Expression of ΔDNMT3B variants and its association with promoter methylation of p16 and RASSF1A in primary non-small cell lung cancer
Expression of ΔDNMT3B variants and its association with promoter methylation of p16 and RASSF1A in primary non-small cell lung cancer
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DOI：
10.1158/0008-5472.can-06-2031
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Mao, Li
中科院分区：
文献类型：
--
作者：
Wang, Jie;Walsh, Garret;Mao, Li
尽管Dnmt3b在从头DNA甲基化中发挥作用，但在肿瘤中Dnmt3b表达和启动子DNA甲基化之间的相关性尚未建立。我们最近报道了Dnmt3b的一个亚家族Delta Dnmt3b，它有7个变异体，是非小细胞肺癌(NSCLC)的主要表达形式。我们假设Delta Dnmt3b变异体的表达在肺肿瘤发生过程中启动子甲基化的形成中起作用。应用逆转录-聚合酶链式反应技术检测119例非小细胞肺癌及相应正常肺组织中7种Delta Dnmt3b变异体的表达。根据肿瘤中p16和RASSF1A启动子甲基化状态以及患者的临床变量(包括预后)分析Delta Dnmt3b变异体的表达模式。DeltaDnmt3b变异体在94例(80%)肿瘤中表达，而在相应的正常肺组织中仅有22例(18%)表达(P<；0.0001)。Delta DNMT3B1、Delta DNMT3B2和Delta DNMT3B4是肿瘤中最常见的转录本(分别为62%、76%和46%)。Delta Dnmt3b变异体的表达与p16和RASSF1A启动子甲基化有关，但Delta DNMT3B4和RASSF1A之间的相关性最强。46例有RASSF1A启动子甲基化的肿瘤中有42例(91%)表达Delta DNMT3B4，而73例无启动子甲基化的肿瘤中只有13例(18%)表达Delta DNMT3B4(P<；0.0001)。变异体在肿瘤中的表达与患者的临床结果之间也有很强的相关性。Delta Dnmt3b变异体在非小细胞肺癌中的表达是常见的，可能在启动子甲基化的发生发展中起重要作用。
Despite the role of DNMT3B in de novo DNA methylation, a correlation between DNMT3B expression and promoter DNA methylation has not being established in tumors. We recently reported Delta DNMT3B, a subfamily of DNMT3B, with seven variants, as the predominant expression forms in non-small cell lung cancer (NSCLC). We hypothesized that expression of the Delta DNMT3B variants plays a role in promoter methylation formation during lung tumorigenesis. Expression of seven Delta DNMT3B variants was measured in 119 NSCLCs and the corresponding normal lungs using reverse transcription-PCR. The expression patterns of Delta DNMT3B variants were analyzed with the status of p16 and RASSF1A promoter methylation in the tumors as well as in patients' clinical variables, including outcomes. Expression of Delta DNMT3B variants was detected in 94 of 119 (80%) tumors but in only 22 (18%) of the corresponding normal lungs (P < 0.0001). Delta DNMT3B1, Delta DNMT3B2, and Delta DNMT3B4 were the most frequently detected transcripts in the tumors (62%, 76%, and 46%, respectively). The expression of Delta DNMT3B variants was associated with p16 and RASSF1A promoter methylation in the tumors, but the strongest association was between Delta DNMT3B4 and RASSF1A. Forty-two of 46 (91%) tumors with RASSF1A promoter methylation expressed Delta DNMT3B4 compared with only 13 of 73 (18%) tumors without the promoter methylation (P < 0.0001). Strong associations were also observed between expression of the variants in the tumors and in patients' clinical outcomes. Expression of Delta DNMT3B variants is common in NSCLC and may play an important role in the development of promoter methylation.