DNA methylation alterations of ADCY5, MICAL2, and PLEKHG2 during the developmental stage of cryptogenic hepatocellular carcinoma

Abstract

AimThe aim of this study was to clarify the significance of DNA methylation alterations of cryptogenic hepatocellular carcinomas (HCCs).MethodsUsing the Infinium assay, we performed genome‐wide DNA methylation analysis of 250 liver tissue samples, including non‐cancerous liver tissue (U‐N) and corresponding cancerous tissue (U‐T) from patients with cryptogenic HCC without a history of excessive alcohol use and hepatitis virus infection, and whose U‐N samples showed no remarkable histological features (no microscopic evidence of simple steatosis, any form of hepatitis including non‐alcoholic steatohepatitis [NASH], or liver cirrhosis).ResultsWe identified 3,272 probes that showed significant differences of DNA methylation levels between U‐N and normal liver tissue samples from patients without HCC, indicating that a distinct DNA methylation profile had already been established at the precancerous U‐N stage. U‐Ns have a DNA methylation profile differing from that of non‐cancerous liver tissue of patients with NASH‐related, viral hepatitis‐related, and alcoholic liver disease‐related HCCs. Such DNA methylation alterations in U‐Ns were inherited by U‐Ts. The U‐Ns showed DNA methylation alteration of ADCY5 resulting in alteration of its mRNA expression, whereas non‐cancerous liver tissue of patients with NASH‐, viral hepatitis‐, or alcoholic liver disease‐related HCCs did not. DNA methylation levels of MICAL2 and PLEKHG2 in U‐Ts were correlated with larger tumor diameter and portal vein involvement, respectively.ConclusionsU‐N‐specific DNA hypermethylation of ADCY5 may have significance even from the precancerous stage in liver showing no remarkable histological features. DNA hypomethylation of MICAL2 and PLEKHG2 may determine the clinicopathological features of cryptogenic HCC.This article is protected by copyright. All rights reserved.

Molecular pathological approach to cancer epigenomics and its clinical application

“…These non-inflammatory and cryptogenic HCCs have a distinct DNA methylation profile, differing from those of patients with NASH-related, viral hepatitis-related, and alcoholic liver disease-related HCCs, that is already established at the precancerous stage. 95 DNA hypermethylation of ADCY5 96 may participate in cryptogenic hepatocarcinogenesis even from the precancerous stage, while DNA hypomethylation of MICAL2 97 and PLEKHG2 98 in cryptogenic HCCs may determine tumor aggressiveness 95 through alterations of their mRNA expression levels.…”