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. Nathanson; Judy 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

doi:10.1086/522611

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 journal › Article › peer-review

201 Scopus citations

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 language	English (US)
Pages (from-to)	1186-1200
Number of pages	15
Journal	American journal of human genetics
Volume	81
Issue number	6
DOIs	https://doi.org/10.1086/522611
State	Published - Dec 1 2007

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1086/522611

Cite this

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

Antoniou, AC, Sinilnikova, OM, Simard, J, Léoné, M, Dumont, M, Neuhausen, SL, Struewing, JP, Stoppa-Lyonnet, D, Barjhoux, L, Hughes, DJ, Coupier, I, Belotti, M, Lasset, C, Bonadona, V, Bignon, YJ, Rebbeck, TR, Wagner, T, Lynch, HT, Domchek, SM, Nathanson, KL, Garber, JE, Weitzel, J, Narod, SA, Tomlinson, G, Olopade, OI, Godwin, A, Isaacs, C, Jakubowska, A, Lubinski, J, Gronwald, J, Górski, B, Byrski, T, Huzarski, T, Peock, S, Cook, M, Baynes, C, Murray, A, Rogers, M, Daly, PA, Dorkins, H, Schmutzler, RK, Versmold, B, Engel, C, Meindl, A, Arnold, N, Niederacher, D, Deissler, H, Spurdle, AB, Chen, X, Waddell, N, Cloonan, N, Kirchhoff, T, Offit, K, Friedman, E, Kaufmann, B, Laitman, Y, Galore, G, Rennert, G, Lejbkowicz, F, Raskin, L, Andrulis, IL, Ilyushik, E, Ozcelik, H, Devilee, P, Vreeswijk, MPG, Greene, MH, Prindiville, SA, Osorio, A, Benítez, J, Zikan, M, Szabo, CI, Kilpivaara, O, Nevanlinna, H, Hamann, U, Durocher, F, Arason, A, Couch, FJ, Easton, DF, Chenevix-Trench, G, Chompret, A, Bressac-de-Paillerets, B, Byrde, V, Capoulade, C, Lenoir, G, Uhrhammer, N, Gauthier-Villars, M, De Pauw, A, Sinilnikova, O, Giraud, S, Hardouin, A, Berthet, P, Sobol, H, Bourdon, V, Eisinger, F, Coulet, F, Colas, C, Soubrier, F, Peyrat, JP, Fournier, J, Vennin, P, Adenis, C, Nogues, C, Lidereau, R, Muller, D, Fricker, JP, Longy, M, Toulas, C, Guimbaud, R, Gladieff, L, Feillel, V, Leroux, D, Dreyfus, H, Rebischung, C, Olivier-Faivre, L, Prieur, F, Frénay, M, Mazoyer, S, Yannoukakos, D, Engel, C, Haites, N, Gregory, H, Morrison, P, Cole, T, McKeown, C, Donaldson, A, Paterson, J, Gray, J, Daly, P, Barton, D, Porteous, M, Steel, M, Brewer, C, Rankin, J, Davidson, R, Murday, V, Izatt, L, Pichert, G, Trembath, R, Bishop, T, Chu, C, Ellis, I, Evans, G, Lalloo, F, Shenton, A, Mackay, J, Robinson, A, Ritchie, S, Douglas, F, Burn, J, Side, L, Durell, S, Eeles, R, Cook, J, Quarrell, O, Hodgson, S, Eccles, D & 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, vol. 81, no. 6, pp. 1186-1200. https://doi.org/10.1086/522611

