Makiuchi Satomi, Tian Ying, Fujimoto Mao, Kuramoto Junko, Tsuda Noboru, Ojima Hidenori, Gotoh Masahiro, Hiraoka Nobuyoshi, Yoshida Teruhiko, Kanai Yae, Arai Eri
Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
Hepatol Res. 2024 Mar;54(3):284-299. doi: 10.1111/hepr.13984. Epub 2023 Nov 21.
The aim of this study was to clarify the significance of DNA methylation alterations of cryptogenic hepatocellular carcinomas (HCCs).
Using the Infinium assay, we performed genome-wide DNA methylation analysis of 250 liver tissue samples, including noncancerous 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 nonalcoholic steatohepatitis, or liver cirrhosis).
We identified 3272 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 noncancerous liver tissue of patients with nonalcoholic steatohepatitis-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 noncancerous liver tissue of patients with nonalcoholic steatohepatitis-, 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.
U-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.
本研究旨在阐明隐源性肝细胞癌（HCC）DNA甲基化改变的意义。
使用Infinium检测法，我们对250份肝组织样本进行了全基因组DNA甲基化分析，这些样本包括来自无过量饮酒史和肝炎病毒感染史的隐源性HCC患者的非癌性肝组织（U-N）和相应的癌组织（U-T），且其U-N样本无明显组织学特征（无单纯性脂肪变性、任何形式的肝炎包括非酒精性脂肪性肝炎或肝硬化的微观证据）。
我们鉴定出3272个探针，这些探针在U-N和无HCC患者的正常肝组织样本之间显示出DNA甲基化水平的显著差异，表明在癌前U-N阶段已经建立了独特的DNA甲基化谱。U-N的DNA甲基化谱与非酒精性脂肪性肝炎相关、病毒性肝炎相关和酒精性肝病相关HCC患者的非癌性肝组织不同。U-N中的这种DNA甲基化改变被U-T继承。U-N显示出ADCY5的DNA甲基化改变，导致其mRNA表达改变，而非酒精性脂肪性肝炎、病毒性肝炎或酒精性肝病相关HCC患者的非癌性肝组织则没有。U-T中MICAL2和PLEKHG2的DNA甲基化水平分别与更大的肿瘤直径和门静脉受累相关。
即使在无明显组织学特征的肝脏癌前阶段，ADCY5的U-N特异性DNA高甲基化也可能具有重要意义。MICAL2和PLEKHG2的DNA低甲基化可能决定隐源性HCC的临床病理特征。
