LINE-1 methylation in leukocyte DNA, interaction with phosphatidylethanolamine N-methyltransferase variants and bladder cancer risk

• Published in: British journal of cancer Vol. 110; no. 8; pp. 2123 - 2130
• Main Authors: Tajuddin, S M, Amaral, A F S, Fernández, A F, Chanock, S, Silverman, D T, Tardón, A, Carrato, A, García-Closas, M, Jackson, B P, Toraño, E G, Márquez, M, Urdinguio, R G, García-Closas, R, Rothman, N, Kogevinas, M, Real, F X, Fraga, M F, Malats, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2014; Nature Publishing Group; Cancer Research UK
• Subjects: 631/208/176/1988; 692/420/2489/68; 692/699/67/589/1336; Aged; Aged, 80 and over; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Bufeta; Cancer Research; CpG Islands - genetics; Càncer; DNA methylation; DNA Methylation - genetics; Drug Resistance; Epidemiology; Epigenetic–gene interaction; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetics & Genomics; genetics-and-genomics; High-Throughput Nucleotide Sequencing; Humans; Leucòcits; Leukocytes - pathology; LINE-1 repetitive sequences; Long Interspersed Nucleotide Elements - genetics; Male; Medical sciences; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oncology; One-carbon metabolism; Phosphatidylethanolamine N-Methyltransferase - genetics; Polymorphism, Single Nucleotide; Risk Factors; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urinary tract. Prostate gland; LINE-1 repetitive sequences; DNA methylation; epigenetic–gene interaction; bladder cancer; one-carbon metabolism; Genetic variability; Gene interaction; Leukocyte; Repeated sequence; Risk; Cancerology; Phosphatidylethanolamine N-methyltransferase; Urinary system disease; epigenetic-gene interaction; Enzyme; Transferases; Genotype; Urinary tract disease; Malignant tumor; Metabolism; Bladder cancer; Carbon; Variant; Methyltransferases; Risk factor; Epigenetics; Bladder disease; Methylation; Cancer
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/bjc.2014.67

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.