Abstract
PurposeLeukocyte 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.Experimental DesignLINE-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.ResultsLINE-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.ConclusionsHigher 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.
Highlights
Region-specific hypermethylation and global hypomethylation of DNA are associated with carcinogenesis [1]
LINE-1 methylation levels were significantly higher in renal cell cancer (RCC) cases with a median of 81.97% compared to 81.67% (IQR: 80.35–83.03) among controls (p = 0.003, Wilcoxon)
Higher levels of LINE-1 methylation appear to be positively associated with RCC risk, among current smokers
Summary
Region-specific hypermethylation and global hypomethylation of DNA are associated with carcinogenesis [1]. LINE-1 elements are typically heavily methylated in normal tissues, while LINE-1 hypomethylation has been reported in cancer tissues [9]. Quantification of CpG methylation within LINE-1 elements is an inexpensive high-throughput assay that has been extensively used as a proxy of global cytosine methylation (5MeC) levels [10,11]. Several case-control studies have suggested that LINE-1 methylation levels measured in leukocyte DNA could be a potential biomarker of cancer susceptibility and genomic instability; the relationship between LINE1 and other biomarkers of global methylation status such as Alu [12] is only beginning to be explored in large well-designed studies of cancer risk [13,14,15,16]. Relationships between methylation levels in target tissues and non-invasively collected proxy tissue DNA samples are not well understood
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