Dataset Information

Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.

ABSTRACT: Prevalence of pancreatic ductal carcinoma (PDC) is nearly twice in patients with diabetes mellitus, but the reason for this close association remains obscure. Recently promoter methylation of E-cadherin1 (CDH1) and CDKN2A genes, encoding E-cadherin and P16 respectively, are invoked in development of PDC. It is still unclear whether diabetes affects such epigenetic changes and malignant behavior in PDC. In this study, we studied whether diabetes influences the clinico-pathological profile and methylation status of CDH1 and CDKN2A genes in patients with PDC. PDC subjects were divided into 3 groups; 59 cases without diabetes (non-DM), 17 cases with short-term diabetes (short-DM)(diabetes duration 3?yrs>) and 33 cases with long-term diabetes (long-DM)(?3 yrs). Compared to non-DM or short-DM, long-DM was associated with a higher histological grade of malignancy and a higher tumor stage. Promoter methylation of both CDH1 and CDKN2A was encountered more frequently in PDC patients with long-DM than non-DM or short DM. Cases with CDH1 promoter methylation showed reduced E-cadherin expression and worsened survival. We consider that the presence of long-DM has a negative impact on the prognosis of PDC patients which may be relevant to a high frequency of promoter methylation of CDH1.

SUBMITTER: Saito T

PROVIDER: S-EPMC5741711 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.

Saito Takeshi T Mizukami Hiroki H Umetsu Satoko S Uchida Chiaki C Inaba Wataru W Abe Makoto M Takahashi Kazuhisa K Kudo Kazuhiro K Itabashi Chieko C Yagihashi Soroku S Hakamada Kenichi K

Scientific reports 20171222 1

Prevalence of pancreatic ductal carcinoma (PDC) is nearly twice in patients with diabetes mellitus, but the reason for this close association remains obscure. Recently promoter methylation of E-cadherin1 (CDH1) and CDKN2A genes, encoding E-cadherin and P16 respectively, are invoked in development of PDC. It is still unclear whether diabetes affects such epigenetic changes and malignant behavior in PDC. In this study, we studied whether diabetes influences the clinico-pathological profile and met ...[more]

PMID: 29273724

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Project description:BackgroundEarly metastasis and infiltration are survival limiting characteristics of pancreatic ductal adenocarcinoma (PDAC). Thus, PDAC is likely to harbor alterations in metastasis suppressor genes that may provide novel diagnostic and therapeutic opportunities. This study investigates a panel of metastasis suppressor genes in correlation to PDAC phenotype and examines promoter methylation for regulatory influence on metastasis suppressor gene expression and for its potential as a diagnostic tool.MethodsMetastatic and invasive potential of 16 PDAC cell lines were quantified in an orthotopic mouse model and mRNA expression of 11 metastasis suppressor genes determined by quantitative RT-PCR. Analysis for promoter methylation was performed using methylation specific PCR and bisulfite sequencing PCR. Protein expression was determined by Western blot.ResultsIn general, higher metastasis suppressor gene mRNA expression was not consistent with less aggressive phenotypes of PDAC. Instead, mRNA overexpression of several metastasis suppressor genes was found in PDAC cell lines vs. normal pancreatic RNA. Of the investigated metastasis suppressor genes, only higher AKAP12 mRNA expression was correlated with decreased metastasis (P < 0.05) and invasion scores (P < 0.01) while higher SERPINB5 mRNA expression was correlated with increased metastasis scores (P < 0.05). Both genes' promoters showed methylation, but only increased SERPINB5 methylation was associated with loss of mRNA and protein expression (P < 0.05). SERPINB5 methylation was also directly correlated to decreased metastasis scores (P < 0.05).ConclusionsAKAP12 mRNA expression was correlated to attenuated invasive and metastatic potential and may be associated with less aggressive phenotypes of PDAC while no such evidence was obtained for the remaining metastasis suppressor genes. Increased SERPINB5 mRNA expression was correlated to increased metastasis and mRNA expression was regulated by methylation. Thus, SERPINB5 methylation was directly correlated to metastasis scores and may provide a diagnostic tool for PDAC.

