DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma.
DNA methylation profiles at precancerous stages associated with recurrence of lung adenocarcinoma.
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DOI：
10.1371/journal.pone.0059444
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kanai Y
中科院分区：
文献类型：
--
作者：
Sato T;Arai E;Kohno T;Tsuta K;Watanabe S;Soejima K;Betsuyaku T;Kanai Y
本研究的目的是阐明DNA甲基化改变在肺腺癌癌前阶段的意义。应用单CpG分辨率Infinium芯片，对36例非原发肺癌患者的正常肺组织、145例肺腺癌患者的非癌肺组织(N)和145例肿瘤组织(T)进行了全基因组DNA甲基化分析。在3,270个CpG位点处观察到从正常肺组织到肺腺癌患者的非癌肺组织，再到肿瘤组织的DNA甲基化改变的循序渐进过程，提示肺腺癌患者的非癌肺组织处于DNA甲基化改变的癌前阶段。在2,083个基因的CpG位点上，肺腺癌患者非癌肺组织中DNA甲基化状态与肺腺癌复发显著相关。在这些复发相关基因中，有28个基因正常情况下没有甲基化(基于Infinium法在正常肺组织样本中的平均β值小于0.2DNA值)，并且它们在癌前阶段的DNA超甲基化在进展为肺腺癌的过程中被加强(ΔβT-N>；0.1)。在这28个基因中，我们重点研究了其中6个基因在转录调控、细胞凋亡或细胞黏附中的作用。ADCY5、EVX1、GFRA1、PDE9A和TBX20基因的DNA超甲基化导致肿瘤组织样本中的mRNA表达减少。5-氮杂-2‘-脱氧胞苷作用于肺癌细胞株后，这5个基因的mRNA表达水平有所恢复。肿瘤组织标本中mRNA表达降低与肿瘤侵袭性显著相关。这些数据表明，癌前阶段的DNA甲基化改变通过沉默特定基因来决定肿瘤的侵袭性和预后。
The aim of this study was to clarify the significance of DNA methylation alterations at precancerous stages of lung adenocarcinoma. Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue obtained from patients without any primary lung tumor, 145 samples of non-cancerous lung tissue (N) obtained from patients with lung adenocarcinomas, and 145 samples of tumorous tissue (T). Stepwise progression of DNA methylation alterations from normal lung tissue to non-cancerous lung tissue obtained from patients with lung adenocarcinomas, and then tumorous tissue samples, was observed at 3,270 CpG sites, suggesting that non-cancerous lung tissue obtained from patients with lung adenocarcinomas was at precancerous stages with DNA methylation alterations. At CpG sites of 2,083 genes, DNA methylation status in samples of non-cancerous lung tissue obtained from patients with lung adenocarcinomas was significantly correlated with recurrence after establishment of lung adenocarcinomas. Among such recurrence-related genes, 28 genes are normally unmethylated (average β-values based on Infinium assay in normal lung tissue samples was less than 0.2) and their DNA hypermethylation at precancerous stages was strengthened during progression to lung adenocarcinomas (ΔβT–N>0.1). Among these 28 genes, we focused on 6 for which implications in transcription regulation, apoptosis or cell adhesion had been reported. DNA hypermethylation of the ADCY5, EVX1, GFRA1, PDE9A, and TBX20 genes resulted in reduced mRNA expression in tumorous tissue samples. 5-Aza-2′-deoxycytidine treatment of lung cancer cell lines restored the mRNA expression levels of these 5 genes. Reduced mRNA expression in tumorous tissue samples was significantly correlated with tumor aggressiveness. These data suggest that DNA methylation alterations at precancerous stages determine tumor aggressiveness and outcome through silencing of specific genes.
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影响因子：
4.8
作者：
BRIATA, P;VANDEWERKEN, B;CORTE, G
通讯作者：
CORTE, G
影响因子：
8
作者：
Bralten, L. B. C.;Gravendeel, A. M.;French, P. J.
通讯作者：
French, P. J.
影响因子：
25
作者：
Ledda, Fernanda;Paratcha, Gustavo;Ibanez, Carlos F.
通讯作者：
Ibanez, Carlos F.
影响因子：
3.9
作者：
Carvalho RH;Haberle V;Hou J;van Gent T;Thongjuea S;van Ijcken W;Kockx C;Brouwer R;Rijkers E;Sieuwerts A;Foekens J;van Vroonhoven M;Aerts J;Grosveld F;Lenhard B;Philipsen S
通讯作者：
Philipsen S
影响因子：
11.5
作者：
de Fraipont, Florence;Levallet, Guenaelle;Zalcman, Gerard
通讯作者：
Zalcman, Gerard