@article{318757b616654e279b9e3b378b6dfb4e,

title = "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 = .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.",

author = "Antoniou, {Antonis C.} and Sinilnikova, {Olga M.} and Jacques Simard and M{\'e}lanie L{\'e}on{\'e} and Martine Dumont and Neuhausen, {Susan L.} and Struewing, {Jeffery P.} and Dominique Stoppa-Lyonnet and Laure Barjhoux and Hughes, {David J.} and Isabelle Coupier and Muriel Belotti and Christine Lasset and Val{\'e}rie Bonadona and Bignon, {Yves Jean} and Rebbeck, {Timothy R.} and Theresa Wagner and Lynch, {Henry T.} and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Garber, {Judy E.} and Jeffrey Weitzel and Narod, {Steven A.} and Gail Tomlinson and Olopade, {Olufunmilayo I.} 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 Daly, {Peter A.} and Huw Dorkins and Schmutzler, {Rita K.} and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Dieter Niederacher and Helmut Deissler and Spurdle, {Amanda B.} 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 Andrulis, {Irene L.} and Eduard Ilyushik and Hilmi Ozcelik and Peter Devilee and Vreeswijk, {Maaike P.G.} and Greene, {Mark H.} and Prindiville, {Sheila A.} and Ana Osorio and Javier Ben{\'i}tez and Michal Zikan and Szabo, {Csilla I.} and Outi Kilpivaara and Heli Nevanlinna and Ute Hamann and Francine Durocher and Adalgeir Arason and Couch, {Fergus J.} and Easton, {Douglas F.} and Georgia Chenevix-Trench and Agn{\`e}s Chompret and Brigitte Bressac-de-Paillerets and V{\'e}ronique Byrde and Corinne Capoulade and Gilbert Lenoir and Nancy Uhrhammer and Marion Gauthier-Villars and {De Pauw}, Antoine and Olga Sinilnikova and Sophie Giraud and Agn{\`e}s Hardouin and Pascaline Berthet and Hagay Sobol and Violaine Bourdon and Fran{\c c}ois Eisinger and Florence Coulet and Chrystelle Colas and Florent Soubrier and Peyrat, {Jean Philippe} and Jo{\"e}lle Fournier and Philippe Vennin and Claude Adenis and Catherine Nogues and Rosette Lidereau and Dani{\`e}le Muller and Fricker, {Jean Pierre} and Michel Longy and Christine Toulas and Rosine Guimbaud and Laurence Gladieff and Viviane Feillel and Dominique Leroux and H{\'e}l{\`e}ne Dreyfus and Christine Rebischung and Laurence Olivier-Faivre and Fabienne Prieur and Marc Fr{\'e}nay and Sylvie Mazoyer and Drakoulis Yannoukakos and Cassandra Engel and Neva Haites and Helen Gregory and Patrick Morrison and Trevor Cole and Carole McKeown and Alan Donaldson and Joan Paterson and Jonathon Gray and Peter Daly and David Barton and Mary Porteous and Michael Steel and Carole Brewer and Julia Rankin and Rosemarie Davidson and Victoria Murday and Louise Izatt and Gabriella Pichert and Richard Trembath and Tim Bishop and Carol Chu and Ian Ellis and Gareth Evans and Fiona Lalloo and Andrew Shenton and James Mackay and Anne Robinson and Susan Ritchie and Fiona Douglas and John Burn and Lucy Side and Sarah Durell and Ros Eeles and Jackie Cook and Oliver Quarrell and Shirley Hodgson and Diana Eccles and Anneke Lucassen",

