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

被引：205

作者：

Antoniou, Antonis C. ^{[1
]}

Sinilnikova, Olga M. ^{[1
]}

Simard, Jacques ^{[1
]}

Leone, Melanie ^{[1
]}

Dumont, Martine ^{[1
]}

Neuhausen, Susan L. ^{[1
]}

Struewing, Jeffery P. ^{[1
]}

Stoppa-Lyonnet, Dominique ^{[1
]}

Barjhoux, Laure ^{[1
]}

Hughes, David J. ^{[1
]}

Coupier, Isabelle ^{[1
]}

Belotti, Muriel ^{[1
]}

Lasset, Christine ^{[1
]}

Rebbeck, Timothy R. ^{[1
]}

Wagner, Theresa ^{[1
]}

Lynch, Henry T. ^{[1
]}

Domchek, Susan M. ^{[1
]}

Nathanson, Katherine L. ^{[1
]}

Garber, Judy E. ^{[1
]}

Weitzel, Jeffrey ^{[1
]}

Narod, Steven A. ^{[1
]}

Tomlinson, Gail ^{[1
]}

Olopade, Olufunmilayo I. ^{[1
]}

Godwin, Andrew ^{[1
]}

Isaacs, Claudine ^{[1
]}

Jakubowska, Anna ^{[1
]}

Lubinski, Jan ^{[1
]}

Gronwald, Jacek ^{[1
]}

Gorski, Bohdan ^{[1
]}

Byrski, Tomasz ^{[1
]}

Huzarski, Tomasz ^{[1
]}

Peock, Susan ^{[1
]}

Cook, Margaret ^{[1
]}

Baynes, Caroline ^{[1
]}

Murray, Alexandra ^{[1
]}

Rogers, Mark ^{[1
]}

Daly, Peter A. ^{[1
]}

Dorkins, Huw ^{[1
]}

Schmutzler, Rita K. ^{[1
]}

Versmold, Beatrix ^{[1
]}

Engel, Christoph ^{[1
]}

Meindl, Alfons ^{[1
]}

Arnold, Norbert ^{[1
]}

Niederacher, Dieter ^{[1
]}

Deissler, Helmut ^{[1
]}

Spurdle, Amanda B. ^{[1
]}

Chen, Xiaoqing ^{[1
]}

Waddell, Nicola ^{[1
]}

Cloonan, Nicole ^{[1
]}

Kirchhoff, Tomas ^{[1
]}

机构：

[1] Strangeways Res Lab, Genet Epidemiol Unit, Cambridge CB1 8RN, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2007年 / 81卷 / 06期

关键词：

D O I：

10.1086/522611

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 {Cl} 1.25-2.94) but not in heterozygotes (HR 0.95 [95% Cl 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% Cl 0.91-1.51) among heterozygotes and 3.18 (95% Cl 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.

引用

页码：1186 / 1200

页数：15

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