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.

DOI: 10.1016/j.ajhg.2008.02.008

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@article{Antoniou2008CommonBC, title={Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.}, author={Antonis C Antoniou and Amanda B Spurdle and Olga M Sinilnikova and Sue Healey and Karen A Pooley and Rita K Schmutzler and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Wera Hofmann and Christian Sutter and Dieter Niederacher and Helmut Deissler and Trinidad Caldes and Kati K{\"a}mpj{\"a}rvi and Heli Nevanlinna and Jacques Simard and Jonathan Beesley and Xiaoqing Chen and Susan L Neuhausen and Timothy R Rebbeck and Theresa Wagner and Henry T Lynch and Claudine Isaacs and Jeffrey Weitzel and Patricia A Ganz and Mary B Daly and Gail Tomlinson and Olufunmilayo I Olopade and Joanne L Blum and Fergus J Couch and Paolo Peterlongo and Siranoush Manoukian and Monica Barile and Paolo Radice and Csilla I Szabo and Lutecia H Mateus Pereira and Mark H Greene and Gad Rennert and Flavio Lejbkowicz and Ofra Barnett-Griness and Irene L Andrulis and Hilmi Ozcelik and Anne-Marie Gerdes and Maria A Caligo and Yael Laitman and Bella Kaufman and Roni Milgrom and Eitan Friedman and Susan M Domchek and Katherine L Nathanson and Ana Osorio and Gemma Llort and Roger L Milne and Javier Ben{\'i}tez and Ute Hamann and Frans B L Hogervorst and Peggy Manders and Marjolijn J L Ligtenberg and Ans M W van den Ouweland and Susan Peock and Margaret Cook and Radka Platte and D Gareth Evans and Rosalind Eeles and Gabriella Pichert and Carol Chu and Diana Eccles and Rosemarie Davidson and Fiona Douglas and Andrew K Godwin and Laure Barjhoux and Sylvie Mazoyer and Hagay Sobol and Violaine Bourdon and François Eisinger and Agn{\`e}s Chompret and Corinne Capoulade and Brigitte Bressac-de Paillerets and Gilbert M Lenoir and Marion Gauthier-Villars and Claude Houdayer and Dominique Stoppa-Lyonnet and Georgia Chenevix-Trench and Douglas F Easton}, journal={American journal of human genetics}, year={2008}, volume={82 4}, pages={937-48} }