note = "Funding Information: A.C.A., C.B., M.C., S.P., the CIMBA data management, and EMBRACE are funded by Cancer Research UK. D.F.E. is a Principal Research Fellow of Cancer Research UK. The GEMO study was supported by the Programme Hospitalier de Recherche Clinique grant AOR01082, by the Programme Incitatif et Coop{\'e}ratif G{\'e}n{\'e}tique et Biologie de Cancer du Sein, Institut Curie, and by the Association “Le cancer du sein, parlons-en!” Award. This publication was supported in part by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also received from National Institutes of Health (NIH) grants 5UO1 CA86389 (to H.T.L.), R01-CA083855 (to S.L.N.), R01-CA74415 (to S.L.N.), R01-CA102776 (to T.R.R.), and R01-CA083855 (to T.R.R.). Sample collection and participation for J.W. was supported in part by a General Clinical Research Center grant from the NIH (MO1 RR00043) awarded to the City of Hope National Medical Center, Duarte, California. The EMBRACE team thanks C. Luccarini for technical assistance with the DNA samples. The GEMO collaborators thank Benjamin Bouchet and Ga{\"e}l Grelier for their assistance with real-time PCR analysis. The GCHBOC is supported by German Cancer Aid grant 107054 and Center for Molecular Medicine Cologne grant TV 93 (to R.K.S.). GCHBOC acknowledges the contributions of Christian Sutter, Institute of Human Genetics, University of Heidelberg; Juergen Horst, Institute of Human Genetics, University of Muenster; Dieter Schaefer, Institute of Human Genetics, University of Frankfurt; Wera Hofmann, Division of Tumorgenetics, Max Delbr{\"u}ck Center for Molecular Medicine, Berlin; Karin Kast, Department of Gynecology and Obstetrics, University of Dresden; and Dorothea Gadzicki, Department of Human Genetics, Medical University, Hannover. kConFab thanks Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by National Health and Medical Research Council [NHMRC] grants 145684 and 288704), for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab genotyping was supported by an NHMRC Programme grant (to G.C.T.). G.C.T. is an NHMRC Senior Principal Research Fellow, and A.B.S. is an NHMRC Career Development Award recipient. This research was supported in part by funding from the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research, and by Clinical Genetic Branch{\textquoteright}s support services contract NO2-CP-11019-50 with Westat. We acknowledge the long-term clinical support of Jennifer Loud, Ruthann Giusti, and Ron Kase and his staff, as well as Lutecia H. Mateus Pereira and Marbin A. Pineda for laboratory assistance. This work was supported by Cancer Care Ontario and Request For Application CA-95-003 as part of the NCI Breast Cancer Family Registries (to I.L.A.). This work was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs program, the CURE Foundation, and the Fonds de la recherche en Sant{\'e} du Quebec/Reseau de Medecine Genetique Appliquee. J.S. holds the Canada Research Chair in Oncogenetics. K.O. is supported by funding from Komen Foundation grant BCTR0601361, and T.K. holds a Frankel Fellowship. This work was partially funded by grants from the Israeli Cancer Association and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv (to E.F.). M.P.G.V. was supported by Dutch Cancer Society grant UL-2001-2471. We thank Hans Vasen, Hanne Meijers-Heijboer, and Christi van Asperen, for their ascertainment and blood sampling of breast cancer families, and Dieneke Biemans, for providing follow-up data. The Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2 (Spanish National Cancer Centre [CNIO]) was supported by the “Mutua Madrile{\~n}a” and “Genoma Espa{\~n}a” foundations. We acknowledge Roger Milne, Rosario Alonso, Guillermo Pita, Jes{\'u}s L{\'o}pez, and Miguel Urioste for their assistance. HEBCS was supported by Academy of Finland grant 110663, the Finnish Cancer Society, the Helsinki University Central Hospital Research Fund, and the Sigrid Juselius Fund. We thank Drs. Kristiina Aittom{\"a}ki, Carl Blomqvist, and Kirsimari Aaltonen, as well as Anitta Tamminen, for their kind help. For Modifier Study of Quantitative Effects on Disease (Mod-Squad), C.I.S. is partially supported by Susan G. Komen Foundation Basic, Clinical, and Translational Research grant BCTR0402923, Research Project of the Ministry of Education, Youth, and Sports of the Czech Republic grant MSM0021620808 (to M.Z., Zdenek Kleibl, and Petr Pohlreich). We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and Lenka Foretova, Machakova Eva, and Lukesova Miroslava (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic) with the support of Ministry of Health grant CR-MZ0 MOU 2005. We thank Diana Torres and Muhammad U. Rashid for providing DNA samples and supplying data. We thank Antje Seidel-Renkert and Michael Gilbert for expert technical assistance. This work was supported in part by grants from the Breast Cancer Research Foundation, U.S. Army Medical Research and Materiel Command grant W81XWH-04-1-0588, and Mayo Clinic Breast Cancer Specialized Programs of Research Excellence grant P50-CA116201 (to F.J.C.). The Mayo Clinic study thanks Noralane Lindor and Linda Wadum for their contributions. ILUH collaborators are Rosa B. Barkardottir, Gudrun Johannesdottir, Bjarni A. Agnarsson, and Oskar T. Johannsson. ILUH was funded by the Science Fund of Landspitali-University Hospital and by the Memorial Fund of Bergthora Magnusdottir and Jakob Bjarnason. ",

