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Title: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.
Authors: Antoniou AC,  Spurdle AB,  Sinilnikova OM,  Healey S,  Pooley KA,  Schmutzler RK,  Versmold B,  Engel C,  Meindl A,  Arnold N,  Hofmann W,  Sutter C,  Niederacher D,  Deissler H,  Caldes T,  Kämpjärvi K,  Nevanlinna H,  Simard J,  Beesley J,  Chen X,  Kathleen Cuningham Consortium for Research into Familial Breast Cancer,  Neuhausen SL,  Rebbeck TR,  Wagner T,  Lynch HT,  Isaacs C,  Weitzel J,  Ganz PA,  Daly MB,  Tomlinson G,  Olopade OI,  Blum JL,  Couch FJ,  Peterlongo P,  Manoukian S,  Barile M,  Radice P,  Szabo CI,  Pereira LH,  Greene MH,  Rennert G,  Lejbkowicz F,  Barnett-Griness O,  Andrulis IL,  Ozcelik H,  OCGN,  Gerdes AM,  Caligo MA,  Laitman Y,  Kaufman B,  Milgrom R,  Friedman E,  Swedish BRCA1 and BRCA2 study collaborators,  Domchek SM,  Nathanson KL,  Osorio A,  Llort G,  Milne RL,  Benítez J,  Hamann U,  Hogervorst FB,  Manders P,  Ligtenberg MJ,  van den Ouweland AM,  DNA-HEBON collaborators,  Peock S,  Cook M,  Platte R,  Evans DG,  Eeles R,  Pichert G,  Chu C,  Eccles D,  Davidson R,  Douglas F,  EMBRACE,  Godwin AK,  Barjhoux L,  Mazoyer S,  Sobol H,  Bourdon V,  Eisinger F,  Chompret A,  Capoulade C,  Bressac-de Paillerets B,  Lenoir GM,  Gauthier-Villars M,  Houdayer C,  Stoppa-Lyonnet D,  GEMO,  Chenevix-Trench G,  Easton DF,  CIMBA
Journal: Am J Hum Genet
Date: 2008 Apr
Branches: CGB
PubMed ID: 18355772
PMC ID: PMC2427217
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.