Genetic Susceptibility to Lung Cancer

描述(申请人提供)：肺癌是美国男性和女性癌症死亡的最常见原因。尽管高达90%的肺癌可归因于吸烟，但只有10%-20%的吸烟者在一生中患上肺癌。这一观察和大量文献表明，其他环境和宿主因素影响个体对烟草烟雾的易感性。这项建议将利用分子流行病学在这一竞争延续(R01 CA 74386)中的最新进展，扩展我们最初评估肺癌中六种异物代谢多态的目标，包括评估最近描述的控制氧化代谢的多态基因(第一阶段)和活性中间产物的结合(第二阶段)。此外，还将评估一些其他影响肺部炎症过程、DNA修复、生长因子功能和肿瘤抑制(癌基因)的多态基因，因为越来越多的证据支持这些非代谢多态等位基因在肺癌发生中的作用。此外，本研究还探讨了吸烟、饮食和遗传因素作为基因多态与肺癌风险之间关联的效应调节剂的作用，以及年龄和性别在这些关联中的潜在作用。为了评估这种扩大的多态基因组中的这些基因-环境和基因基因相关性，我们的建议将建立在我们的生产性R01的基础上，增加我们的样本量，并通过增加少数民族招募来包括更大的种群多样性。更好地了解这些风险将导致改进预防战略。该提案直接涉及国家癌症研究所的两个“特殊机会”，特别是确定与环境因素共同影响癌症风险的基因变异的目标，以及对烟草相关问题的研究。

DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer mortality among both men and women in the United States. Although up to 90 percent of lung cancer is attributable to cigarette smoking, only 10-20 percent of smokers develop bronchogenic carcinoma over their lifetimes. This observation, along with substantial literature implicating heritable polymorphic factors, indicates that other environmental and host factors influence individual susceptibility to tobacco smoke. This proposal will take advantage of recent advances in molecular epidemiology in this competing continuation (R01 CA 74386) by expanding our original aims of evaluating six xenobiotic metabolic polymorphisms in lung cancer to include the assessment of more recently described polymorphic genes that control oxidative metabolism (Phase I) and the conjugation of reactive intermediates (Phase II). In addition, a number of other polymorphic genes that affect lung inflammatory processes, DNA repair, growth factor function, and tumor suppression (oncogenes) will be evaluated, as there is accumulating evidence supporting the role of these non-metabolism polymorphic alleles in lung cancer development. Moreover, this proposal addresses the role of smoking, diet, and genetic factors as effect modifiers for the association between polymorphisms and lung cancer risk, and the potential roles of age and gender in these associations. To assess these gene-environment and gene gene associations in this expanded group of polymorphic genes, our proposal will build on our productive R01 by increasing our sample size and including greater population diversity by increasing minority recruitment. A better understanding of these risks will lead to improved preventive strategies. The proposal directly addresses two "Extraordinary Opportunities" of the National Cancer Institute, specifically the aim to identify genetic variations that affect cancer risk in concert with environmental factors, and research on tobacco-related concerns.