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

描述(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。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、潜在生物学、进展和预后方面不同。小细胞肺癌的发病率低于非小细胞肺癌，但侵袭性更强，因此小细胞肺癌的5年死亡率与非小细胞肺癌相当。虽然这两种类型都与吸烟有关，但这种关联在小细胞肺癌中更强；然而，很少有研究专门关注小细胞肺癌。已有研究表明，烟草烟雾暴露(TSE)可改变支气管上皮细胞中多种基因的表达。我们提出了一种两步法来识别和验证表达改变导致小细胞肺癌的候选基因。在第一步中，我们将结合生物信息学和统计学方法来预测其表达变化可能导致小细胞肺癌的基因。在第二步中，我们将使用病例对照设计验证前10个候选基因(5个用于小细胞肺癌，5个用于非小细胞肺癌)。1.通过对吸烟诱导上皮基因表达数据库(SIEGE)和基因表达总集(GEO)数据库中基因表达数据的分析，预测和鉴定TSE导致小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC)的基因表达改变的基因。2.为了用病例对照研究验证前10个候选基因(5个是小细胞肺癌，5个是非小细胞肺癌)，我们将用非同义单核苷酸多态(SNPs)和位于剪接重要部位的SNPs来评估它们是否与肺癌的发生有关。因此，这项拟议的研究将确定TSE表达受损导致小细胞肺癌的基因。这些基因的识别不仅将提高我们早期诊断和治疗小细胞肺癌的能力，而且还将提高预防小细胞肺癌的能力。

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.