RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers: Results from a combined analysis of 19 studies Journal Article
| Authors: | 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.; Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers Study (GEMO); Rebbeck, T. R.; Wagner, T.; Lynch, H. T.; Domchek, S. M.; Nathanson, K. L.; Garber, J. E.; Weitzel, J.; Narod, S. A.; Tomlinson, G.; Olopade, O. I.; 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, P. A.; Dorkins, H.; Epidemiological Study of BRCA1 and BRCA2 Mutation Carriers (EMBRACE); Schmutzler, R. K.; Versmold, B.; Engel, C.; Meindl, A.; Arnold, N.; Niederacher, D.; Deissler, H.; German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC); Spurdle, A. B.; Chen, X.; Waddell, N.; Cloonan, N.; The 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, I. L.; Ilyushik, E.; Ozcelik, H.; Devilee, P.; Vreeswijk, M. P. G.; Greene, M. H.; Prindiville, S. A.; Osorio, A.; Benítez, J.; Zikan, M.; Szabo, C. I.; Kilpivaara, O.; Nevanlinna, H.; Hamann, U.; Durocher, F.; Arason, A.; Couch, F. J.; Easton, D. F.; Chenevix-Trench, G.; on behalf of the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) |
| Article 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. © 2007 by The American Society of Human Genetics. All rights reserved. |
| Keywords: | adolescent; adult; middle aged; unclassified drug; gene mutation; human cell; single nucleotide polymorphism; genetics; mutation; polymorphism, single nucleotide; clinical trial; cancer risk; dna repair; reverse transcription polymerase chain reaction; breast cancer; gene expression; amino acid substitution; genetic variability; genotype; mutational analysis; breast neoplasms; brca1 protein; brca2 protein; heterozygote; confidence interval; homozygosity; statistical significance; reverse transcriptase polymerase chain reaction; guanine; 5' untranslated region; heterozygosity; multicenter study; nucleotide sequence; breast tumor; alternative splicing; alternative rna splicing; homozygote; dna primers; primer dna; genetic risk; rad51 protein; family; genetic heterogeneity; rad51 recombinase; cytosine; rad51 protein, human; variation (genetics); hazard assessment |
| Journal Title: | American Journal of Human Genetics |
| Volume: | 81 |
| Issue: | 6 |
| ISSN: | 0002-9297 |
| Publisher: | Cell Press |
| Date Published: | 2007-12-01 |
| Start Page: | 1186 |
| End Page: | 1200 |
| Language: | English |
| DOI: | 10.1086/522611 |
| PUBMED: | 17999359 |
| PROVIDER: | scopus |
| PMCID: | PMC2276351 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):122 - "Export Date: 12 June 2013" - "CODEN: AJHGA" - "Source: Scopus" |
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