Gaudet, Mia M2; Kuchenbaecker, Karoline B2; Vijai, Joseph2; Klein, Robert J2; Kirchhoff, Tomas2; McGuffog, Lesley2; Barrowdale, Daniel2; Dunning, Alison M2; Lee, Andrew Roger3; Dennis, Joe2; Healey, Sue2; Dicks, Ed2; Soucy, Penny2; Sinilnikova, Olga M2; Pankratz, Vernon S2; Wang, Xianshu2; Eldridge, Ronald C2; Tessier, Daniel C2; Vincent, Daniel2; Bacot, Francois2; Hogervorst, Frans B L2; Peock, Susan2; Stoppa-Lyonnet, Dominique2; Peterlongo, Paolo2; Schmutzler, Rita K2; Nathanson, Katherine L2; Piedmonte, Marion2; Singer, Christian F2; Thomassen, Mads4; Hansen, Thomas V O8; Neuhausen, Susan L2; Blanco, Ignacio2; Greene, Mark H2; Garber, Judith2; Weitzel, Jeffrey N2; Andrulis, Irene L2; Goldgar, David E2; D'Andrea, Emma2; Caldes, Trinidad2; Nevanlinna, Heli2; Osorio, Ana2; van Rensburg, Elizabeth J2; Arason, Adalgeir2; Rennert, Gad2; van den Ouweland, Ans M W2; van der Hout, Annemarie H2; Kets, Carolien M2; Aalfs, Cora M2; Wijnen, Juul T2; Ausems, Margreet G E M2; Frost, Debra2; Ellis, Steve2; Fineberg, Elena2; Platte, Radka2; Evans, D Gareth2; Jacobs, Chris2; Adlard, Julian2; Tischkowitz, Marc2; Porteous, Mary E2; Damiola, Francesca2; Golmard, Lisa2; Barjhoux, Laure2; Longy, Michel2; Belotti, Muriel2; Ferrer, Sandra Fert2; Mazoyer, Sylvie2; Spurdle, Amanda B2; Manoukian, Siranoush2; Barile, Monica2; Genuardi, Maurizio2; Arnold, Norbert2; Meindl, Alfons2; Sutter, Christian2; Wappenschmidt, Barbara2; Domchek, Susan M2; Pfeiler, Georg2; Friedman, Eitan2; Jensen, Uffe Birk9; Robson, Mark2; Shah, Sohela2; Lazaro, Conxi2; Mai, Phuong L2; Benitez, Javier2; Southey, Melissa C2; Schmidt, Marjanka K2; Fasching, Peter A2; Peto, Julian2; Humphreys, Manjeet K2; Wang, Qin6; Michailidou, Kyriaki2; Sawyer, Elinor J2; Burwinkel, Barbara2; Guénel, Pascal2; Bojesen, Stig Egil7; Milne, Roger L2; Brenner, Hermann2; Lochmann, Magdalena2; Aittomäki, Kristiina2; Dörk, Thilo2; Margolin, Sara2; Mannermaa, Arto2; Lambrechts, Diether2; Chang-Claude, Jenny2; Radice, Paolo2; Giles, Graham G2; Haiman, Christopher A2; Winqvist, Robert2; Devillee, Peter2; García-Closas, Montserrat2; Schoof, Nils2; Hooning, Maartje J2; Cox, Angela2; Pharoah, Paul D P2; Jakubowska, Anna2; Orr, Nick2; González-Neira, Anna2; Pita, Guillermo2; Alonso, M Rosario2; Hall, Per2; Couch, Fergus J2; Simard, Jacques2; Altshuler, David2; Easton, Douglas F2; Chenevix-Trench, Georgia2; Antoniou, Antonis C2; Offit, Kenneth2
1 Department of Clinical Medicine - Department for Clinical Genetics, Department of Clinical Medicine, Health, Aarhus University2 unknown3 Risø National Laboratory for Sustainable Energy4 Human Genetik5 ST Administrative Centre - AU IT Support ST, Roskilde, ST Administrative Centre, Science and Technology, Aarhus University6 Department of Photonics Engineering7 Afd. for Undervisning8 ST Administrative Centre - AU IT Support ST, Roskilde, ST Administrative Centre, Science and Technology, Aarhus University9 Department of Clinical Medicine - Department for Clinical Genetics, Department of Clinical Medicine, Health, Aarhus University
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.
Plos 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