Global DNA methylation levels in white blood cells as a biomarker for hepatocellular carcinoma risk: a nested casecontrol study

Global DNA hypomethylation is associated with genomic instability and human cancer and blood DNAs collected at the time of cancer diagnosis have been used to examine the relationship between global methylation and cancer risk. To test the hypothesis that global hypomethylation is associated with increased risk of hepatocellular carcinoma (HCC), we conducted a prospective casecontrol study nested within a community-based cohort with 16 years of follow-up. We measured methylation levels in Satellite 2 (Sat2) by MethyLight and LINE-1 by pyrosequencing using baseline white blood cell DNA from 305 HCC cases and 1254 matched controls. We found that Sat2 hypomethylation was associated with HCC risk [odds ratio (OR) per unit decrease in natural log Sat2 methylation = 1.77, 95% confidence interval (CI) = 1.062.95]. The association was significant among individuals diagnosed with HCC before age 62 (OR per unit decrease in natural log Sat2 methylation = 2.47, 95% CI = 1.065.73) but not after (OR = 1.67, 95% CI = 0.843.32). We did not observe an association of LINE-1 with HCC overall risk by age at diagnosis. Among carriers of hepatitis B virus surface antigen (HBsAg), with each 1U decrease in natural log Sat2 methylation level, the OR for HCC increased by 2.19 (95% CI = 1.004.89). LINE-1 hypomethylation was associated with about a 2-fold increased risk of HCC, with ORs (95% CI) of 2.39 (1.065.39), 2.09 (0.914.77) and 2.28 (0.955.51, P-trend = 0.14) for HBsAg carriers in the third, second and lowest quartile of LINE-1 methylation, respectively compared with carriers in the fourth. These results suggest that global hypomethylation may be a useful biomarker of HCC susceptibility.