Association Between WRN Cys1367Arg (T>C) and Cancer Risk

Abstract

Growing evidence suggests that aberration of the DNA repair pathway significantly contributes to tumorigenesis. Singlenucleotide polymorphisms in DNA repair-related genes such as WRN have been implicated in cancer risk. However, the results of published studies remain inconclusive. Therefore, we performed a meta-analysis of all available and relevant published studies to clarify the role of this polymorphism in cancer. We performed a computerized search of PubMed for publications on WRN Cys1367Arg (T>C) polymorphism and cancer risk and analyzed the genotype data. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, heterogeneity test, cumulative meta-analysis, and bias assessment were performed using STATA software 11.0. No association was found between WRN Cys1367Arg (T>C) polymorphism and cancer risk in all genetic models. When stratified by cancer type, results showed that this polymorphism increased the risk of breast cancer (2CCþCT vs 2TTþCT: perallele OR ¼ 1.14, 95% CI ¼ 1.03-1.26, P trend ¼ .012; CC vs TT: OR ¼ 1.43, 95% CI ¼ 1.04-1.95, P value ¼ .026; CCþCT vs TT: OR ¼ 1.14, 95% CI ¼ 1.02-1.28, P value ¼ .027). In another analysis stratified by ethnicity, WRN Cys1367Arg (T>C) polymorphism was significantly associated with cancer susceptibility in Europeans (2CCþCT vs 2TTþCT: perallele OR ¼ 1.09, 95% CI ¼ 1.00-1.19, P trend ¼ .042; CT vs TT: OR ¼ 1.13, 95% CI ¼ 1.01-1.27, P value ¼ .032; and CCþCT vs TT: OR ¼ 1.13, 95% CI ¼ 1.02-1.26, P value ¼ .025). Our study suggests that WRN Cys1367Arg (T>C) polymorphism is not associated with overall cancer risk, although subgroup analyses suggested an association with breast cancer and overall cancer specifically in European populations.

Werner Syndrome Helicase (WRN) Gene Variants and Cancer in Japanese Elderly: An Autopsy Study

“…In our study p.V114L was not associated with total cancer, but only nominally associated with adenocarcinoma, which is likely a spurious association (data not shown). p.C1367R has also been shown to associate with various cancers [14][15][16][17][18], but we did not find any sign of association with total cancer presence in our cohort.…”

Werner Syndrome Protein Expression in Breast Cancer

“…27 In addition, a meta-analysis evaluated 7 epidemiologic studies and demonstrated that the CC genotype of Cys1367Arg polymorphism was also associated with a 1.43-times increased risk of breast cancer. 25 A case-control study in Chinese women that included approximately 4000 patients also showed that the variant genotype of WRN Leu1074Phe was associated with a 1.36-times higher risk of breast cancer. 26 We have previously shown, at a transcriptomic level, that low WRN mRNA expression was associated with aggressive clinicopathologic features such as high grade, lymph node stage, and human epidermal growth factor receptor 2 (HER2) overexpression and distinct aggressive molecular phenotypes as described by Curtis et al, 28 including PAM50.Her2, PAM50.LumB, Genufu subtype (ER þ /HER2 À /high proliferation), and Genufu subtype (HER2 þ ) breast tumors.…”

“…[22][23][24] Genetic epidemiologic studies identified certain polymorphisms of the WRN gene that are associated with increased risk of breast cancer. [25][26][27] Specifically, the CC genotype of WRN rs1346044 has been associated with a 2-fold risk of developing breast cancer. 27 In addition, a meta-analysis evaluated 7 epidemiologic studies and demonstrated that the CC genotype of Cys1367Arg polymorphism was also associated with a 1.43-times increased risk of breast cancer.…”