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 | |
State | Published - Dec 1 2007 |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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In: American Journal of Human Genetics, Vol. 81, No. 6, 01.12.2007, p. 1186-1200.
Research output: Contribution to journal › Article › peer-review
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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 -