year = "2007",

month = dec,

day = "1",

doi = "10.1086/522611",

language = "English (US)",

volume = "81",

pages = "1186--1200",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers

T2 - Results from a combined analysis of 19 studies

AU - Antoniou, Antonis C.

AU - Sinilnikova, Olga M.

AU - Simard, Jacques

AU - Léoné, Mélanie

AU - Dumont, Martine

AU - Neuhausen, Susan L.

AU - Struewing, Jeffery P.

AU - Stoppa-Lyonnet, Dominique

AU - Barjhoux, Laure

AU - Hughes, David J.

AU - Coupier, Isabelle

AU - Belotti, Muriel

AU - Lasset, Christine

AU - Bonadona, Valérie

AU - Bignon, Yves Jean

AU - Rebbeck, Timothy R.

AU - Wagner, Theresa

AU - Lynch, Henry T.

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Garber, Judy E.

AU - Weitzel, Jeffrey

AU - Narod, Steven A.

AU - Tomlinson, Gail

AU - Olopade, Olufunmilayo I.

AU - Godwin, Andrew

AU - Isaacs, Claudine

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Gronwald, Jacek

AU - Górski, Bohdan

AU - Byrski, Tomasz

AU - Huzarski, Tomasz

AU - Peock, Susan

AU - Cook, Margaret

AU - Baynes, Caroline

AU - Murray, Alexandra

AU - Rogers, Mark

AU - Daly, Peter A.

AU - Dorkins, Huw

AU - Schmutzler, Rita K.

AU - Versmold, Beatrix

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Arnold, Norbert

AU - Niederacher, Dieter

AU - Deissler, Helmut

AU - Spurdle, Amanda B.

AU - Chen, Xiaoqing

AU - Waddell, Nicola

AU - Cloonan, Nicole

AU - Kirchhoff, Tomas

AU - Offit, Kenneth

AU - Friedman, Eitan

AU - Kaufmann, Bella

AU - Laitman, Yael

AU - Galore, Gilli

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Raskin, Leon

AU - Andrulis, Irene L.

AU - Ilyushik, Eduard

AU - Ozcelik, Hilmi

AU - Devilee, Peter

AU - Vreeswijk, Maaike P.G.

AU - Greene, Mark H.

AU - Prindiville, Sheila A.

AU - Osorio, Ana

AU - Benítez, Javier

AU - Zikan, Michal

AU - Szabo, Csilla I.

AU - Kilpivaara, Outi

AU - Nevanlinna, Heli

AU - Hamann, Ute

AU - Durocher, Francine

AU - Arason, Adalgeir

AU - Couch, Fergus J.

AU - Easton, Douglas F.

