Clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma: prediction of early recurrence based on genome-wide DNA methylation profiling

Endo, Yutaka; Fujimoto, M. Stanley; Ito, Norihisa; Takahashi, Yoshinori; Kitago, Minoru; Gotoh, Masahiro; Hiraoka, Nobuyoshi; Yoshida, Teruhiko; Kitagawa, Yuko; Kanai, Yae; Arai, Eri

doi:10.1007/s00432-021-03541-6

Cited by 18 publications

(14 citation statements)

References 49 publications

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“…Moreover, among the genes included in Table 2 , only three showed a significant correlation between the levels of DNA methylation and expression ( P < 0.05 and r < −0.2 or r > 0.2) (Additional file 1 : Table S5). These findings are consistent with our previous studies, which revealed that even DNA methylation alterations at CpG sites not involved in regulating the expression of functionally important genes can become excellent surrogate markers for DNA methylation diagnostics [ 41 , 42 ]. Particularly at the carcinogenic risk stage, but not in established cancers, it is feasible that DNA methylation alterations would not yet have expanded immediately to involve important tumor-related genes [ 19 – 22 ].…”

Section: Discussionsupporting

confidence: 93%

Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis

et al. 2022

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Background In recent years, non-alcoholic steatohepatitis (NASH) has become the main cause of hepatocellular carcinoma (HCC). As a means of improving the treatment of NASH-related HCCs based on early detection, this study investigated the feasibility of carcinogenic risk estimation in patients with NASH. Results Normal liver tissue (NLT), non-cancerous liver tissue showing histological findings compatible with non-alcoholic fatty liver from patients without HCC (NAFL-O), non-cancerous liver tissue showing NASH from patients without HCC (NASH-O), non-cancerous liver tissue showing non-alcoholic fatty liver from patients with HCC (NAFL-W), non-cancerous liver tissue showing NASH from patients with HCC (NASH-W) and NASH-related HCC were analyzed. An initial cohort of 171 tissue samples and a validation cohort of 55 tissue samples were used. Genome-wide DNA methylation screening using the Infinium HumanMethylation450 BeadChip and DNA methylation quantification using high-performance liquid chromatography (HPLC) with a newly developed anion-exchange column were performed. Based on the Infinium assay, 4050 CpG sites showed alterations of DNA methylation in NASH-W samples relative to NLT samples. Such alterations at the precancerous NASH stage were inherited by or strengthened in HCC samples. Receiver operating characteristic curve analysis identified 415 CpG sites discriminating NASH-W from NLT samples with area under the curve values of more than 0.95. Among them, we focused on 21 CpG sites showing more than 85% specificity, even for discrimination of NASH-W from NASH-O samples. The DNA methylation status of these 21 CpG sites was able to predict the coincidence of HCC independently from histopathological findings such as ballooning and fibrosis stage. The methylation status of 5 candidate marker CpG sites was assessed using a HPLC-based system, and for 3 of them sufficient sensitivity and specificity were successfully validated in the validation cohort. By combining these 3 CpG sites including the ZC3H3 gene, NAFL-W and NASH-W samples from which HCCs had already arisen were confirmed to show carcinogenic risk with 95% sensitivity in the validation cohort. Conclusions After a further prospective validation study using a larger cohort, carcinogenic risk estimation in liver biopsy specimens of patients with NASH may become clinically applicable using this HPLC-based system for quantification of DNA methylation.

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Section: Discussionsupporting

confidence: 93%

Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis

et al. 2022

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“…In a mass spectrometry-based study [ 45 ], galectin 4, a group of carbohydrate-binding proteins involved in neoplastic development and progression, was identified as a down-regulated protein in short-term survivors of pancreatic cancer and correlated with an ER [ 46 ]. Genome-wide DNA methylation screening revealed that three CpG marker sites including a CpG site in CDK14 could predict an ER in formalin-fixed, paraffin-embedded surgically resected tissue [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Perioperative Predictors of Early Recurrence for Resectable and Borderline-Resectable Pancreatic Cancer

Imamura

Nagayama

Kyuno

et al. 2021

Cancers

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We aimed to identify the perioperative predictors of the early recurrence (ER) of resectable and borderline-resectable pancreatic ductal adenocarcinomas (PDACs). After surgery for a PDAC, most patients develop a recurrence. Predictive factors may therefore guide therapeutic decision-making. Patients (n = 234) who underwent a pancreatectomy for a PDAC between 2006 and 2019 were included. The postrecurrence survival (PRS) was estimated using Kaplan–Meier curves. Predictive factors for an ER were assessed using logistic regression analyses; 93 patients (39.7%) were recurrence-free at the last follow-up. Patients with an ER (n = 85, 36.3%), defined as a recurrence within the first 12 months after surgery, had 1- and 2-year PRS rates of 38.7% and 9.5%, respectively, compared with 66.9% and 37.2% for those with a late recurrence (n = 56, 23.9%; both p < 0.001). The most common site of an ER was the liver (55.3%) with a significantly shorter median overall survival time than that with either a local or a lung recurrence (14.5 months; p < 0.001). Preoperative and postoperative risk factors for an ER included a tumor size >3.0 cm (odds ratio (OR): 3.11, 95% confidence interval (CI): 1.35–7.14) and preoperative carbohydrate antigen 19-9 (CA19-9) levels >52 U/mL (OR: 3.25, 95% CI: 1.67–6.30) and a pathological tumor size >3.0 cm (OR: 2.00, 95% CI: 1.03–3.90) and postoperative carbohydrate antigen 19-9 levels >37 U/mL (OR: 2.11, 95% CI: 1.02–4.36), respectively. Preoperatively (>52 U/mL) and postoperatively (>37 U/mL) elevated CA19-9 and a tumor size >3.0 cm were independent predictors for an ER after a pancreatectomy for a PDAC.

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“…Immunohistochemistry for one of the marker molecules, CDK14, 112 was also found to serve as an adjunctive diagnostic tool for DNA methylation-based prediction of early recurrence. 111 Genome-wide DNA methylation analysis of blood samples from patients with LA before and after treatment with a tyrosine kinase inhibitor revealed that changes in DNA methylation profiles occur after treatment relative to the situation before treatment (unpublished data). In particular, using pretreatment blood samples, we were able to identify genes for which DNA methylation levels were significantly correlated with the response to treatment and disease-free survival (unpublished data), suggesting that measurement of DNA methylation levels in blood samples may be useful for prognostication.…”

Section: Dna Methylation Alterations As Biomarkersmentioning

confidence: 99%

“…103 based on their DNA methylation profiles, all patients showing early recurrence within 6 months after surgery were grouped only in a specific cluster. 111 Again, we analyzed both frozen tissue and FFPE specimens and developed a diagnostic panel for prediction of early recurrence that can be applied to FFPE specimens prepared routinely for pathological diagnosis. Immunohistochemistry for one of the marker molecules, CDK14, 112 was also found to serve as an adjunctive diagnostic tool for DNA methylation-based prediction of early recurrence.…”

Section: Dna Methylation Alterations As Biomarkersmentioning

confidence: 99%

Molecular pathological approach to cancer epigenomics and its clinical application

Kanai

2024

Pathology International

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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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Clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma: prediction of early recurrence based on genome-wide DNA methylation profiling

Cited by 18 publications

References 49 publications

Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis

Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis

Perioperative Predictors of Early Recurrence for Resectable and Borderline-Resectable Pancreatic Cancer

Molecular pathological approach to cancer epigenomics and its clinical application

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