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

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.

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

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