AU - Chenevix-Trench, Georgia

AU - Chompret, Agnès

AU - Bressac-de-Paillerets, Brigitte

AU - Byrde, Véronique

AU - Capoulade, Corinne

AU - Lenoir, Gilbert

AU - Uhrhammer, Nancy

AU - Gauthier-Villars, Marion

AU - De Pauw, Antoine

AU - Sinilnikova, Olga

AU - Giraud, Sophie

AU - Hardouin, Agnès

AU - Berthet, Pascaline

AU - Sobol, Hagay

AU - Bourdon, Violaine

AU - Eisinger, François

AU - Coulet, Florence

AU - Colas, Chrystelle

AU - Soubrier, Florent

AU - Peyrat, Jean Philippe

AU - Fournier, Joëlle

AU - Vennin, Philippe

AU - Adenis, Claude

AU - Nogues, Catherine

AU - Lidereau, Rosette

AU - Muller, Danièle

AU - Fricker, Jean Pierre

AU - Longy, Michel

AU - Toulas, Christine

AU - Guimbaud, Rosine

AU - Gladieff, Laurence

AU - Feillel, Viviane

AU - Leroux, Dominique

AU - Dreyfus, Hélène

AU - Rebischung, Christine

AU - Olivier-Faivre, Laurence

AU - Prieur, Fabienne

AU - Frénay, Marc

AU - Mazoyer, Sylvie

AU - Yannoukakos, Drakoulis

AU - Engel, Cassandra

AU - Haites, Neva

AU - Gregory, Helen

AU - Morrison, Patrick

AU - Cole, Trevor

AU - McKeown, Carole

AU - Donaldson, Alan

AU - Paterson, Joan

AU - Gray, Jonathon

AU - Daly, Peter

AU - Barton, David

AU - Porteous, Mary

AU - Steel, Michael

AU - Brewer, Carole

AU - Rankin, Julia

AU - Davidson, Rosemarie

AU - Murday, Victoria

AU - Izatt, Louise

AU - Pichert, Gabriella

AU - Trembath, Richard

AU - Bishop, Tim

AU - Chu, Carol

AU - Ellis, Ian

AU - Evans, Gareth

AU - Lalloo, Fiona

AU - Shenton, Andrew

AU - Mackay, James

AU - Robinson, Anne

AU - Ritchie, Susan

AU - Douglas, Fiona

AU - Burn, John

AU - Side, Lucy

AU - Durell, Sarah

AU - Eeles, Ros

AU - Cook, Jackie

AU - Quarrell, Oliver

AU - Hodgson, Shirley

AU - Eccles, Diana

AU - Lucassen, Anneke

N1 - Funding Information: A.C.A., C.B., M.C., S.P., the CIMBA data management, and EMBRACE are funded by Cancer Research UK. D.F.E. is a Principal Research Fellow of Cancer Research UK. The GEMO study was supported by the Programme Hospitalier de Recherche Clinique grant AOR01082, by the Programme Incitatif et Coopératif Génétique et Biologie de Cancer du Sein, Institut Curie, and by the Association “Le cancer du sein, parlons-en!” Award. This publication was supported in part by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also received from National Institutes of Health (NIH) grants 5UO1 CA86389 (to H.T.L.), R01-CA083855 (to S.L.N.), R01-CA74415 (to S.L.N.), R01-CA102776 (to T.R.R.), and R01-CA083855 (to T.R.R.). Sample collection and participation for J.W. was supported in part by a General Clinical Research Center grant from the NIH (MO1 RR00043) awarded to the City of Hope National Medical Center, Duarte, California. The EMBRACE team thanks C. Luccarini for technical assistance with the DNA samples. The GEMO collaborators thank Benjamin Bouchet and Gaël Grelier for their assistance with real-time PCR analysis. The GCHBOC is supported by German Cancer Aid grant 107054 and Center for Molecular Medicine Cologne grant TV 93 (to R.K.S.). GCHBOC acknowledges the contributions of Christian Sutter, Institute of Human Genetics, University of Heidelberg; Juergen Horst, Institute of Human Genetics, University of Muenster; Dieter Schaefer, Institute of Human Genetics, University of Frankfurt; Wera Hofmann, Division of Tumorgenetics, Max Delbrück Center for Molecular Medicine, Berlin; Karin Kast, Department of Gynecology and Obstetrics, University of Dresden; and Dorothea Gadzicki, Department of Human Genetics, Medical University, Hannover. kConFab thanks Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by National Health and Medical Research Council [NHMRC] grants 145684 and 288704), for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab genotyping was supported by an NHMRC Programme grant (to G.C.T.). G.C.T. is an NHMRC Senior Principal