Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma
Association of increased DNA methyltransferase expression with carcinogenesis and poor prognosis in pancreatic ductal adenocarcinoma
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DNA甲基转移酶表达增加与胰腺导管腺癌致癌和不良预后的关系
DOI：
10.1007/s12094-012-0770-x
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Miao, Yi
中科院分区：
文献类型：
--
作者：
Zhang, Jing-Jing;Zhu, Yi;Miao, Yi
表观遗传修饰在多阶段癌变中起重要作用。三种功能性DNA甲基转移酶（dnmt）在胰腺癌发生中的作用尚未完全了解。本研究的主要目的是检测DNMT在胰腺导管腺癌（PDAC）不同阶段的表达，并评估其在PDAC中的预后意义。材料与方法手工显微解剖获得大量胰腺癌前病变和恶性病变。采用实时定量RT-PCR检测DNMTs mRNA表达。采用非参数检验、log-rank检验和Cox回归分析评价DNMT表达的临床意义。结果3种dnmt mRNA的表达随胰腺癌从正常导管到胰腺导管内瘤变、再到PDAC的发展而升高，且具有统计学相关性。三种dnmt的表达与TNM分期和慢性胰腺炎病史有统计学相关性。DNMT3A和DNMT3B的表达与肿瘤大小有统计学相关性，而DNMT1的表达与肿瘤大小无统计学相关性。DNMT1、DNMT3A和/或DNMT3B表达水平较高的患者总体生存率低于表达水平较低的患者。单因素分析显示，dnmt的高表达水平、饮酒、肿瘤分化和TNM分期是具有统计学意义的危险因素。多因素分析显示，高水平的DNMT3B表达和肿瘤分化是具有统计学意义的独立预后不良因素。结论胰腺癌的发生与三种dnmt mRNA表达的增加有关，它们可能成为胰腺癌的诊断和预后指标以及潜在的治疗靶点。
IntroductionEpigenetic 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.Materials and methodsA 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, log-rank test and Cox regression analysis were used to evaluate the clinical significance of DNMT expression.ResultsThe 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.ConclusionsThese 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.