LINE-1 methylation levels in leukocyte DNA and risk of renal cell cancer |
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Authors: | Liao Linda M Brennan Paul van Bemmel Dana M Zaridze David Matveev Vsevolod Janout Vladimir Kollarova Hellena Bencko Vladimir Navratilova Marie Szeszenia-Dabrowska Neonila Mates Dana Rothman Nathaniel Boffetta Paolo Chow Wong-Ho Moore Lee E |
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Institution: | Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America. liaolm@mail.nih.gov |
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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 rangeIQR]: 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. |
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