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Multicenter Study
. 2008 Apr;82(4):937-48.
doi: 10.1016/j.ajhg.2008.02.008. Epub 2008 Mar 20.

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

Antonis C Antoniou  1 , Amanda B Spurdle, Olga M Sinilnikova, Sue Healey, Karen A Pooley, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Wera Hofmann, Christian Sutter, Dieter Niederacher, Helmut Deissler, Trinidad Caldes, Kati Kämpjärvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing Chen; Kathleen Cuningham Consortium for Research into Familial Breast Cancer; Susan L Neuhausen, Timothy R Rebbeck, Theresa Wagner, Henry T Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A Ganz, Mary B Daly, Gail Tomlinson, Olufunmilayo I Olopade, Joanne L Blum, Fergus J Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I Szabo, Lutecia H Mateus Pereira, Mark H Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L Andrulis, Hilmi Ozcelik; OCGN; Anne-Marie Gerdes, Maria A Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman; Swedish BRCA1 and BRCA2 study collaborators; Susan M Domchek, Katherine L Nathanson, Ana Osorio, Gemma Llort, Roger L Milne, Javier Benítez, Ute Hamann, Frans B L Hogervorst, Peggy Manders, Marjolijn J L Ligtenberg, Ans M W van den Ouweland; DNA-HEBON collaborators; Susan Peock, Margaret Cook, Radka Platte, D Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas; EMBRACE; Andrew K Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet; GEMO; Georgia Chenevix-Trench, Douglas F Easton; CIMBA
Affiliations
Multicenter Study

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

Antonis C Antoniou et al. Am J Hum Genet. 2008 Apr.

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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Figures

Figure 1
Figure 1
Study-Specific Estimates of the Per-Allele Hazard Ratio for SNP rs2981582 in FGFR2 The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
Figure 2
Figure 2
Study-Specific Estimates of the Per-Allele Hazard Ratio for SNP rs3803662 in TNRC9 The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
Figure 3
Figure 3
Study-Specific Estimates of the Per-Allele Hazard Ratio for SNP rs889312 in MAP3K1 The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
Figure 4
Figure 4
Cumulative Risk of Breast Cancer among BRCA2 Mutation Carriers by Combined FGFR2 and TNRC9 Genotype under a Multiplicative Model for the Joint Effects of the Loci The combined FGFR2 and TNRC9 genotypes are as follows: FGFR2 = GG, GA, or AA; TNRC9 = CC, CT, or TT. “Average” represents the cumulative breast cancer risk over all possible modifying effects among BRCA2 mutation carriers born after 1950. The minor allele frequencies for the FGFR2 and TNRC9 SNPs were assumed to be 0.39 and 0.26, respectively.
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