Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
Pathol Int. 2024 Apr;74(4):167-186. doi: 10.1111/pin.13418. Epub 2024 Mar 14.
Careful microscopic observation of histopathological specimens, accumulation of large numbers of high-quality tissue specimens, and analysis of molecular pathology in relation to morphological features are considered to yield realistic data on the nature of multistage carcinogenesis. Since the morphological hallmark of cancer is disruption of the normal histological structure maintained through cell-cell adhesiveness and cellular polarity, attempts have been made to investigate abnormalities of the cadherin-catenin cell adhesion system in human cancer cells. It has been shown that the CDH1 tumor suppressor gene encoding E-cadherin is silenced by DNA methylation, suggesting that a "double hit" involving DNA methylation and loss of heterozygosity leads to carcinogenesis. Therefore, in the 1990s, we focused on epigenomic mechanisms, which until then had not received much attention. In chronic hepatitis and liver cirrhosis associated with hepatitis virus infection, DNA methylation abnormalities were found to occur frequently, being one of the earliest indications that such abnormalities are present even in precancerous tissue. Aberrant expression and splicing of DNA methyltransferases, such as DNMT1 and DNMT3B, was found to underlie the mechanism of DNA methylation alterations in various organs. The CpG island methylator phenotype in renal cell carcinoma was identified for the first time, and its therapeutic targets were identified by multilayer omics analysis. Furthermore, the DNA methylation profile of nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma was clarified in groundbreaking studies. Since then, we have developed diagnostic markers for carcinogenesis risk in NASH patients and noninvasive diagnostic markers for upper urinary tract cancer, as well as developing a new high-performance liquid chromatography-based diagnostic system for DNA methylation diagnosis. Research on the cancer epigenome has revealed that DNA methylation alterations occur from the precancerous stage as a result of exposure to carcinogenic factors such as inflammation, smoking, and viral infections, and continuously contribute to multistage carcinogenesis through aberrant expression of cancer-related genes and genomic instability. DNA methylation alterations at the precancerous stages are inherited by or strengthened in cancers themselves and determine the clinicopathological aggressiveness of cancers as well as patient outcome. DNA methylation alterations have applications as biomarkers, and are expected to contribute to diagnosis, as well as preventive and preemptive medicine.
仔细观察组织病理学标本的微观结构，积累大量高质量的组织标本，并结合形态学特征分析分子病理学，被认为可以提供关于多阶段致癌发生的真实数据。由于癌症的形态标志是破坏通过细胞间黏附性和细胞极性维持的正常组织学结构，因此人们试图研究人类癌细胞中钙黏蛋白-连环蛋白细胞黏附系统的异常。已经表明，编码 E-钙黏蛋白的 CDH1 肿瘤抑制基因因 DNA 甲基化而沉默，这表明涉及 DNA 甲基化和杂合性丢失的“双重打击”导致了癌变。因此，在 20 世纪 90 年代，我们专注于表观基因组机制，这些机制在此之前并没有受到太多关注。在与肝炎病毒感染相关的慢性肝炎和肝硬化中，经常发现 DNA 甲基化异常，这是最早表明这些异常甚至存在于癌前组织中的迹象之一。在各种器官中，发现异常表达和剪接的 DNA 甲基转移酶，如 DNMT1 和 DNMT3B，是导致 DNA 甲基化改变的机制。首次在肾细胞癌中鉴定出 CpG 岛甲基化表型，并通过多层组学分析鉴定其治疗靶点。此外，在开创性研究中阐明了非酒精性脂肪性肝炎（NASH）相关肝细胞癌的 DNA 甲基化谱。从那时起，我们为 NASH 患者的致癌风险开发了诊断标志物，为上尿路癌开发了非侵入性诊断标志物，并开发了一种新的基于高效液相色谱的 DNA 甲基化诊断系统。癌症表观基因组学的研究表明，DNA 甲基化改变是由于炎症、吸烟和病毒感染等致癌因素暴露于癌前阶段而发生的，并通过癌相关基因的异常表达和基因组不稳定性持续促进多阶段致癌发生。癌前阶段的 DNA 甲基化改变在癌症自身中被遗传或增强，并决定了癌症的临床病理侵袭性以及患者的预后。DNA 甲基化改变可用作生物标志物，并有望应用于诊断以及预防和抢先医学。
