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

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posted on 12.04.2015, 17:44 by Mia M. Gaudet, Karoline B. Kuchenbaecker, Joseph Vijai, Robert J. Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M. Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M. Sinilnikova, Vernon S. Pankratz, Xianshu Wang, Ronald C. Eldridge, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Frans B. L. Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Rita K. Schmutzler, Katherine L. Nathanson, Marion Piedmonte, Christian F. Singer, Mads Thomassen, Thomas v. O. Hansen, Susan L. Neuhausen, Ignacio Blanco, Mark H. Greene, Judith Garber, Jeffrey N. Weitzel, Irene L. Andrulis, David E. Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J. van Rensburg, Adalgeir Arason, Gad Rennert, Ans M. W. van den Ouweland, Annemarie H. van der Hout, Carolien M. Kets, Cora M. Aalfs, Juul T. Wijnen, Margreet G. E. M. Ausems, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D. Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E. Porteous, Francesca Damiola, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B. Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M. Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L. Mai, Javier Benitez, Melissa C. Southey, Marjanka K. Schmidt, Peter A. Fasching, Julian Peto, Manjeet K. Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J. Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E. Bojesen, Roger L. Milne, Hermann Brenner, Magdalena Lochmann, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G. Giles, Christopher A. Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J. Hooning, Angela Cox, Paul D. P. Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Per Hall, Fergus J. Couch, Jacques Simard, David Altshuler, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Kenneth Offit

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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