Abstract

INTRODUCTION: Epigenetic modifications playan important role in multistage carcinogenesis. The role of the threefunctional DNA methyltransferases (DNMTs) in pancreatic carcinogenesis has notbeen fully understood. The main goal of this study was to examine DNMTexpression in different stages of pancreatic ductal adenocarcinoma (PDAC), andevaluate their prognostic significance in PDAC.

MATERIALS AND METHODS: A large number ofpremalignant and malignant pancreatic lesions were obtained by manual microdissection.Quantitative real-time RT-PCR was used to detect DNMTs mRNA expression.Nonparametric test, logrank test and Cox regression analysis were used toevaluate the clinical significance of DNMT expression.

RESULTS: The mRNA expression of the threeDNMTs increased with the development of pancreatic cancer from normal duct topancreatic intraductal neoplasia and further to PDAC, and were statisticallycorrelated with each other. Expression of the three DNMTs was statisticallycorrelated with TNM staging and history of chronic pancreatitis. DNMT3A andDNMT3B, but not DNMT1 expression, was statistically correlated with tumoursize. Patients with higher levels of DNMT1, DNMT3A and/or DNMT3B expression hadan overall lower survival than those with lower levels of expression.Univariate analysis showed that high expression levels of DNMTs, alcoholconsumption, tumour differentiation and TNM staging were statisticallysignificant risk factors. Multivariate analysis showed that high level ofDNMT3B expression and tumour differentiation were statistically significantindependent poor prognostic factors.

CONCLUSIONS: These results suggested thatpancreatic carcinogenesis involves an increased mRNA expression of three DNMTs,and they may become valuable diagnostic and prognostic markers as well aspotential therapeutic targets for pancreatic cancer.