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.

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癌症表观基因组学的分子病理学方法及其临床应用

组织病理学标本的仔细显微镜观察、大量高质量组织标本的积累以及与形态特征相关的分子病理学分析被认为可以产生有关多阶段癌变本质的真实数据。由于癌症的形态学标志是通过细胞间粘附和细胞极性维持的正常组织学结构的破坏，因此人们尝试研究人类癌细胞中钙粘蛋白-连环蛋白细胞粘附系统的异常。研究表明，编码 E-钙粘蛋白的CDH1肿瘤抑制基因会被 DNA 甲基化沉默，这表明涉及 DNA 甲基化和杂合性丧失的“双重打击”会导致癌变。因此，在20世纪90年代，我们将重点放在了表观基因组机制上，而在此之前，表观基因组机制尚未受到太多关注。在与肝炎病毒感染相关的慢性肝炎和肝硬化中，DNA甲基化异常经常发生，这是这种异常甚至在癌前组织中也存在的最早迹象之一。人们发现 DNA 甲基转移酶（例如 DNMT1 和 DNMT3B）的异常表达和剪接是各种器官中 DNA 甲基化改变机制的基础。首次鉴定肾细胞癌中CpG岛甲基化表型，并通过多层组学分析确定其治疗靶点。此外，突破性研究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。此后，我们开发了NASH患者致癌风险的诊断标记物和上尿路癌的无创诊断标记物，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。癌症表观基因组研究表明，由于炎症、吸烟和病毒感染等致癌因素，DNA甲基化从癌前阶段就发生改变，并通过癌症相关基因和基因组的异常表达持续促进多阶段癌变。不稳定。癌前阶段的 DNA 甲基化改变由癌症本身遗传或增强，并决定癌症的临床病理侵袭性以及患者的预后。 DNA 甲基化改变可作为生物标志物应用，预计将有助于诊断以及预防和先发性医学。