Research Fellow, and A.B.S. is an NHMRC Career Development Award recipient. This research was supported in part by funding from the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics, and the Center for Cancer Research, and by Clinical Genetic Branch’s support services contract NO2-CP-11019-50 with Westat. We acknowledge the long-term clinical support of Jennifer Loud, Ruthann Giusti, and Ron Kase and his staff, as well as Lutecia H. Mateus Pereira and Marbin A. Pineda for laboratory assistance. This work was supported by Cancer Care Ontario and Request For Application CA-95-003 as part of the NCI Breast Cancer Family Registries (to I.L.A.). This work was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs program, the CURE Foundation, and the Fonds de la recherche en Santé du Quebec/Reseau de Medecine Genetique Appliquee. J.S. holds the Canada Research Chair in Oncogenetics. K.O. is supported by funding from Komen Foundation grant BCTR0601361, and T.K. holds a Frankel Fellowship. This work was partially funded by grants from the Israeli Cancer Association and the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv (to E.F.). M.P.G.V. was supported by Dutch Cancer Society grant UL-2001-2471. We thank Hans Vasen, Hanne Meijers-Heijboer, and Christi van Asperen, for their ascertainment and blood sampling of breast cancer families, and Dieneke Biemans, for providing follow-up data. The Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2 (Spanish National Cancer Centre [CNIO]) was supported by the “Mutua Madrileña” and “Genoma España” foundations. We acknowledge Roger Milne, Rosario Alonso, Guillermo Pita, Jesús López, and Miguel Urioste for their assistance. HEBCS was supported by Academy of Finland grant 110663, the Finnish Cancer Society, the Helsinki University Central Hospital Research Fund, and the Sigrid Juselius Fund. We thank Drs. Kristiina Aittomäki, Carl Blomqvist, and Kirsimari Aaltonen, as well as Anitta Tamminen, for their kind help. For Modifier Study of Quantitative Effects on Disease (Mod-Squad), C.I.S. is partially supported by Susan G. Komen Foundation Basic, Clinical, and Translational Research grant BCTR0402923, Research Project of the Ministry of Education, Youth, and Sports of the Czech Republic grant MSM0021620808 (to M.Z., Zdenek Kleibl, and Petr Pohlreich). We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and Lenka Foretova, Machakova Eva, and Lukesova Miroslava (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic) with the support of Ministry of Health grant CR-MZ0 MOU 2005. We thank Diana Torres and Muhammad U. Rashid for providing DNA samples and supplying data. We thank Antje Seidel-Renkert and Michael Gilbert for expert technical assistance. This work was supported in part by grants from the Breast Cancer Research Foundation, U.S. Army Medical Research and Materiel Command grant W81XWH-04-1-0588, and Mayo Clinic Breast Cancer Specialized Programs of Research Excellence grant P50-CA116201 (to F.J.C.). The Mayo Clinic study thanks Noralane Lindor and Linda Wadum for their contributions. ILUH collaborators are Rosa B. Barkardottir, Gudrun Johannesdottir, Bjarni A. Agnarsson, and Oskar T. Johannsson. ILUH was funded by the Science Fund of Landspitali-University Hospital and by the Memorial Fund of Bergthora Magnusdottir and Jakob Bjarnason.

PY - 2007/12/1

Y1 - 2007/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=36749002743&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36749002743&partnerID=8YFLogxK

U2 - 10.1086/522611

DO - 10.1086/522611

M3 - Article

C2 - 17999359

AN - SCOPUS:36749002743

SN - 0002-9297

VL - 81

SP - 1186

EP - 1200

JO - American journal of human genetics

JF - American journal of human genetics

IS - 6

ER -

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

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