Genomic DNA hypomethylation and risk of renal cell carcinoma: A case-control study

Purpose: Genomic DNA hypomethylation is a hallmark of most cancer genomes, promoting genomic instability and cell transformation. In the present study, we sought to determine whether global DNA methylation in peripheral blood is associated with risk of renal cell carcinoma (RCC). Experimental Design: A retrospective case-control study consisting of 889 RCC cases and an equal number of age, gender, and ethnicity-matched controls was applied. GlobalDNAmethylation was measured as 5-mC% content. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between DNA methylation level and the risk of RCC. Results: The median 5-mC% was significantly lower in cases than in healthy controls (P < 0.001). In multivariate logistic regression analysis, individuals in the lowest tertile (T1) of 5-mC% had higher risk of RCC with OR of 1.40 (95% CI, 1.06-1.84), compared with individuals in the highest tertile (T3; P_{for trend} = 0.02). When stratified by RCC risk factors, associations between hypomethylation and increased RCC risk appeared to be stronger among males (OR, 1.61; P_{for trend} = 0.01), younger age (OR, 1.47; P_{for trend}=0.03), never smokers (OR, 1.55; Pfor trend=0.02), family history of other cancer (OR, 1.64; P_{for trend} = 1.22E-03), and late stage (OR, 2.06, P_{for trend} = 4.98E-04). Additionally, we observed significant interaction between gender and 5-mC% in elevating RCC risk (_{Pfor interaction} = 0.03). Conclusions: Our findings suggest an association between global DNA hypomethylation and RCC risk. To establish global DNA hypomethylation as a risk factor for RCC, future prospective studies are warranted. This study may provide further understanding of the etiology of RCC tumorigenesis.