Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis
Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis
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DOI：
10.1002/ijc.23494
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发表时间：
2008-07-15
影响因子：
6.4
通讯作者：
Cheung, Annie Nga-Yin
中科院分区：
文献类型：
--
作者：
Liao, Xiaoyun;Siu, Michelle Kwan-Yee;Cheung, Annie Nga-Yin
已知表观遗传畸变在人类致癌中是重要的。应用甲基化特异性PCR检测76例子宫内膜癌及其非肿瘤性子宫内膜组织中RAS效应相关基因RASSF 1A、RASSF 2A、hDAB 2 IP（m2 a和m2 b区）和BLU启动子甲基化状态。在73.7%的肿瘤中检测到至少一个基因的甲基化。hDAB 2 IP基因甲基化与RASSF 1A、RASSF 2A基因甲基化之间存在显著相关性（分别为p = 0.042、p = 0.012）。值得注意的是，在I型胶质瘤样癌中发现RASSF 1A超甲基化比II型癌更频繁（p = 0.049）。在子宫内膜样癌中，观察到RASSF 1A高甲基化与晚期之间以及m2 a区域hDAB 2 IP甲基化与子宫深肌层浸润之间的显著关联（p < 0.05）。子宫内膜癌细胞系中RASSF 1A、RASSF 2A和BLU的mRNA表达在用去甲基化剂5-Aza-2 '-deoxycytidine处理后显著增加，支持高甲基化对其转录的抑制作用。对8例正常子宫内膜、16例增生性子宫内膜、40例不典型复合体增生和79例子宫内膜癌的DNMT 1免疫组化研究显示，从正常子宫内膜到子宫内膜增生和子宫内膜样癌，DNMT 1免疫反应性逐渐增加（p = 0.001）。在癌中，观察到DNMT 1在I型类胶质瘤中的表达明显较高（p < 0.001）。DNMT 1免疫反应性与RASSF 1A和RASSF 2A甲基化相关（p < 0.05）。数据表明，RAS相关基因（尤其是RASSF 1A）的超甲基化参与了子宫内膜癌的发生，但在不同组织学类型中可能存在不同的模式。DNMT 1蛋白的过度表达可能导致子宫内膜癌中特异性抑癌基因的异常DNA高甲基化。(C)2008 Wiley-Liss，Inc.
Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of RAS effector related genes, RASSF1A, RASSF2A, hDAB2IP (m2a and m2b regions) and BLU, was evaluated in 76 endometrial carcinomas and their non-neoplastic endometrial tissue by methylation specific PCR. Hypermethylation of at least one of the 5 genes was detected in 73.7% of carcinomas. There were significant correlations between methylation of hDAB2IP and RASSF1A, RASSF2A (p = 0.042, p = 0.012, respectively). Significantly, more frequent RASSF1A hypermethylation was found in Type I endometrioid carcinomas than Type II carcinomas (p = 0.049). Among endometrioid cancers, significant association between RASSF1A hypermethylation and advanced stage, as well as between methylation of hDAB2IP at m2a region with deep myometrial invasion (p < 0.05) was observed. mRNA expression of RASSF1A, RASSF2A and BLU in endometrial cancer cell lines significantly increased after treatment with the demethylating agent 5-Aza-2'-deoxycytidine supporting the repressive effect of hypermethylation on their transcription. Immunohistochemical study of DNMT1 on eight normal endometrium, 16 hyperplastic endometrium without atypia, 40 atypical complex hyperplasia and 79 endometrial carcinomas showed progressive increase in DNMT1 immunoreactivity from normal endometrium to endometrial hyperplasia and endometrioid carcinomas (p = 0.001). Among carcinomas, distinctly higher DNMT1 expression was observed in Type I endometrioid carcinomas (p < 0.001). DNMT1 immunoreactivity correlated with RASSF1A and RASSF2A methylation (p < 0.05). The data suggested that hypermethylation of RAS related genes, particularly RASSF1A, was involved in endometrial carcinogenesis with possible divergent patterns in different histological types. DNMT1 protein overexpression might contribute to such aberrant DNA hypermethylation of specific tumor suppressor genes in endometrial cancers. (C) 2008 Wiley-Liss, Inc.