DNA methylation profile during multistage progression of pulmonary adenocarcinomas
DNA methylation profile during multistage progression of pulmonary adenocarcinomas
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DOI：
10.1007/s00428-011-1079-9
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发表时间：
2011-08-01
期刊：
影响因子：
3.5
通讯作者：
Kang, Gyeong Hoon
中科院分区：
文献类型：
--
作者：
Chung, Jin-Haeng;Lee, Hyun Ju;Kang, Gyeong Hoon
外周型肺腺癌（ADC）的发生与多种遗传学和表观遗传学改变有关。然而，表观遗传异常尚未在以下多阶段进展序列中进行广泛研究：非典型腺瘤性增生（AAH）到原位腺癌（AIS），再到侵袭性ADC。为了确定启动子甲基化在肺ADC发展过程中的潜在作用，我们检测了20例正常、20例AAH、30例AIS和60例ADC肺组织的甲基化状态，并比较了病变之间的甲基化状态。使用MethyLight分析来确定18个CpG岛基因座的甲基化状态，其在ADC中与非癌肺组织相比是高甲基化的。ADC中甲基化CpG岛基因座的平均数显著高于AAH和AIS（ADC与AAH之间p < 0.003，ADC与AIS之间p < 0.005）。HOXA 1、TMEFF 2和RARB的异常甲基化常见于浸润前病变，包括AAH和AIS。此外，PENK、BCL 2、RUNX 3、DLEC 1、MT 1G、GRIN 2B、CDH 13、CCND 2和HOXA 10的甲基化在侵袭性ADC中的发生率显著高于AAH或AIS。我们的研究结果表明，表观遗传学改变参与了肺ADC发展的多步进程，并且异常CpG岛甲基化在多步癌变过程中积累。此外，HOXA 1，TMEFF 2和RARB的异常甲基化发生在浸润前病变中，这表明这些基因的表观遗传学改变参与了肺ADC发展的早期阶段。相反，PENK、BCL 2、RUNX 3、DLEC 1、MT 1G、GRIN 2B、CDH 13、CCND 2和HOXA 10的高甲基化在侵袭性ADC中比在侵袭前病变中更频繁，这表明这些基因的甲基化在AAH-AIS-ADC序列中的肿瘤侵袭期间发生较晚。
Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.