Project description:Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer that typically manifests itself at an advanced stage and does not respond to most treatment modalities. The survival rate of a PDAC patient is less than 5%, with a median survival of just a couple of months. A better understanding of the molecular pathology of PDAC is needed to guide research for the development of better clinical treatment modalities for PDAC patients. Gene expression studies performed to date have identified different subtypes of PDAC with prognostic and clinical relevance. Subtypes identified to date are highly heterogeneous since pancreatic cancer is heterogeneous cancer. Tumor microenvironment and stroma constitute a major chunk of PDAC and contribute to the heterogeneity. Better subtyping methods are need of the hour for better prognosis and classification of PDAC for future personalized treatment. In this work, we have performed an integrated analysis of DNA methylation and gene expression datasets to provide better mechanistic and molecular insights into Pancreatic cancers, especially PDAC. The use of varied and diverse datasets has provided valuable insights into different cancer types and can play an integral role in revealing the complex nature of underlying biological mechanisms. We performed subtyping of TCGA-PAAD gene expression and methylation datasets into different subtypes using state-of-the-art normalization methods and unsupervised clustering methods that reveal latent hidden factors, leading to additional insights for subtyping. Differential expression and differential methylation were performed for each of the subtypes obtained from clustering. Our analysis gave a consensus of five cluster solution with relevant pathways like MAPK, MET. The five subtypes corresponded to the tumor and stromal subtypes. This analysis helps in distinguishing and identifying different subtypes based on enriched putative genes. These results help propose novel experimentally-verifiable PDAC subtyping and demonstrate that using varied data sets and integrated methods can contribute to disease prognostication and precision medicine in PDAC treatment.

Project description:Pancreatic ductal adenocarcinoma (PDA) is notorious for its poor prognosis. The current mainstay of treatment for PDA is surgical resection followed by adjuvant chemotherapy. However, it is difficult to predict the post-operative outcome because of the lack of reliable markers. The single-nucleotide polymorphism (SNP) of N-acetylgalactosaminyltransferase14 (GALNT14) has been proven to predict the progression-free survival (PFS), overall survival (OS) and response to chemotherapy in various types of gastrointestinal (GI) cancers. However, its role in PDA has not been studied. This study aims to investigate whether the GALNT14 SNP genotype can be a prognostic marker for PDA. A cohort of one hundred and three PDA patients having received surgical resection were retrospectively enrolled. GALNT14 genotypes and the clinicopathological parameters were correlated with postoperative prognosis. The genotype analysis revealed that 19.4%, 60.2% and 20.4% of patients had the GALNT14 "TT", "TG" and "GG" genotypes, respectively. The patients with the "GG" genotype had a mean OS time of 37.1 months (95% confidence interval [CI]: 18.2-56.1) and those with the "non-GG" genotype had a mean OS time of 16.1 months (95% CI: 13.1-19.2). Kaplan-Meier analysis showed that the "GG" genotype had a significantly better OS compared to the "non-GG" genotype (p = 0.005). However, there was no significant difference between the "GG" and "non-GG" genotypes in PFS (p = 0.172). The baseline characteristics between patients with the "GG" and "non-GG" genotypes were compared, and no significant difference was found. Univariate followed by multivariate Cox proportional hazard models demonstrated the GALNT14 "GG" genotype, negative resection margin, and locoregional disease as independent predictors for favorable OS (p = 0.003, p = 0.037, p = 0.021, respectively). Sensitivity analysis was performed in each subgroup to examine the relationship of GALNT14 with different clinicopathological variables and no heterogeneity was found. The GALNT14 "GG" genotype is associated with favorable survival outcome, especially OS, in patients with resected PDA and could serve as a prognostic marker.

Dataset Information

Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.

Publications

Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.

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