Early Detection Research Network

Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

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.

Andrulis IL, Antoniou AC, Arnold N, Barile M, Barjhoux L, Barnett-Griness O, Beesley J, Benítez J, Blum JL, Bourdon V, Bressac-de Paillerets B, Caldes T, Caligo MA, Capoulade C, Chen X, Chenevix-Trench G, Chompret A, Chu C, Cook M, Couch FJ, Daly MB, Davidson R, Deissler H, Domchek SM, Douglas F, Easton DF, Eccles D, Eeles R, Eisinger F, Engel C, Evans DG, Friedman E, Ganz PA, Gauthier-Villars M, Gerdes AM, Godwin AK, Greene MH, Hamann U, Healey S, Hofmann W, Hogervorst FB, Houdayer C, Isaacs C, Kaufman B, Kämpjärvi K, Laitman Y, Lejbkowicz F, Lenoir GM, Ligtenberg MJ, Llort G, Lynch HT, Manders P, Manoukian S, Mazoyer S, Meindl A, Milgrom R, Milne RL, Nathanson KL, Neuhausen SL, Nevanlinna H, Niederacher D, Olopade OI, Osorio A, Ozcelik H, Peock S, Pereira LH, Peterlongo P, Pichert G, Platte R, Pooley KA, Radice P, Rebbeck TR, Rennert G, Schmutzler RK, Simard J, Sinilnikova OM, Sobol H, Spurdle AB, Stoppa-Lyonnet D, Sutter C, Szabo CI, Tomlinson G, Versmold B, Wagner T, Weitzel J, van den Ouweland AM

18355772

Am. J. Hum. Genet., 2008, 82 (4)