The University of Southampton
University of Southampton Institutional Repository

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

RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: Results from a combined analysis of 19 studies
RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: Results from a combined analysis of 19 studies
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.
0002-9297
1186-1200
Antoniou, Antonis C.
e5c475a7-25bb-4973-b7aa-689c00c7edab
Sinilnikova, Olga M.
5dd23fd3-9301-473e-9458-4fe26f507f14
Simard, Jacques
6269fd00-31ae-40f0-b016-5f60cb9f5b96
Léoné, Mélanie
b7b6f247-73ff-4ffa-8f22-aeaf49576531
Dumont, Martine
ef010ca0-c12f-44f7-9d4f-59a78a978387
Neuhausen, Susan L.
5ec0d6f4-54ff-4cdd-8157-444281357949
Struewing, Jeffery P.
129c3269-39c8-442a-a63f-522c0a928e75
Stoppa-Lyonnet, Dominique
c110a3bd-17a1-4b82-9b32-75728172bfc5
Barjhoux, Laure
e5969462-17f0-4bed-b904-e30f6d246d5d
Hughes, David J.
374615ee-f4de-4e21-b0a5-df8182d3f110
Coupier, Isabelle
97ca1b6d-db10-4fd8-b8bb-e76eb6fd1c37
Belotti, Muriel
80dfd1e9-51bc-4ebb-bba9-849334509afb
Lasset, Christine
b16ee5ce-49c4-4c51-b793-9d2b3a3d314a
Bonadona, Valérie
4c4e4c27-c5eb-4325-b320-daa9301a8d1f
Bignon, Yves Jean
cd1cb161-7fd1-4e32-86da-5e6a20fc611a
Rebbeck, Timothy R.
b01c5fe6-6c04-4e08-8db1-329f9123cbea
Wagner, Theresa
59831efe-12cb-4191-9bea-701ff20572ce
Lynch, Henry T.
4515a3de-428a-476c-ad48-621c7928e874
Domchek, Susan M.
cd5e1b28-de58-4b3d-86db-3bc3e9648282
Nathanson, Katherine L.
11f46b05-ad01-4b07-bfad-4a6e781edbe8
Garber, Judy E.
a66f1ea9-2b7c-4e60-a2d8-8dc5984298f7
Weitzel, Jeffrey
99d8e58b-194c-412e-9b29-d5620c701c9d
Narod, Steven A.
d41a39f2-5994-485c-a320-313dabcffc16
Tomlinson, Gail
abec81c2-80a5-424c-9c69-764157863d48
Olopade, Olufunmilayo I.
1bca3013-9855-4c89-8afe-7ecb9bcb5689
Godwin, Andrew
083552f2-1869-47ec-857f-727121f30d35
Isaacs, Claudine
6e60951b-1f07-471a-8ca3-1941e83bbf83
Jakubowska, Anna
ecdb73a5-85f8-49ba-b03e-dcf4b559d5b1
Lubinski, Jan
e7a9709c-36b3-44ed-a5e0-675177ca3d51
Gronwald, Jacek
4a0117ac-84f8-4351-a97d-637a60db25f6
Górski, Bohdan
7747bd7e-6df7-4e26-9a7e-4c83e93a0795
Byrski, Tomasz
9cb401e1-f220-4cab-b2c6-566bd3877c24
Huzarski, Tomasz
66e38515-375a-430f-9528-41912816378d
Peock, Susan
7e420471-9ee5-4a07-9536-bfdc4c6f1297
Cook, Margaret
b693d851-afb5-4cf6-ad02-4bb9169b5fe3
Baynes, Caroline
f635152b-abbf-40b9-8276-c69bc06465e6
Murray, Alexandra
6db653ae-afc9-4856-a97a-2e40aa405b53
Rogers, Mark
f9e6e17c-7ff9-4d40-8a5b-18fa6a64430d
Daly, Peter A.
ec062c10-9f90-4a83-bbe7-0b3cf1e68c65
Dorkins, Huw
713e497f-c4cd-4d73-a190-9d1d8bcf53b1
Schmutzler, Rita K.
8d66752b-bb4d-4af9-8ac8-6ff6ba235ac8
Versmold, Beatrix
8c485d50-05aa-4d4e-9cca-22f7fd9d3a56
Engel, Christoph
9a19bfa5-28a5-49dd-897b-038a50c33cbd
Meindl, Alfons
10b41dbc-4030-4b19-976f-212367b636af
Arnold, Norbert
2296ee7c-7ba5-48cb-8514-c0a9c4a25eb9
Niederacher, Dieter
b6a4a233-f88d-416b-a22e-9902d732d8e6
Deissler, Helmut
