RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: Results from a combined analysis of 19 studies

Antonis C. Antoniou, Olga M. Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L. Neuhausen, Jeffery P. Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J. Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves Jean Bignon, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Susan M. Domchek, Katherine L. NathansonJudy E. Garber, Jeffrey Weitzel, Steven A. Narod, Gail Tomlinson, Olufunmilayo I. Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A. Daly, Huw Dorkins, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B. Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L. Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P.G. Vreeswijk, Mark H. Greene, Sheila A. Prindiville, Ana Osorio, Javier Benítez, Michal Zikan, Csilla I. Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix-Trench, Agnès Chompret, Brigitte Bressac-de-Paillerets, Véronique Byrde, Corinne Capoulade, Gilbert Lenoir, Nancy Uhrhammer, Marion Gauthier-Villars, Antoine De Pauw, Olga Sinilnikova, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, Violaine Bourdon, François Eisinger, Florence Coulet, Chrystelle Colas, Florent Soubrier, Jean Philippe Peyrat, Joëlle Fournier, Philippe Vennin, Claude Adenis, Catherine Nogues, Rosette Lidereau, Danièle Muller, Jean Pierre Fricker, Michel Longy, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel, Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Laurence Olivier-Faivre, Fabienne Prieur, Marc Frénay, Sylvie Mazoyer, Drakoulis Yannoukakos, Cassandra Engel, Neva Haites, Helen Gregory, Patrick Morrison, Trevor Cole, Carole McKeown, Alan Donaldson, Joan Paterson, Jonathon Gray, Peter Daly, David Barton, Mary Porteous, Michael Steel, Carole Brewer, Julia Rankin, Rosemarie Davidson, Victoria Murday, Louise Izatt, Gabriella Pichert, Richard Trembath, Tim Bishop, Carol Chu, Ian Ellis, Gareth Evans, Fiona Lalloo, Andrew Shenton, James Mackay, Anne Robinson, Susan Ritchie, Fiona Douglas, John Burn, Lucy Side, Sarah Durell, Ros Eeles, Jackie Cook, Oliver Quarrell, Shirley Hodgson, Diana Eccles, Anneke Lucassen

Research output: Contribution to journalArticle

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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 = .007, 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.

Original languageEnglish (US)
Pages (from-to)1186-1200
Number of pages15
JournalAmerican journal of human genetics
Volume81
Issue number6
DOIs
StatePublished - 2007

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Antoniou, A. C., Sinilnikova, O. M., Simard, J., Léoné, M., Dumont, M., Neuhausen, S. L., Struewing, J. P., Stoppa-Lyonnet, D., Barjhoux, L., Hughes, D. J., Coupier, I., Belotti, M., Lasset, C., Bonadona, V., Bignon, Y. J., Rebbeck, T. R., Wagner, T., Lynch, H. T., Domchek, S. M., ... Lucassen, A. (2007). RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: Results from a combined analysis of 19 studies. American journal of human genetics, 81(6), 1186-1200. https://doi.org/10.1086/522611