healey, Queensland Institute of Medical Research; Ed Dicks, University of Cambridge; Penny Soucy, Centre Hospitalier Universitaire de Québec; Olga M. Sinilnikova, Hospices Civils de Lyon; Vernon S. Pankratz, Université Lyon 1; Xianshu Wang, Mayo Clinic; Ronald Eldridge, Emory University; Daniel C. Tessier, Emory University; Daniel Vincent, Centre d'Innovation Génome Québec et Université McGill; Francois Bacot, Centre d'Innovation Génome Québec et Université McGill
• Language: English
• Date: 2013-03-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1003173
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 9
• Issue: 3
• Start Page: e1003173
• End Page: e1003173
• Grant/Funding Information: Complete funding list available in full text.
• Keywords: BRCA2 MUTATION CARRIERS; POPULATION; GENOME-WIDE ASSOCIATION; Life Sciences & Biomedicine; CONSORTIUM; Genetics & Heredity; SUBTYPES; SUSCEPTIBILITY ALLELES; ZNF365; COMMON VARIANTS; OVARIAN-CANCER; TRANSCRIPTION FACTOR AP-2; Science & Technology
• Research Categories: Health Sciences, Oncology; Health Sciences, Epidemiology; Biology, Genetics

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.