58cbec72-5288-4cdd-9e55-f0ca1331bb53
Evans, Gareth
672b0824-0879-446f-a2df-06b73b52b46c
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Lucassen, Anneke
2eb85efc-c6e8-4c3f-b963-0290f6c038a5
Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO)
Antoniou, Antonis C.
e5c475a7-25bb-4973-b7aa-689c00c7edab
Sinilnikova, Olga M.
5dd23fd3-9301-473e-9458-4fe26f507f14
Simard, Jacques
6269fd00-31ae-40f0-b016-5f60cb9f5b96
Léoné, Mélanie
b7b6f247-73ff-4ffa-8f22-aeaf49576531
Dumont, Martine
ef010ca0-c12f-44f7-9d4f-59a78a978387
Neuhausen, Susan L.
5ec0d6f4-54ff-4cdd-8157-444281357949
Struewing, Jeffery P.
129c3269-39c8-442a-a63f-522c0a928e75
Stoppa-Lyonnet, Dominique
c110a3bd-17a1-4b82-9b32-75728172bfc5
Barjhoux, Laure
e5969462-17f0-4bed-b904-e30f6d246d5d
Hughes, David J.
374615ee-f4de-4e21-b0a5-df8182d3f110
Coupier, Isabelle
97ca1b6d-db10-4fd8-b8bb-e76eb6fd1c37
Belotti, Muriel
80dfd1e9-51bc-4ebb-bba9-849334509afb
Lasset, Christine
b16ee5ce-49c4-4c51-b793-9d2b3a3d314a
Bonadona, Valérie
4c4e4c27-c5eb-4325-b320-daa9301a8d1f
Bignon, Yves Jean
cd1cb161-7fd1-4e32-86da-5e6a20fc611a
Rebbeck, Timothy R.
b01c5fe6-6c04-4e08-8db1-329f9123cbea
Wagner, Theresa
59831efe-12cb-4191-9bea-701ff20572ce
Lynch, Henry T.
4515a3de-428a-476c-ad48-621c7928e874
Domchek, Susan M.
cd5e1b28-de58-4b3d-86db-3bc3e9648282
Nathanson, Katherine L.
11f46b05-ad01-4b07-bfad-4a6e781edbe8
Garber, Judy E.
a66f1ea9-2b7c-4e60-a2d8-8dc5984298f7
Weitzel, Jeffrey
99d8e58b-194c-412e-9b29-d5620c701c9d
Narod, Steven A.
d41a39f2-5994-485c-a320-313dabcffc16
Tomlinson, Gail
abec81c2-80a5-424c-9c69-764157863d48
Olopade, Olufunmilayo I.
1bca3013-9855-4c89-8afe-7ecb9bcb5689
Godwin, Andrew
083552f2-1869-47ec-857f-727121f30d35
Isaacs, Claudine
6e60951b-1f07-471a-8ca3-1941e83bbf83
Jakubowska, Anna
ecdb73a5-85f8-49ba-b03e-dcf4b559d5b1
Lubinski, Jan
e7a9709c-36b3-44ed-a5e0-675177ca3d51
Gronwald, Jacek
4a0117ac-84f8-4351-a97d-637a60db25f6
Górski, Bohdan
7747bd7e-6df7-4e26-9a7e-4c83e93a0795
Byrski, Tomasz
9cb401e1-f220-4cab-b2c6-566bd3877c24
Huzarski, Tomasz
66e38515-375a-430f-9528-41912816378d
Peock, Susan
7e420471-9ee5-4a07-9536-bfdc4c6f1297
Cook, Margaret
b693d851-afb5-4cf6-ad02-4bb9169b5fe3
Baynes, Caroline
f635152b-abbf-40b9-8276-c69bc06465e6
Murray, Alexandra
6db653ae-afc9-4856-a97a-2e40aa405b53
Rogers, Mark
f9e6e17c-7ff9-4d40-8a5b-18fa6a64430d
Daly, Peter A.
ec062c10-9f90-4a83-bbe7-0b3cf1e68c65
Dorkins, Huw
713e497f-c4cd-4d73-a190-9d1d8bcf53b1
Schmutzler, Rita K.
8d66752b-bb4d-4af9-8ac8-6ff6ba235ac8
Versmold, Beatrix
8c485d50-05aa-4d4e-9cca-22f7fd9d3a56
Engel, Christoph
9a19bfa5-28a5-49dd-897b-038a50c33cbd
Meindl, Alfons
10b41dbc-4030-4b19-976f-212367b636af
Arnold, Norbert
2296ee7c-7ba5-48cb-8514-c0a9c4a25eb9
Niederacher, Dieter
b6a4a233-f88d-416b-a22e-9902d732d8e6
Deissler, Helmut
58cbec72-5288-4cdd-9e55-f0ca1331bb53
Evans, Gareth
672b0824-0879-446f-a2df-06b73b52b46c
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Lucassen, Anneke
2eb85efc-c6e8-4c3f-b963-0290f6c038a5

