Dataset Information

LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer.

ABSTRACT: Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes was quantified by pyrosequencing measured in triplicate, and averaged across 4 CpG sites. A total of 328 RCC cases and 654 controls frequency-matched(2?1) on age(±5years), sex and study center, from a large case-control study conducted in Central and Eastern Europe were evaluated.LINE-1 methylation levels were significantly higher in RCC cases with a median of 81.97% (interquartile range[IQR]: 80.84-83.47) compared to 81.67% (IQR: 80.35-83.03) among controls (p?=?0.003, Wilcoxon). Compared to the lowest LINE-1 methylation quartile(Q1), the adjusted ORs for increasing methylation quartiles were as follows: OR(Q2)?=?1.84(1.20-2.81), OR(Q3)?=?1.72(1.11-2.65) and OR(Q4)?=?2.06(1.34-3.17), with a p-trend?=?0.004. The association was stronger among current smokers (p-trend<0.001) than former or never smokers (p-interaction?=?0.03). To eliminate the possibility of selection bias among controls, the relationship between LINE-1 methylation and smoking was evaluated and confirmed in a case-only analysis, as well.Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, particularly among current smokers. Further investigations using both post- and pre-diagnostic genomic DNA is warranted to confirm findings and will be necessary to determine whether the observed differences occur prior to, or as a result of carcinogenesis.

SUBMITTER: Liao LM

PROVIDER: S-EPMC3208631 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer.

Liao Linda M LM Brennan Paul P van Bemmel Dana M DM Zaridze David D Matveev Vsevolod V Janout Vladimir V Kollarova Hellena H Bencko Vladimir V Navratilova Marie M Szeszenia-Dabrowska Neonila N Mates Dana D Rothman Nathaniel N Boffetta Paolo P Chow Wong-Ho WH Moore Lee E LE

PloS one 20111104 11

<h4>Purpose</h4>Leukocyte global DNA methylation levels are currently being considered as biomarkers of cancer susceptibility and have been associated with risk of several cancers. In this study, we aimed to examine the association between long interspersed nuclear elements (LINE-1) methylation levels, as a biomarker of global DNA methylation in blood cell DNA, and renal cell cancer risk.<h4>Experimental design</h4>LINE-1 methylation of bisulfite-converted genomic DNA isolated from leukocytes wa ...[more]

PMID: 22076155

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Project description:BackgroundChanges in DNA methylation over the course of life may provide an indicator of risk for cancer. We explored longitudinal changes in CpG methylation from blood leukocytes, and likelihood of future cancer diagnosis.MethodsPeripheral blood samples were obtained at baseline and at follow-up visit from 20 participants in the Health, Aging and Body Composition prospective cohort study. Genome-wide CpG methylation was assayed using the Illumina Infinium Human MethylationEPIC (HM850K) microarray.ResultsGlobal patterns in DNA methylation from CpG-based analyses showed extensive changes in cell composition over time in participants who developed cancer. By visit year 6, the proportion of CD8+ T-cells decreased (p-value = 0.02), while granulocytes cell levels increased (p-value = 0.04) among participants diagnosed with cancer compared to those who remained cancer-free (cancer-free vs. cancer-present: 0.03 ± 0.02 vs. 0.003 ± 0.005 for CD8+ T-cells; 0.52 ± 0.14 vs. 0.66 ± 0.09 for granulocytes). Epigenome-wide analysis identified three CpGs with suggestive p-values ≤10- 5 for differential methylation between cancer-free and cancer-present groups, including a CpG located in MTA3, a gene linked with metastasis. At a lenient statistical threshold (p-value ≤3 × 10- 5), the top 10 cancer-associated CpGs included a site near RPTOR that is involved in the mTOR pathway, and the candidate tumor suppressor genes REC8, KCNQ1, and ZSWIM5. However, only the CpG in RPTOR (cg08129331) was replicated in an independent data set. Analysis of within-individual change from baseline to Year 6 found significant correlations between the rates of change in methylation in RPTOR, REC8 and ZSWIM5, and time to cancer diagnosis.ConclusionThe results show that changes in cellular composition explains much of the cross-sectional and longitudinal variation in CpG methylation. Additionally, differential methylation and longitudinal dynamics at specific CpGs could provide powerful indicators of cancer development and/or progression. In particular, we highlight CpG methylation in the RPTOR gene as a potential biomarker of cancer that awaits further validation.

Dataset Information

LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer.

Publications

LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer.

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