Tobacco Smoke Sensitive Genes and Genetic Susceptibility to Small-Cell Lung Cance

描述（由申请人提供）：肺癌 (LC) 是全世界最致命的癌症，每年导致多达 300 万人死亡。 LC 的两种主要类型是小细胞肺癌 (SCLC) 和非小细胞肺癌 (NSCLC)。这两种类型在发病率、基础生物学、进展和预后方面有所不同。 SCLC的发病率低于NSCLC，但侵袭性更强，因此SCLC的5年死亡率与NSCLC相当。尽管这两种类型都与吸烟有关，但 SCLC 的这种关联更为强烈。尽管如此，很少有研究专门关注 SCLC。已经证明，烟草烟雾暴露（TSE）会改变支气管上皮细胞中许多基因的表达。我们提出了一种两步法来识别和验证其表达改变导致 SCLC 的候选基因。第一步，我们将结合生物信息学和统计方法来预测表达改变可导致 SCLC 的基因。第二步，我们将使用病例对照设计验证前 10 个候选基因（5 个用于 SCLC，5 个用于 NSCLC）。我们提出以下具体目标： 1. 预测和鉴定其表达被 TSE 改变、导致 SCLC 和 NSCLC（腺癌）的基因 通过分析吸烟诱导上皮基因表达（SIEGE）数据库和基因表达综合（GEO）数据库中的基因表达数据来鉴定候选基因。 2. 使用病例对照关联研究验证前 10 个候选基因（5 个用于 SCLC，5 个用于 NSCLC）。顶级候选基因启动子区域的多态性、非同义单核苷酸多态性 (SNP) 以及位于剪接重要位点的 SNP 将用于评估它们是否会带来肺癌风险。因此，拟议的研究将鉴定因 TSE 表达受损而导致 SCLC 的基因。这些基因的鉴定不仅可以提高我们早期诊断和治疗 SCLC 的能力，还可以提高我们预防 SCLC 的能力。

DESCRIPTION (provided by applicant): Lung cancer (LC) is the most deadly cancer worldwide, causing up to 3 million deaths annually. The two major types of LC are small-cell lung cancer (SCLC) and non- small-cell lung cancer (NSCLC). These two types differ by incidence, underlying biology, progression, and prognosis. The incidence of SCLC is lower than that of NSCLC, but it is more aggressive, so the 5-year death rate for SCLC is comparable to that for NSCLC. Although both types are associated with smoking, that association is stronger for SCLC; nonetheless, very few studies have specifically focused on SCLC. It has been demonstrated that tobacco-smoke exposure (TSE) alters the expression of numerous genes in bronchial epithelial cells. We propose a two-step approach to identify and validate candidate genes whose altered expression causes SCLC. In the first step, we will combine bioinformatics and statistical methods to predict genes whose altered expression can cause SCLC. In the second step, we will validate the top 10 candidate genes (5 for SCLC and 5 for NSCLC) using a case-control design. We propose following specific aims: 1. To predict and identify genes whose expression is altered by TSE, leading to SCLC and NSCLC (adenocarcinomas) The candidate genes will be identified by analysis of gene expression data in the Smoking-Induced Epithelial Gene Expression (SIEGE) database and Gene Expression Omnibus (GEO) database. 2. To validate the top 10 candidate genes (5 for SCLC and 5 for NSCLC) using a case-control association study Polymorphisms in the promoter regions of the top candidate genes, nonsynonymous single-nucleotide polymorphisms (SNPs), and SNPs located in the sites important for splicing will be used to evaluate whether they confer risk for lung cancer. The proposed study will thus identify genes whose impaired expression by TSE causes SCLC. The identification of these genes will improve our ability not only to diagnose and treat SCLC early but also to prevent it.