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

H.-C Wu,W.-Y Tsai,C.-J Chen,Q Wang,H.-I Yang,R M Santella

doi:10.1093/carcin/bgs160

Abstract

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 case-control 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) = 1.06-2.95]. 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 = 1.06-5.73) but not after (OR = 1.67, 95% CI = 0.84-3.32). 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 = 1.00-4.89). LINE-1 hypomethylation was associated with about a 2-fold increased risk of HCC, with ORs (95% CI) of 2.39 (1.06-5.39), 2.09 (0.91-4.77) and 2.28 (0.95-5.51, 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.

Highlights

Hepatocellular carcinoma (HCC), the predominant form of human liver cancer, is the sixth most common tumor worldwide and globally the third leading cause of cancer mortality [1]
We demonstrated that decreased Satellite 2 (Sat2) methylation of white blood cell (WBC) DNA was significantly associated with increased hepatocellular carcinoma (HCC) risk later in life
Integration of Hepatitis B virus (HBV) DNA and resulting induction of genomic instability is one of the proposed mechanisms suggested for HBV-related liver carcinogenesis [35]

Summary

Introduction

Hepatocellular carcinoma (HCC), the predominant form of human liver cancer, is the sixth most common tumor worldwide and globally the third leading cause of cancer mortality [1]. DNA methylation is involved in cancer etiology by silencing tumor suppressor genes through hypermethylation or activating oncogenes through demethylation [10,11]. Total 5-methylcytosine content of human HCC tissues was about 20–40% less than that of normal liver [14]. The majority of methylation studies have used DNA obtained from tumor and adjacent tissues to assess differences in methylation levels between HCC tumor and histologically normal tissues [14,15,16]. Limited data suggest that DNA methylation changes in plasma can serve as a marker of circulating liver tumor DNA [17]

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