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PMID: 17999359 Published · ppublish English Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·2007-12-00 ·Pages 1186-200

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, Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study GEMO, 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, Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers EMBRACE, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Niederacher D, Deissler H, German Consortium for Hereditary Breast and Ovarian Cancer GCHBOC, Spurdle AB, Chen X, Waddell N, Cloonan N, Kathleen Cuningham Consortium for Research into Familial Breast Cancer kConFab, 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 MP, Greene MH, Prindiville SA, Osorio A, Benitez J, Zikan M, Szabo CI, Kilpivaara O, Nevanlinna H, Hamann U, Durocher F, Arason A, Couch FJ, Easton DF, Chenevix-Trench G, Consortium of Investigators of Modifiers of BRCA1/2 CIMBA

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=.0007, 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.

MeSH Terms
Adolescent Adult Alternative Splicing BRCA1 Protein/genetics BRCA2 Protein/genetics Breast Neoplasms/genetics,prevention & control DNA Primers DNA Repair/genetics Family Female Genetic Variation Heterozygote Homozygote Humans Middle Aged Mutation Polymorphism, Single Nucleotide Rad51 Recombinase/genetics Reverse Transcriptase Polymerase Chain Reaction
Chemicals
BRCA1 Protein BRCA2 Protein DNA Primers RAD51 protein, human Rad51 Recombinase
Authors & Affiliations
84 authors, click to expand affiliations / ORCID
Antoniou Antonis C
Cancer Research UK, Genetic Epidemiology Unit, Strangeways Research Laboratory, Cambridge, CB1 8RN, UK. [email protected]
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
Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO)
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
Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE)
Schmutzler Rita K
Versmold Beatrix
Engel Christoph
Meindl Alfons
Arnold Norbert
Niederacher Dieter
Deissler Helmut
German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC)
Spurdle Amanda B
Chen Xiaoqing
Waddell Nicola
Cloonan Nicole
Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab)
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
Benitez 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
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1086/522611
Email
[email protected]
Published
2007-12-00
Epub
2007-00-16
Pages
1186-200
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2276351
Subset
IM
Grants
NCI NIH HHS · R01-CA102776 · United States
NCI NIH HHS · R01-CA74415 · United States
NCI NIH HHS · N02-CP-11019-50 · United States
NCI NIH HHS · U01 CA086389 · United States
NCI NIH HHS · R01 CA083855 · United States
NCI NIH HHS · P50 CA116201 · United States
NCI NIH HHS · R01-CA083855 · United States
NCI NIH HHS · R01 CA102776 · United States
NCRR NIH HHS · M01 RR000043 · United States
NCRR NIH HHS · MO1 RR00043 · United States
NCI NIH HHS · P50-CA116201 · United States
NCI NIH HHS · CA-95-003 · United States
NCI NIH HHS · R01 CA074415 · United States
Cancer Research UK · 10118 · United Kingdom
NCI NIH HHS · 5UO1 CA86389 · United States
NCI NIH HHS · N02CP11019 · United States
External Links
PubMed source DOI: 10.1086/522611 PMC Full Text View journal details
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