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Early DNA methylation abnormalities in hepatitis and cirrhosis, DNMT dysregulation, CIMP identification in renal cell carcinoma, and multilayer omics–guided targets illustrate translational value. DNA methylation profiles in NASH-related hepatocellular carcinoma further enable risk and noninvasive diagnostic markers, including HPLC-based testing for methylation.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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epigenomicsand its clinical application  \nYae Kanai   \nDepartment of Pathology, Keio University School of Medicine, Tokyo, Japan  \nCorrespondence  \nYae Kanai, MD, PhD, Department of Pathology, Keio University School of Medicine, 35 Shinano‐machi, Shinjuku‐ku, Tokyo 160‐8582, Japan.  \nEmail: [ykanai@keio.jp](ykanai@keio.jp)  \nAbstract  \nCareful 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  \nAbbreviations: AUC, area under the curve; BAC, bacterial artificial chromosome; CIMP, CpG island methylator phenotype; COPD, chronic obstructive pulmonary disease; DNMT, DNA methyltransferase; EEC, endometrioid endometrial cancer; FFPE, formalin‐fixed paraffin‐embedded; GC, gastric cancer; HCC, hepatocellular carcinoma; HIC1 , hypermethylated‐in‐cancer 1; HPLC, high‐performance liquid chromatography; IHEC, International Human Epigenome Consortium; LA, lung adenocarcinoma; LOH, loss of heterozygosity; NASH, nonalcoholic steatohepatitis; NASH‐O, noncancerous liver tissue with nonalcoholic steatohepatitis obtained from patients without hepatocellular carcinoma; NASH‐W, noncancerous liver tissue with nonalcoholic steatohepatitis obtained from patients with hepatocellular carcinoma; pcDMR, precancerous condition‐associated differentially methylated region; RCC, renal cell carcinoma; ROC, receiver operating characteristic; UC, urothelial carcinoma; UTUC, upper urinary tract urothelial carcinoma.  \nThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.  \n© 2024 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.  \nmultis","cbCaiuukVSbyW1gJ","https://ap.wps.com/l/cbCaiuukVSbyW1gJ","pdf",12471704,"English","# Abstract\n# Introduction: From cancer morphogenesis to cancer epigenome research","[{\"question\":\"What evidence is used to support multistage carcinogenesis in the article?\",\"answer\":\"The article emphasizes careful microscopic histopathology, accumulation of high-quality tissue specimens, and analysis of molecular pathology in relation to morphological features.\"},{\"question\":\"How does DNA methylation contribute to cancer development according to the abstract?\",\"answer\":\"It states that CDH1 (E-cadherin) is silenced by DNA methylation and that DNA methylation changes, including in precancerous tissues, contribute continuously to multistage carcinogenesis and aggressiveness.\"},{\"question\":\"Which molecular targets and technologies are highlighted for clinical application?\",\"answer\":\"The abstract highlights targets such as those linked to the CpG island methylator phenotype and describes diagnostic development including a high-performance liquid chromatography (HPLC)-based system for DNA methylation diagnosis.\"}]","Molecular pathological approach to cancer epigenomics and its clinical application | PDF",1789983978]