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LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants.

ABSTRACT: Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/778 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, and sex was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs) using study- and sex-specific methylation quartiles. In PLCO, higher, although non-significant, bladder cancer risks were observed for participants in the highest three quartiles (Q2-Q4) compared with the lowest quartile (Q1) (OR = 1.36, 95% CI: 0.96 -1.92). The association was stronger in males (Q2-Q4 vs. Q1 OR = 1.48, 95% CI: 1.00-2.20) and statistically significant among male smokers (Q2-Q4 vs. Q1 OR = 1.83, 95% CI: 1.14-2.95). No association was found among females or female smokers. Findings for male smokers were validated in ATBC (Q2-Q4 vs. Q1: OR = 2.31, 95% CI: 1.62-3.30) and a highly significant trend was observed (P = 8.7 × 10(-7)). After determining that study data could be combined, pooled analysis of PLCO and ATBC male smokers (580 cases/1119 controls), ORs were significantly higher in Q2-Q4 compared with Q1 (OR = 2.03, 95% CI: 1.52-2.72), and a trend across quartiles was observed (P = 0.0001). These findings suggest that higher global methylation levels prior to diagnosis may increase bladder cancer risk, particularly among male smokers.

SUBMITTER: Andreotti G

PROVIDER: S-EPMC4053459 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants.

Andreotti Gabriella G Karami Sara S Pfeiffer Ruth M RM Hurwitz Lauren L Liao Linda M LM Weinstein Stephanie J SJ Albanes Demetrius D Virtamo Jarmo J Silverman Debra T DT Rothman Nathaniel N Moore Lee E LE

Epigenetics 20131206 3

Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/ ...[more]

PMID: 24316677

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Project description:We present here the first high resolution melt (HRM) assay to quantitatively analyze differences in murine DNA methylation levels utilizing CpG methylation of Long Interspersed Elements-1 (LINE1 or L1). By calculating the integral difference in melt temperature between samples and a methylated control, and biasing PCR primers for unmethylated CpGs, the assay demonstrates enhanced sensitivity to detect changes in methylation in a cell line treated with low doses of 5-aza-2'-deoxycytidine (5-aza). The L1 assay was confirmed to be a good marker of changes in DNA methylation of L1 elements at multiple regions across the genome when compared with total 5-methyl-cytosine content, measured by Liquid Chromatography-Mass Spectrometry (LC-MS). The assay design was also used to detect changes in methylation at other murine repeat elements (B1 and Intracisternal-A-particle Long-terminal Repeat elements). Pyrosequencing analysis revealed that L1 methylation changes were non-uniform across the CpGs within the L1-HRM target region, demonstrating that the L1 assay can detect small changes in CpG methylation among a large pool of heterogeneously methylated DNA templates. Application of the assay to various tissues from Balb/c and CBA mice, including previously unreported peripheral blood (PB), revealed a tissue hierarchy (from hypermethylated to hypomethylated) of PB > kidney > liver > prostate > spleen. CBA mice demonstrated overall greater methylation than Balb/c mice, and male mice demonstrated higher tissue methylation compared with female mice in both strains. Changes in DNA methylation have been reported to be an early and fundamental event in the pathogenesis of many human diseases, including cancer. Mouse studies designed to identify modulators of DNA methylation, the critical doses, relevant time points and the tissues affected are limited by the low throughput nature and exorbitant cost of many DNA methylation assays. The L1 assay provides a high throughput, inexpensive and sensitive screening tool for identifying and characterizing DNA methylation changes to L1 elements at multiple regions across the genome.

Dataset Information

LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants.

Publications

LINE1 methylation levels associated with increased bladder cancer risk in pre-diagnostic blood DNA among US (PLCO) and European (ATBC) cohort study participants.

Similar Datasets

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