GENETIC DIFFERENCES IN SUSCEPTIBILITY FOR LUNG CANCER

虽然有充分的证据表明，估计85%的肺癌可能归因于吸烟，但只有10%-20%的吸烟者在一生中患上肺癌，这清楚地表明，肺癌的发生不仅仅是简单地吸入香烟烟雾。 这表明许多其他环境和遗传因素可能与该疾病的发病机制有关。 尽管分子流行病学在记录肺癌的致癌暴露和宿主易感性因素方面取得了进展，但不幸的是，许多这些暴露风险因素仅被单独确定。 知识的状态已经发展到这样的程度，这些风险因素应结合多种宿主易感因素进行研究，以便评估基因-环境相互作用。我们建议利用分子技术的最新进展，分析人类样本的遗传多态性影响营养状况，全球和基因特异性DNA甲基化，使这些因素可以沿着已知的肺癌危险因素，包括肿瘤抑制基因和癌基因的遗传突变进行研究。 这可能会揭示可能影响遗传或获得性肺癌易感性的变异性来源。在这项提议中要检验的假设是，与那些不吸烟的人相比，患肺癌的吸烟者之间存在重要的遗传和表观遗传差异。 我们将把我们的研究重点放在遗传多态性（亚甲基四氢叶酸还原酶[MTHFR]），这可能会影响状态，最有可能的是，局部缺乏浓度的特定维生素（叶酸）在肺和相关的变化DNA的发展癌症的关键。 为了验证这一假设，将在60名患鳞状细胞肺癌（SCC）的吸烟者和60名未患SCC的吸烟者之间比较MTHFR多态性、总体和基因特异性甲基化以及几种中间终点生物标志物的表达的频率。 还将研究这些变量之间的相互作用。 本研究产生的结果将用于进行精心设计的肺癌分子流行病学研究。

Although it is well documented that an estimated 85 percent of lung cancer may be attributable to cigarette smoking, only 10-20 percent of smokers develop lung cancer during their lifetime indicating clearly that there is more to its initiation than the simple inhalation of cigarette smoke. This is suggestive of numerous other environmental and genetic factors that may be implicated in the pathogenesis of the disease. Although the molecular epidemiology has made progress in documenting carcinogenic exposures and host susceptibility factors for lung cancer, unfortunately, many of these exposure risk factors are only identified individually. The state of knowledge has advanced to the point that these risk factors should be investigated in conjunction with multiple host susceptibility factors so that gene-environmental interactions can be assessed. We propose to take advantage of the recent advances in molecular techniques to analyze human samples for genetic polymorphisms affecting nutritional status, global and gene specific DNA methylation so that these factors can be studied along with known risk factors for lung cancer, including inherited mutations in tumor suppressor genes and oncogenes. This may shed light on the sources of variability that may affect inherited or acquired susceptibility to lung cancer. The hypothesis to be tested in this proposal is that there are important genetic and epigenetic differences between smokers who develop lung cancer compared to those who do not. We will focus our study on a genetic polymorphism (methylene tetrahydrofolate reductase [MTHFR]) that might affect the status, most likely, of a locally deficient concentration of a specific vitamin (folate) in the lung and associated changes in DNA critical for the development of cancer. To test this hypothesis, the frequency of MTHFR polymorphism, global and gene specific methylation and the expression of several intermediate end point biomarkers will be compared between 60 smokers who developed squamous cell lung cancer (SCC) and 60 smokers who did not. Interactions among and between these variables will also be investigated. The results generated by this study will be used to conduct a well-designed molecular epidemiological study of lung cancer.