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

Chiaki Uchida,Satoko Umetsu,Hiroki Mizukami,Kenichi Hakamada,Kazuhisa Takahashi,Takeshi Saito,Kazuhiro Kudo,Soroku Yagihashi,Makoto Abe,Chieko Itabashi,Wataru Inaba

doi:10.1038/s41598-017-18438-z

Chiaki Uchida, Satoko Umetsu + Show 9 more

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https://doi.org/10.1038/s41598-017-18438-z

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Journal: Scientific Reports	Publication Date: Dec 1, 2017
Citations: 10	License type: open-access

Affiliation: Hirosaki University

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.

Highlights

Pancreatic ductal carcinoma (PDC) is a highly aggressive tumor and its prevalence is increasing worldwide[1]
Promoter methylation of cyclin-dependent kinase inhibitor 2A (CDKN2A) and CDH1 was demonstrated in 14–39% and 7% of pancreatic ductal carcinoma (PDC) cases, respectively[20,26], it remains unclear whether concomitant presence of diabetes has any influences on the above epigenetic changes or invasive or metastatic natures of PDC
We first found that PDC commonly underwent methylation of both CDH1 and CDKN2A promoter genes, and positive cases for CDH1 and CDKN2A were more prevalent in long-DM compared to non-DM and short-DM

Summary

Introduction

Pancreatic ductal carcinoma (PDC) is a highly aggressive tumor and its prevalence is increasing worldwide[1]. Promoter methylation of CDKN2A and CDH1 was demonstrated in 14–39% and 7% of PDC cases, respectively[20,26], it remains unclear whether concomitant presence of diabetes has any influences on the above epigenetic changes or invasive or metastatic natures of PDC. We evaluated the methylation status of CDH1 and CDKN2A promoters in PDC tissues and non-neoplastic tissues obtained from patients with or without diabetes and explored to clarify whether diabetes influences tumor behavior and prognosis of the patients. The selection of these genes may be explained by following reasons. There is a high probability of promoter methylation of the above genes in diabetic state[27,28,29], because promoter methylation is shown to occur in various tissues in patients with diabetes[15,16,17,18]

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