Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma.
BACKGROUND
Epigenetic modifications play an important role in multistage carcinogenesis. The role of the three functional DNA methyltransferases (DNMTs) in pancreatic carcinogenesis has not been fully understood. The main goal of this study was to examine DNMT expression in different stages of pancreatic ductal adenocarcinoma (PDAC), and evaluate their prognostic significance in PDAC.


METHODS
A large number of premalignant 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 to evaluate the clinical significance of DNMT expression.


RESULTS
The mRNA expression of the three DNMTs increased with the development of pancreatic cancer from normal duct to pancreatic intraductal neoplasia and further to PDAC, and were statistically correlated with each other. Expression of the three DNMTs was statistically correlated with TNM staging and history of chronic pancreatitis. DNMT3A and DNMT3B, but not DNMT1 expression, was statistically correlated with tumour size. Patients with higher levels of DNMT1, DNMT3A and/or DNMT3B expression had an overall lower survival than those with lower levels of expression. Univariate analysis showed that high expression levels of DNMTs, alcohol consumption, tumour differentiation and TNM staging were statistically significant risk factors. Multivariate analysis showed that high level of DNMT3B expression and tumour differentiation were statistically significant independent poor prognostic factors.


CONCLUSIONS
These results suggested that pancreatic carcinogenesis involves an increased mRNA expression of three DNMTs, and they may become valuable diagnostic and prognostic markers as well as potential therapeutic targets for pancreatic cancer.
Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China.
Jing-Jing
JJ
Zhang
Yi
Y
Zhu
Yan
Y
Zhu
Jun-Li
JL
Wu
Wen-Biao
WB
Liang
Rong
R
Zhu
Ze-Kuan
ZK
Xu
Qing
Q
Du
Yi
Y
Miao
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D016896:Treatment Outcome; D000097584:DNA Methyltransferase 3B
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D012333:RNA, Messenger; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000619380:DNMT1 protein, human