Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer.
Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer.
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DOI：
10.1158/1055-9965.epi-08-0192
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Hoque MO
中科院分区：
文献类型：
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作者：
Brait M;Begum S;Carvalho AL;Dasgupta S;Vettore AL;Czerniak B;Caballero OL;Westra WH;Sidransky D;Hoque MO
我们研究的目的是阐明在膀胱癌的多阶段发病机制中一个大的基因组甲基化的作用，并将我们的发现与患者的年龄和其他临床病理特征相关联。我们研究了21个基因的甲基化状态，通过定量甲基化特异性PCR在25个肿瘤和5个正常样本的评估集。基于基因评估集中肿瘤和正常人的甲基化频率，我们选择了7个候选基因，并测试了93个肿瘤和26个正常人的独立组。使用交叉表和χ2或Fisher精确检验（视情况而定）评估甲基化的存在或不存在与癌症的关联。所有统计学检验均为双侧检验。大多数原发性肿瘤（93例中的89例，96%）有一个或多个独立集基因的甲基化; 53例（57%）CCNA 1，29例（31%）MINT 1，36例（39%）CRBP，53例（57%）CCND 2，66例（71%）PGP 9.5，60例（65%）CALCA和78例（84%）AIM 1。来自26个对照组的正常泌尿上皮样本显示CCNA 1和MINT 1基因没有甲基化，而CRBP、CCND 2、PGP9.5和CALCA的甲基化水平较低。独立集中的7个基因之间均密切相关，其中3个基因的甲基化频率随年龄增长而增加。PGP9.5和AIM 1甲基化与原发性肿瘤侵袭相关。我们的研究结果表明，膀胱癌中新基因的甲基化谱与预后不良的临床病理特征相关，并且是一种年龄相关现象。
The aims of our study were to elucidate the role of methylation of a large panel of genes during multistage pathogenesis of bladder cancer and to correlate our findings with patient age and other clinicopathologic features. We studied the methylation status of 21 genes by quantitative methylation-specific PCR in an evaluation set of 25 tumor and 5 normal samples. Based on methylation frequency in tumors and normals in gene evaluation set, we selected 7 candidate genes and tested an independent set of 93 tumors and 26 normals. The presence or absence of methylation was evaluated for an association with cancer using cross-tabulations and χ2 or Fisher’s exact tests as appropriate. All statistical tests were two-sided. Most primary tumors (89 of 93, 96%) had methylation of one or more genes of independent set; 53 (57%) CCNA1, 29 (31%) MINT1, 36 (39%) CRBP, 53 (57%) CCND2, 66 (71%) PGP9.5, 60 (65%) CALCA, and 78 (84%) AIM1. Normal uroepithelium samples from 26 controls revealed no methylation of the CCNA1 and MINT1 genes, whereas methylation of CRBP, CCND2, PGP9.5, and CALCA was detected at low levels. All the 7 genes in independent set were tightly correlated with each other and 3 of these genes showed increased methylation frequencies in bladder cancer with increasing age. PGP9.5 and AIM1 methylation correlated with primary tumor invasion. Our results indicate that the methylation profile of novel genes in bladder cancers correlates with clinicopathologic features of poor prognosis and is an age-related phenomenon.