Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers by Antoniou Antonis C, Spurdle Amanda B, Sinilnikova Olga M, Healey Sue, Pooley Karen A, Schmutzler Rita K, Versmold Beatrix, Engel Christoph, Meindl Alfons, Arnold Norbert, Hofmann Wera, Sutter Christian, Niederacher Dieter, Deissler Helmut, Caldes Trinidad, Kämpjärvi Kati, Nevanlinna Heli, Simard Jacques, Beesley Jonathan, Chen Xiaoqing, Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Neuhausen Susan L, Rebbeck Timothy R, Wagner Theresa, Lynch Henry T, Isaacs Claudine, Weitzel Jeffrey, Ganz Patricia A, Daly Mary B, Tomlinson Gail, Olopade Olufunmilayo I, Blum Joanne L, Couch Fergus J, Peterlongo Paolo, Manoukian Siranoush, Barile Monica, Radice Paolo, Szabo Csilla I, Pereira Lutecia H Mateus, Greene Mark H, Rennert Gad, Lejbkowicz Flavio, Barnett-Griness Ofra, Andrulis Irene L, Ozcelik Hilmi, OCGN, Gerdes Anne-Marie, Caligo Maria A, Laitman Yael, Kaufman Bella, Milgrom Roni, Friedman Eitan, Swedish BRCA1 and BRCA2 study collaborators, Domchek Susan M, Nathanson Katherine L, Osorio Ana, Llort Gemma, Milne Roger L, Benítez Javier, Hamann Ute, Hogervorst Frans B L, Manders Peggy, Ligtenberg Marjolijn J L, van den Ouweland Ans M W, DNA-HEBON collaborators, Peock Susan, Cook Margaret, Platte Radka, Evans D Gareth, Eeles Rosalind, Pichert Gabriella, Chu Carol, Eccles Diana, Davidson Rosemarie, Douglas Fiona, EMBRACE, Godwin Andrew K, Barjhoux Laure, Mazoyer Sylvie, Sobol Hagay, Bourdon Violaine, Eisinger François, Chompret Agnès, Capoulade Corinne, Bressac-de Paillerets Brigitte, Lenoir Gilbert M, Gauthier-Villars Marion, Houdayer Claude, Stoppa-Lyonnet Dominique, GEMO, Chenevix-Trench Georgia, Easton Douglas F, CIMBA in American journal of human genetics (2008). PubMed

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.

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