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Since the morphological hallmark of cancer is disruption of the normal histological structure maintained through cell\u2212cell adhesiveness and cellular polarity, attempts have been made to investigate abnormalities of the cadherin\u2010catenin cell adhesion system in human cancer cells. It has been shown that the <jats:italic>CDH1<\/jats:italic> tumor suppressor gene encoding E\u2010cadherin is silenced by DNA methylation, suggesting that a \u201cdouble hit\u201d 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\u00a0was identified for the first time, and its therapeutic targets were identified by multilayer omics analysis. Furthermore, the DNA methylation profile of nonalcoholic steatohepatitis (NASH)\u2010related hepatocellular carcinoma\u00a0was 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\u2010performance liquid chromatography\u2010based 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\u2010related 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.<\/jats:p>","DOI":"10.1111\/pin.13418","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T11:55:31Z","timestamp":1710417331000},"page":"167-186","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Molecular pathological approach to cancer epigenomics and its clinical application"],"prefix":"10.1111","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7904-9506","authenticated-orcid":false,"given":"Yae","family":"Kanai","sequence":"first","affiliation":[{"name":"Department of Pathology Keio University School of Medicine Tokyo 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