Br J Cancer. 2014; 110(8): 2123-2130.

Tajuddin SM, Amaral AF, Fernández AF, Chanock S, Silverman DT, Tardón A, Carrato A, García-Closas M, Jackson BP, Toraño EG, Márquez M, Urdinguio RG, García-Closas R, Rothman N, Kogevinas M, Real FX, Fraga MF, Malats N, Spanish Bladder Cancer/EPICURO Study investigators.

Background: Aberrant global DNA methylation is shown to increase cancer risk. LINE-1 has been proven a measure of global DNA methylation. The objectives of this study were to assess the association between LINE-1 methylation level and bladder cancer risk and to evaluate effect modification by environmental and genetic factors.

Methods: Bisulphite-treated leukocyte DNA from 952 cases and 892 hospital controls was used to measure LINE-1 methylation level at four CpG sites by pyrosequencing. Logistic regression model was fitted to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Interactions between LINE-1 methylation levels and environmental and genetic factors were assessed.

Results: The risk of bladder cancer followed a nonlinear association with LINE-1 methylation. Compared with subjects in the middle tertile, the adjusted OR for subjects in the lower and the higher tertiles were 1.26 (95% CI 0.99–1.60, P=0.06) and 1.33 (95% CI 1.05–1.69, P=0.02), respectively. This association significantly increased among individuals homozygous for the major allele of five single-nucleotide polymorphisms located in the phosphatidylethanolamine N-methyltransferase gene (corrected P-interaction<0.05).

Conclusions: The findings from this large-scale study suggest that both low and high levels of global DNA methylation are associated with the risk of bladder cancer.