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

191 Citations (Scopus)

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
Pages (from-to)1186-1200
Number of pages15
JournalAmerican Journal of Human Genetics
Volume81
Issue number6
DOIs
StatePublished - 2007

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Breast Neoplasms
Mutation
Confidence Intervals
5' Untranslated Regions
Homozygote
Heterozygote
Single Nucleotide Polymorphism
DNA Repair
Genotype
DNA
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Antoniou, A. C., Sinilnikova, O. M., Simard, J., Léoné, M., Dumont, M., Neuhausen, S. L., ... 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

RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers : Results from a combined analysis of 19 studies. / 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; 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; Schmutzler, Rita K.; Versmold, Beatrix; Engel, Christoph; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Deissler, Helmut; Spurdle, Amanda B.; Chen, Xiaoqing; Waddell, Nicola; Cloonan, Nicole; 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; Benítez, 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; Chompret, Agnès; Bressac-de-Paillerets, Brigitte; Byrde, Véronique; Capoulade, Corinne; Lenoir, Gilbert; Uhrhammer, Nancy; Gauthier-Villars, Marion; De Pauw, Antoine; Sinilnikova, Olga; Giraud, Sophie; Hardouin, Agnès; Berthet, Pascaline; Sobol, Hagay; Bourdon, Violaine; Eisinger, François; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Peyrat, Jean Philippe; Fournier, Joëlle; Vennin, Philippe; Adenis, Claude; Nogues, Catherine; Lidereau, Rosette; Muller, Danièle; Fricker, Jean Pierre; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Leroux, Dominique; Dreyfus, Hélène; Rebischung, Christine; Olivier-Faivre, Laurence; Prieur, Fabienne; Frénay, Marc; Mazoyer, Sylvie; Yannoukakos, Drakoulis; Engel, Cassandra; Haites, Neva; Gregory, Helen; Morrison, Patrick; Cole, Trevor; McKeown, Carole; Donaldson, Alan; Paterson, Joan; Gray, Jonathon; Daly, Peter; Barton, David; Porteous, Mary; Steel, Michael; Brewer, Carole; Rankin, Julia; Davidson, Rosemarie; Murday, Victoria; Izatt, Louise; Pichert, Gabriella; Trembath, Richard; Bishop, Tim; Chu, Carol; Ellis, Ian; Evans, Gareth; Lalloo, Fiona; Shenton, Andrew; Mackay, James; Robinson, Anne; Ritchie, Susan; Douglas, Fiona; Burn, John; Side, Lucy; Durell, Sarah; Eeles, Ros; Cook, Jackie; Quarrell, Oliver; Hodgson, Shirley; Eccles, Diana; Lucassen, Anneke.

In: American Journal of Human Genetics, Vol. 81, No. 6, 2007, p. 1186-1200.

Research output: Contribution to journalArticle

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
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 ; 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 ; Schmutzler, Rita K. ; Versmold, Beatrix ; Engel, Christoph ; Meindl, Alfons ; Arnold, Norbert ; Niederacher, Dieter ; Deissler, Helmut ; Spurdle, Amanda B. ; Chen, Xiaoqing ; Waddell, Nicola ; Cloonan, Nicole ; 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 ; Benítez, 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 ; Chompret, Agnès ; Bressac-de-Paillerets, Brigitte ; Byrde, Véronique ; Capoulade, Corinne ; Lenoir, Gilbert ; Uhrhammer, Nancy ; Gauthier-Villars, Marion ; De Pauw, Antoine ; Sinilnikova, Olga ; Giraud, Sophie ; Hardouin, Agnès ; Berthet, Pascaline ; Sobol, Hagay ; Bourdon, Violaine ; Eisinger, François ; Coulet, Florence ; Colas, Chrystelle ; Soubrier, Florent ; Peyrat, Jean Philippe ; Fournier, Joëlle ; Vennin, Philippe ; Adenis, Claude ; Nogues, Catherine ; Lidereau, Rosette ; Muller, Danièle ; Fricker, Jean Pierre ; Longy, Michel ; Toulas, Christine ; Guimbaud, Rosine ; Gladieff, Laurence ; Feillel, Viviane ; Leroux, Dominique ; Dreyfus, Hélène ; Rebischung, Christine ; Olivier-Faivre, Laurence ; Prieur, Fabienne ; Frénay, Marc ; Mazoyer, Sylvie ; Yannoukakos, Drakoulis ; Engel, Cassandra ; Haites, Neva ; Gregory, Helen ; Morrison, Patrick ; Cole, Trevor ; McKeown, Carole ; Donaldson, Alan ; Paterson, Joan ; Gray, Jonathon ; Daly, Peter ; Barton, David ; Porteous, Mary ; Steel, Michael ; Brewer, Carole ; Rankin, Julia ; Davidson, Rosemarie ; Murday, Victoria ; Izatt, Louise ; Pichert, Gabriella ; Trembath, Richard ; Bishop, Tim ; Chu, Carol ; Ellis, Ian ; Evans, Gareth ; Lalloo, Fiona ; Shenton, Andrew ; Mackay, James ; Robinson, Anne ; Ritchie, Susan ; Douglas, Fiona ; Burn, John ; Side, Lucy ; Durell, Sarah ; Eeles, Ros ; Cook, Jackie ; Quarrell, Oliver ; Hodgson, Shirley ; Eccles, Diana ; Lucassen, Anneke. / RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers : Results from a combined analysis of 19 studies. In: American Journal of Human Genetics. 2007 ; Vol. 81, No. 6. pp. 1186-1200.
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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{\cc}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",
year = "2007",
doi = "10.1086/522611",
language = "English",
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

PY - 2007

Y1 - 2007

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.

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U2 - 10.1086/522611

DO - 10.1086/522611

M3 - Article

C2 - 17999359

AN - SCOPUS:36749002743

VL - 81

SP - 1186

EP - 1200

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -