RAD51 135G-->C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies by Antoniou Antonis C, Sinilnikova Olga M, Simard Jacques, Léoné Mélanie, Dumont Martine, Neuhausen Susan L, Struewing Jeffery P, Stoppa-Lyonnet Dominique, Barjhoux Laure, Hughes David J, Coupier Isabelle, Belotti Muriel, Lasset Christine, Bonadona Valérie, Bignon Yves-Jean, Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO), Rebbeck Timothy R, Wagner Theresa, Lynch Henry T, Domchek Susan M, Nathanson Katherine L, Garber Judy E, Weitzel Jeffrey, Narod Steven A, Tomlinson Gail, Olopade Olufunmilayo I, Godwin Andrew, Isaacs Claudine, Jakubowska Anna, Lubinski Jan, Gronwald Jacek, Górski Bohdan, Byrski Tomasz, Huzarski Tomasz, Peock Susan, Cook Margaret, Baynes Caroline, Murray Alexandra, Rogers Mark, Daly Peter A, Dorkins Huw, Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE), Schmutzler Rita K, Versmold Beatrix, Engel Christoph, Meindl Alfons, Arnold Norbert, Niederacher Dieter, Deissler Helmut, German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC), Spurdle Amanda B, Chen Xiaoqing, Waddell Nicola, Cloonan Nicole, Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab), Kirchhoff Tomas, Offit Kenneth, Friedman Eitan, Kaufmann Bella, Laitman Yael, Galore Gilli, Rennert Gad, Lejbkowicz Flavio, Raskin Leon, Andrulis Irene L, Ilyushik Eduard, Ozcelik Hilmi, Devilee Peter, Vreeswijk Maaike P G, Greene Mark H, Prindiville Sheila A, Osorio Ana, Benitez Javier, Zikan Michal, Szabo Csilla I, Kilpivaara Outi, Nevanlinna Heli, Hamann Ute, Durocher Francine, Arason Adalgeir, Couch Fergus J, Easton Douglas F, Chenevix-Trench Georgia, Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) in American journal of human genetics (2007).

[PMID: 17999359] PubMed


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.

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