全球DNA甲基化：暴露于环境致癌物或病毒因子的口腔癌病例中的常见早期事件。

Global DNA methylation: a common early event in oral cancer cases with exposure to environmental carcinogens or viral agents.

作者信息

Guerrero-Preston R, Báez A, Blanco A, Berdasco M, Fraga M, Esteller M

机构信息

Otolaryngology Department, Head and Neck Cancer Research Division, Johns Hopkins School of Medicine, Cancer Research Building II, 1550 Orleans Street, Room 5N03, Baltimore, MD 21231, USA.

出版信息

P R Health Sci J. 2009 Mar;28(1):24-9.

PMID:19266736

Abstract

INTRODUCTION

Two separate molecular pathways have been proposed for the early carcinogenic events observed in the oral cavity and pharynx: one is associated with chemical etiological factors such as smoking and drinking, and the other one is associated with HPV insertion.

OBJECTIVE

A proof-of-principle study was performed to ascertain if global DNA methylation could be used to distinguish between the early molecular changes in premalignant oral lesions.

METHODS

Personal histories of tobacco and alcohol use were obtained by questionnaire. HPV insertion in tumor tissue was detected by polymerase chain reaction (PCR). Global DNA methylation levels were obtained using HPLC for fraction separation and mass spectrometry for quantification. Predictive simulations were performed to explore potential associations between different etiological factors and the global DNA methylation index. Significance of results was ascertained using Pearson's Chi-squared test.

RESULTS

The global methylation index was found to be 4.28 (95% CI, 4.1, 4.4) in an oral cancer case series. Pearson's chi squared test showed no statistically significant difference between cases that had smoking (p = 0.21), drinking (p = 0.31) or HPV insertion (p = 0.34) as etiologic risk factors, when compared to cases that did not. An inverse significant association between smoking and DNA methylation was observed. As the smoking effect increases, the global methylation index decreases, In addition, no associations between the probability of DNA methylation and drinking, or DNA methylation and HPV insertion were observed in simulations.

CONCLUSIONS

The global DNA methylation index was shown to vary for oral cancer cases with different etiologies. Smoking was inversely correlated with DNA methylation levels when generalized linear model simulations were performed. Future studies should look at global DNA methylation alterations associated to the progression from normal to premalignant oral epithelium tissue in a cohort of smokers and nonsmokers.

摘要

引言

针对口腔和咽部早期致癌事件，已提出两种不同的分子途径：一种与吸烟和饮酒等化学病因因素有关，另一种与HPV插入有关。

目的

进行一项原理验证研究，以确定全基因组DNA甲基化是否可用于区分口腔癌前病变的早期分子变化。

方法

通过问卷调查获取烟草和酒精使用的个人史。采用聚合酶链反应（PCR）检测肿瘤组织中的HPV插入情况。使用高效液相色谱法进行组分分离，质谱法定量获取全基因组DNA甲基化水平。进行预测模拟，以探索不同病因因素与全基因组DNA甲基化指数之间的潜在关联。使用Pearson卡方检验确定结果的显著性。

结果

在一组口腔癌病例中，全基因组甲基化指数为4.28（95%CI，4.1，4.4）。Pearson卡方检验显示，与无吸烟（p = 0.21）、饮酒（p = 0.31）或HPV插入（p = 0.34）作为病因风险因素的病例相比，有这些因素的病例之间无统计学显著差异。观察到吸烟与DNA甲基化之间存在显著的负相关。随着吸烟影响增加，全基因组甲基化指数降低。此外，在模拟中未观察到DNA甲基化概率与饮酒或DNA甲基化与HPV插入之间的关联。