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

描述（由申请人提供）：肺癌（LC）是世界上最致命的癌症，每年导致多达300万人死亡。肺癌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、潜在生物学、进展和预后方面有所不同。SCLC的发病率低于NSCLC，但其侵袭性更强，因此SCLC的5年死亡率与NSCLC相当。虽然这两种类型都与吸烟有关，但这种关联在SCLC中更强；然而，很少有研究专门关注SCLC。已经证明，烟草烟雾暴露（TSE）改变了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鉴定和验证其表达改变导致SCLC的候选基因。在第一步，我们将结合生物信息学和统计学方法来预测基因的表达改变可能导致SCLC。在第二步，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和5个用于NSCLC）。我们提出以下具体目标：为了预测和鉴定被TSE改变表达导致SCLC和NSCLC（腺癌）的基因，将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. 为了利用病例对照关联研究验证前10个候选基因（5个用于SCLC和5个用于NSCLC），将使用前10个候选基因启动子区域的多态性、非同音单核苷酸多态性（snp）和位于剪接重要位点的snp来评估它们是否会增加肺癌的风险。因此，该研究将确定由TSE导致SCLC的表达受损的基因。这些基因的识别不仅将提高我们早期诊断和治疗SCLC的能力，而且还将提高我们预防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.