p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos
p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos
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DOI：
10.1016/j.lungcan.2009.03.018
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发表时间：
2010-01-01
期刊：
影响因子：
5.3
通讯作者：
Jaurand, Marie-Claude
中科院分区：
文献类型：
--
作者：
Andujar, Pascal;Wang, Jinhui;Jaurand, Marie-Claude
流行病学研究表明，石棉纤维是主要的职业危险因素，石棉与吸烟协同作用，诱发肺癌。虽然肺癌中的一些体细胞基因改变与吸烟有关，但关于石棉纤维的作用的数据很少。P16/CDKN 2A是一个重要的抑癌基因，在肺癌中常通过启动子5 '-CpG岛高甲基化和纯合性缺失而改变，很少通过点突变而改变。许多研究表明，吸烟导致肺癌中P16/CDKN 2A启动子的高甲基化，但该基因与石棉暴露的关系尚未确定。本研究的目的是探讨石棉暴露患者肺癌中P16/CDKN 2A改变的机制。采用职业调查表和肺组织石棉小体检测方法，对75例有明确吸烟习惯、详细石棉暴露评估的非小细胞肺癌（NSCLC）患者进行P16/CDKN 2A基因检测。这项研究的结果证实了已发表的关于烟草烟雾对P16/CDKN 2A基因改变的影响的数据，其特征是重度吸烟者（超过40包-年（P-Y））中的P16/CDKN 2A启动子超甲基化显著高于低于40包-年（P-Y）的吸烟者。这些结果还表明，在调整年龄和累积烟草消费量后，石棉暴露病例中杂合性缺失和纯合性缺失的发生率高于未暴露病例（P=0.0062）。这项研究表明，石棉暴露的NSCLC病例中P16/CDKN 2A基因失活主要通过缺失发生，这一特征也见于恶性间皮瘤，一种独立于吸烟但与石棉暴露相关的肿瘤，这表明可能与石棉纤维的影响有关。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Epidemiological studies have shown that asbestos fibers constitute the major occupational risk factor and that asbestos acts synergistically with tobacco smoking to induce lung cancer. Although some somatic gene alterations in lung cancer have been linked to tobacco smoke, few data are available on the role of asbestos fibers. P16/CDKN2A is an important tumor suppressor gene that is frequently altered in lung cancer via promoter 5'-CpG island hypermethylation and homozygous deletion, and rarely via point mutation. Many studies suggest that tobacco smoking produces P16/CDKN2A promoter hypermethylation in lung cancer, but the status of this gene in relation to asbestos exposure has yet to be determined. The purpose of this study was to investigate the mechanism of P16/CDKN2A alterations in lung cancer in asbestos-exposed patients. P16/CDKN2A gene status was studied in 75 human non-small-cell lung cancer (NSCLC) cases with well-defined smoking habits, and detailed assessment of asbestos exposure, based on occupational questionnaire and determination of asbestos bodies in lung tissue. The results of this study confirm published data on the effect of tobacco smoke on P16/CDKN2A gene alterations, characterized by significantly higher P16/CDKN2A promoter hypermethylation in heavy smokers (more than 40 pack-years (P-Y)) than in smokers of less than 40 P-Y. These results also demonstrate a higher incidence of loss of heterozygosity and homozygous deletion in asbestos-exposed cases, after adjustment for age and cumulative tobacco consumption, than in unexposed cases (P=0.0062). This study suggests that P16/CDKN2A gene inactivation in asbestos-exposed NSCLC cases mainly occurs via deletion, a feature also found in malignant mesothelioma, a tumor independent of tobacco smoking but associated with asbestos exposure, suggesting a possible relationship with an effect of asbestos fibers. (C) 2009 Elsevier Ireland Ltd. All rights reserved.