Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors.
Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors.
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DOI：
10.1158/0008-5472.can-08-2489
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Herceg, Zdenko
中科院分区：
文献类型：
--
作者：
Vaissiere, Thomas;Hung, Rayjean J.;Zaridze, David;Moukeria, Anush;Cuenin, Cyrille;Fasolo, Virgrinie;Ferro, Gilles;Paliwal, Anuparn;Hainaut, Pierre;Brennan, Paul;Tost, Joerg;Boffetta, Paolo;Herceg, Zdenko
全球肺癌负担的增加，加上其较差的生存率和对经典化疗的抵抗力，强调需要鉴定与肺癌发生有关的关键分子事件。在这里，我们将五个癌症相关基因（CDH1、CDKN2A、GSTP1、MTHFR 和 RASSF1A）的 DNA 甲基化状态的定量分析应用于一项大型肺癌病例对照研究。我们的分析显示，与对照血液样本相比，肺肿瘤中 MTHFR、RASSF1A 和 CDKN2A 的异常高甲基化频率较高，而 GSTP1 和 CDH1 的甲基化水平没有观察到显着增加，这与异常 DNA 甲基化以肿瘤特异性和基因特异性方式发生的观点一致。重要的是，我们发现吸烟、性别和饮酒对不同基因（RASSF1A 和 MTHFR）的甲基化水平有很大影响，而叶酸摄入量、年龄和组织学亚型对甲基化状态没有显着影响。我们观察到肺癌中 MTHFR 高甲基化与吸烟之间存在很强的相关性，而 CDH1、CDKN2A、GSTP1 和 RASSF1A 的甲基化水平与吸烟无关，表明烟草烟雾针对特定基因进行高甲基化。我们还发现，RASSF1A 中的甲基化水平受性别影响，但研究中的其他基因不受性别影响，男性表现出更高水平的甲基化。总之，这项研究确定了肺癌中异常的 DNA 甲基化模式，从而举例说明了环境因素可能与参与肿瘤抑制的关键基因相互作用并导致肺癌的机制。
The global rise in lung cancer burden, together with its poor survival and resistance to classical chemotherapy underscores the need for identification of critical molecular events involved in lung carcinogenesis. Here, we have applied quantitative profiling of DNA methylation states in a panel of five cancer-associated genes (CDH1, CDKN2A, GSTP1, MTHFR and RASSF1A) to a large case-control study of lung cancer. Our analyses revealed a high frequency of aberrant hypermethylation of MTHFR, RASSF1A and CDKN2A in lung tumours as compared to control blood samples, whereas no significant increase in methylation levels of GSTP1 and CDH1 was observed, consistent with the notion that aberrant DNA methylation occurs in a tumour-specific and gene-specific manner. Importantly, we found that tobacco smoking, sex, and alcohol intake had a strong influence on the methylation levels of distinct genes (RASSF1A and MTHFR), whereas folate intake, age and histological subtype had no significant influence on methylation states. We observed a strong association between MTHFR hypermethylation in lung cancer and tobacco smoking, whereas methylation levels of CDH1, CDKN2A, GSTP1 and RASSF1A were not associated with smoking, indicating that tobacco smoke targets specific genes for hypermethylation. We also found that methylation levels in RASSF1A, but not the other genes under study, were influenced by sex, with males showing higher levels of methylation. Together, this study identifies aberrant DNA methylation patterns in lung cancer and thus exemplifies the mechanism by which environmental factors may interact with key genes involved in tumour suppression and contribute to lung cancer.