Gaudet, Mia M2; Kuchenbaecker, Karoline B3; Vijai, Joseph3; Klein, Robert J3; Kirchhoff, Tomas3; McGuffog, Lesley3; Barrowdale, Daniel3; Dunning, Alison M3; Lee, Andrew Roger4; Dennis, Joe3; Healey, Sue3; Dicks, Ed3; Soucy, Penny3; Sinilnikova, Olga M3; Pankratz, Vernon S3; Wang, Xianshu3; Eldridge, Ronald C3; Tessier, Daniel C3; Vincent, Daniel3; Bacot, Francois3; Hogervorst, Frans B L3; Peock, Susan3; Stoppa-Lyonnet, Dominique3; Peterlongo, Paolo3; Schmutzler, Rita K3; Nathanson, Katherine L3; Piedmonte, Marion3; Singer, Christian F3; Thomassen, Mads8; Hansen, Thomas v O3; Neuhausen, Susan L3; Blanco, Ignacio3; Greene, Mark H3; Garber, Judith3; Weitzel, Jeffrey N3; Andrulis, Irene L3; Goldgar, David E3; D'Andrea, Emma3; Caldes, Trinidad3; Nevanlinna, Heli3; Osorio, Ana3; van Rensburg, Elizabeth J3; Arason, Adalgeir3; Rennert, Gad3; van den Ouweland, Ans M W3; van der Hout, Annemarie H3; Kets, Carolien M3; Aalfs, Cora M3; Wijnen, Juul T3; Ausems, Margreet G E M3; Frost, Debra3; Ellis, Steve3; Fineberg, Elena3; Platte, Radka3; Evans, D Gareth3; Jacobs, Chris3; Adlard, Julian3; Tischkowitz, Marc3; Porteous, Mary E3; Damiola, Francesca3; Golmard, Lisa3; Barjhoux, Laure3; Longy, Michel3; Belotti, Muriel3; Ferrer, Sandra Fert3; Mazoyer, Sylvie3; Spurdle, Amanda B3; Manoukian, Siranoush3; Barile, Monica3; Genuardi, Maurizio3; Arnold, Norbert3; Meindl, Alfons3; Sutter, Christian3; Wappenschmidt, Barbara3; Domchek, Susan M3; Pfeiler, Georg3; Friedman, Eitan3; Jensen, Uffe Birk5; Robson, Mark3; Shah, Sohela3; Lazaro, Conxi3; Mai, Phuong L3; Benitez, Javier3; Southey, Melissa C3; Schmidt, Marjanka K3; Fasching, Peter A3; Peto, Julian3; Humphreys, Manjeet K3; Wang, Qin6; Michailidou, Kyriaki3; Sawyer, Elinor J3; Burwinkel, Barbara3; Guénel, Pascal3; Bojesen, Stig Egil7; Milne, Roger L3; Brenner, Hermann3; Lochmann, Magdalena3; Aittomäki, Kristiina3; Dörk, Thilo3; Margolin, Sara3; Mannermaa, Arto3; Lambrechts, Diether3; Chang-Claude, Jenny3; Radice, Paolo3; Giles, Graham G3; Haiman, Christopher A3; Winqvist, Robert3; Devillee, Peter3; García-Closas, Montserrat3; Schoof, Nils3; Hooning, Maartje J3; Cox, Angela3; Pharoah, Paul D P3; Jakubowska, Anna3; Orr, Nick3; González-Neira, Anna3; Pita, Guillermo3; Alonso, M Rosario3; Hall, Per3; Couch, Fergus J3; Simard, Jacques3; Altshuler, David3; Easton, Douglas F3; Chenevix-Trench, Georgia3; Antoniou, Antonis C3; Offit, Kenneth3
1 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA.3 unknown4 Risø National Laboratory for Sustainable Energy5 Institut for Human Genetik6 Department of Photonics Engineering7 Afd. for Undervisning8 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
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.
P L O S Genetics, 2013, Vol 9, Issue 3
Adult; Aged; Alleles; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Chromosomes, Human, Pair 6; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Heterozygote; Humans; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Risk Factors; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.