GENETIC DIFFERENCES IN SUSCEPTIBILITY FOR LUNG CANCER

尽管有充分的证据表明，估计85%的肺癌可能与吸烟有关，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。这暗示了许多其他环境和遗传因素可能与该病的发病机制有关。尽管分子流行病学在肺癌的致癌暴露和宿主易感因素方面取得了进展，但不幸的是，许多暴露危险因素只被单独识别。人们的认识已经发展到了这样一个地步，即这些危险因素应该与多种宿主易感因素一起进行调查，以便能够评估基因与环境的相互作用。我们建议利用分子技术的最新进展来分析人类样本中影响营养状况、全球和基因特异性DNA甲基化的基因多态，以便这些因素可以与已知的肺癌危险因素一起研究，包括抑癌基因和癌基因的遗传突变。这可能有助于揭示可能影响肺癌遗传易感性或获得性易感性的变异来源。这项提议要检验的假设是，与不患肺癌的吸烟者相比，吸烟者之间存在重要的遗传和表观遗传学差异。我们将集中研究一种基因多态(亚甲基四氢叶酸还原酶[MTHFR])，这种多态最有可能影响肺中一种特定维生素(叶酸)的局部浓度不足的状态，以及对癌症发展至关重要的DNA的相关变化。为了验证这一假设，将比较60名患有鳞状细胞肺癌(SCC)的吸烟者和60名未患鳞状细胞肺癌的吸烟者的MTHFR多态频率、全球甲基化和基因特异性甲基化以及几个中间终点生物标志物的表达。还将调查这些变量之间的相互作用。这项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.