Dataset Information

Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer.

ABSTRACT: BACKGROUND:Evidence suggests that global blood DNA methylation levels may be associated with the risk of various cancers, but no studies have evaluated this relationship for prostate cancer. METHODS:We used pyrosequencing to quantify DNA methylation levels at the long interspersed nuclear element 1 (LINE-1) and Alu repetitive elements in pre-diagnostic blood samples from 694 prostate cancer cases and 703 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We evaluated prostate cancer risk associated with the mean methylation level for each element using logistic regression, adjusting for potential confounders. RESULTS:We did not observe a significant association with prostate cancer for LINE-1 [odds ratio (OR) for the highest compared to the lowest quartile?=?1.01, 95% confidence interval (CI): 0.73-1.39, Ptrend ?=?0.99] or Alu (OR?=?0.94, 95% CI: 0.68-1.29, Ptrend ?=?0.69) methylation levels overall. However, for Alu, we observed that higher DNA methylation levels were associated with a significant increased risk for those diagnosed 4 or more years after blood draw (OR?=?2.26, 95% CI: 1.27-4.00, Ptrend ?=?4.4?×?10(-3) ). In contrast, there was no association for those diagnosed 2 (OR?=?1.13, 95% CI: 0.67-1.90, Ptrend ?=?0.64) or 3 years after draw (OR?=?1.22, 95% CI: 0.71-2.07, Ptrend ?=?0.32), and a decreased risk for those diagnosed less than 2 years after draw (OR?=?0.40, 95% CI: 0.25-0.65, Ptrend ?=?3.8?×?10(-5) ; Pheterogeneity ?=?5.3?×?10(-6) ). CONCLUSIONS:Although LINE-1 DNA methylation levels were not associated with prostate cancer, we observed an association for Alu that varied by time from blood draw to diagnosis. Our study suggests that elevated Alu blood DNA methylation levels several years before diagnosis may be associated with an increased prostate cancer risk.

SUBMITTER: Barry KH

PROVIDER: S-EPMC4535169 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer.

Barry Kathryn Hughes KH Moore Lee E LE Liao Linda M LM Huang Wen-Yi WY Andreotti Gabriella G Poulin Matthew M Berndt Sonja I SI

The Prostate 20150807 15

<h4>Background</h4>Evidence suggests that global blood DNA methylation levels may be associated with the risk of various cancers, but no studies have evaluated this relationship for prostate cancer.<h4>Methods</h4>We used pyrosequencing to quantify DNA methylation levels at the long interspersed nuclear element 1 (LINE-1) and Alu repetitive elements in pre-diagnostic blood samples from 694 prostate cancer cases and 703 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Tr ...[more]

PMID: 26250474

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Project description:BackgroundProstate Cancer (PCa) is the second most common cancer in men where advancements have been made for early detection using imaging techniques, however these are limited by lesion size. Immune surveillance has emerged as an effective approach for early detection and to monitor disease progression. In recent studies, we have shown that host peripheral blood immune cells undergo changes in DNA methylation in liver and breast cancer.MethodsIn the current study, we examined the DNA methylation status of peripheral blood T cells of men with positive biopsy for PCa versus men with negative biopsy having benign prostate tissue, defined as controls. T cells DNA was isolated and subjected to Illumina Infinium methylation EPIC array and validated using Illumina amplicon sequencing and pyrosequencing platforms.ResultsDifferential methylation of 449 CG sites between control and PCa T cell DNA showed a correlation with Gleason score (p < 0.05). Two hundred twenty-three differentially methylated CGs between control and PCa (∆ß +/- 10%, p < 0.05), were enriched in pathways involved in immune surveillance system. Three CGs which were found differentially methylated following DMP (Differentially methylated probes) analysis of ChAMP remained significant after BH (Benjamini-Hochberg) correction, of which, 2 CGs were validated. Predictive ability of combination of these 3 CGs (polygenic methylation score, PMS) to detect PCa had high sensitivity, specificity and overall accuracy. PMS also showed strong positive correlation with Gleason score and tumor volume of PCa patients.ConclusionsResults from the current study provide for the first-time a potential role of DNA methylation changes in peripheral T cells in PCa. This non-invasive methodology may allow for early intervention and stratification of patients into different prognostic groups to reduce PCa associated morbidity from repeat invasive prostate biopsies and design therapeutic strategy to reduce PCa associated mortality.

Project description:BackgroundEnvironmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.MethodsWe assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.ResultsThe average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).ConclusionsOur data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

Dataset Information

Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer.

Publications

Prospective study of DNA methylation at LINE-1 and Alu in peripheral blood and the risk of prostate cancer.

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