RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

Abstract

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5' untranslated region (UTR) of RAD51, 135G-->C, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G-->C SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval {CI} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G-->C variant affects RAD51 splicing within the 5' UTR. Thus, 135G-->C may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

DOI: 10.1086/522611

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@article{Antoniou2007RAD511M, title={RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.}, author={Antonis C Antoniou and Olga M Sinilnikova and Jacques Simard and M{\'e}lanie L{\'e}on{\'e} and Martine Dumont and Susan L Neuhausen and Jeffery P Struewing and Dominique Stoppa-Lyonnet and Laure Barjhoux and David J Hughes and Isabelle Coupier and Muriel Belotti and Christine Lasset and Val{\'e}rie Bonadona and Yves-Jean Bignon and Timothy R Rebbeck and Theresa Wagner and Henry T Lynch and Susan M Domchek and Katherine L Nathanson and Judy E Garber and Jeffrey Weitzel and Steven A Narod and Gail Tomlinson and Olufunmilayo I Olopade and Andrew Godwin and Claudine Isaacs and Anna Jakubowska and Jan Lubinski and Jacek Gronwald and Bohdan G{\'o}rski and Tomasz Byrski and Tomasz Huzarski and Susan Peock and Margaret Cook and Caroline Baynes and Alexandra Murray and Mark Rogers and Peter A Daly and Huw Dorkins and Rita K Schmutzler and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Dieter Niederacher and Helmut Deissler and Amanda B Spurdle and Xiaoqing Chen and Nicola Waddell and Nicole Cloonan and Tomas Kirchhoff and Kenneth Offit and Eitan Friedman and Bella Kaufmann and Yael Laitman and Gilli Galore and Gad Rennert and Flavio Lejbkowicz and Leon Raskin and Irene L Andrulis and Eduard Ilyushik and Hilmi Ozcelik and Peter Devilee and Maaike P G Vreeswijk and Mark H Greene and Sheila A Prindiville and Ana Osorio and Javier Benitez and Michal Zikan and Csilla I Szabo and Outi Kilpivaara and Heli Nevanlinna and Ute Hamann and Francine Durocher and Adalgeir Arason and Fergus J Couch and Douglas F Easton and Georgia Chenevix-Trench}, journal={American journal of human genetics}, year={2007}, volume={81 6}, pages={1186-200} }