Antoniou, Antonis C., Sinilnikova, Olga M., Simard, Jacques, Léoné, Mélanie, Hughes, David J., Belotti, Muriel, Tomlinson, Gail, Olopade, Olufunmilayo I., Byrski, Tomasz, Evans, Gareth, Eccles, Diana and Lucassen, Anneke , Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO) (2008) 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. (doi:10.1086/522611).

Record type: Article

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.

This record has no associated files available for download.

More information

Accepted/In Press date: 2 August 2007
Published date: 9 January 2008
Additional Information: 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.

Identifiers

Local EPrints ID: 470615
URI: http://eprints.soton.ac.uk/id/eprint/470615
ISSN: 0002-9297
PURE UUID: c5cf7f12-5605-4a2e-8a16-2589e122d9f4
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169
ORCID for Anneke Lucassen: ORCID iD orcid.org/0000-0003-3324-4338

Catalogue record

Date deposited: 14 Oct 2022 16:44
Last modified: 18 Jan 2023 02:38

Export record

Altmetrics

Contributors

Author: Antonis C. Antoniou
Author: Olga M. Sinilnikova
Author: Jacques Simard
Author: Mélanie Léoné
Author: Martine Dumont
Author: Susan L. Neuhausen
Author: Jeffery P. Struewing
Author: Dominique Stoppa-Lyonnet
Author: Laure Barjhoux
Author: David J. Hughes
Author: Isabelle Coupier
Author: Muriel Belotti
Author: Christine Lasset
Author: Valérie Bonadona
Author: Yves Jean Bignon
Author: Timothy R. Rebbeck
Author: Theresa Wagner
Author: Henry T. Lynch
Author: Susan M. Domchek
Author: Katherine L. Nathanson
Author: Judy E. Garber
Author: Jeffrey Weitzel
Author: Steven A. Narod
Author: Gail Tomlinson
Author: Olufunmilayo I. Olopade
Author: Andrew Godwin
Author: Claudine Isaacs
Author: Anna Jakubowska
Author: Jan Lubinski
Author: Jacek Gronwald
Author: Bohdan Górski
Author: Tomasz Byrski
Author: Tomasz Huzarski
Author: Susan Peock
Author: Margaret Cook
Author: Caroline Baynes
Author: Alexandra Murray
Author: Mark Rogers
Author: Peter A. Daly
Author: Huw Dorkins
Author: Rita K. Schmutzler
Author: Beatrix Versmold
Author: Christoph Engel
Author: Alfons Meindl
Author: Norbert Arnold
Author: Dieter Niederacher
Author: Helmut Deissler
Author: Gareth Evans
Author: Diana Eccles ORCID iD
Author: Anneke Lucassen ORCID iD
Corporate Author: Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO)

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×