Genetic Modifiers of Lung Cancer

肺癌的基因修饰

• 批准号: 7848115
• 负责人: YIAN WANG
• 金额: $ 33.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848115
• 关键词: Adenocarcinoma; Alleles; Cancer-Predisposing Gene; Candidate Disease Gene; Carcinogens; Chromosome Mapping; Clinical; Complex; Congenic Mice; Congenic Strain; Databases; Development; Diagnostic Neoplasm Staging; Disease Progression; Environmental Risk Factor; Gene-Modified; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; Goals; Haplotypes; Homologous Gene; Human; Inbred Strains Mice; Individual; Linkage Disequilibrium; Lung; Lung Adenoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mouse Strains; Mus; Neoplasms; Penetrance; Phenotype; Predisposition; Production; Quantitative Trait Loci; Reporting; Resistance; Squamous Cell; Squamous Cell Lung Carcinoma; Squamous cell carcinoma; Structure; Susceptibility Gene; Tumor stage; base; candidate identification; carcinogenesis; genetic linkage; genome wide association study; mouse model; positional cloning; trait; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Genetic linkage studies using various strains of inbred mice have mapped pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci. However, there have been no reports on the mapping of lung squamous cell carcinoma susceptibility loci. We hypothesize that genetic modifiers for lung squamous cell tumorigenesis can be identified using F2 mapping followed by fine mapping strategies of the QTL regions. Four specific aims are proposed to accomplish our goal. In Specific Aim 1, we will conduct genetic mapping of lung tumor QTL in mice exposed to N-nitroso-tris-chloroethylurea (NTCU), a carcinogen that causes squamous cell carcinomas in mice. We propose to use the F2 progeny of the two strains of mice with extreme lung tumor phenotype (the most susceptible and the most resistant) to NTCU. Aim 2 will fine map the major QTL related to genetic susceptibility to mouse lung squamous cell carcinomas by the production of congenic strains of mice in which tumor susceptible allele is substituted onto the genetic background of the resistant mouse. The QTL will be fine-mapped by progressively reducing the QTL region through the production of sub-congenic mouse strains to narrow it to a size of around 0.5 -1 cM. In conjunction with Aim 2, we will conduct haplotype and whole-genome linkage disequilibrium analyses to fine map the major QTL in Aim 3. We have recently demonstrate the feasibility of this approach in the fine mapping and identification of candidate susceptibility genes for lung adenoma/adenocarcinomas. Aim 4 will identify the candidate gene(s) by positional cloning. DMA sequences of the narrowed region will be obtained through completed mouse genomic databases. New and known genes in the target region will be identified and candidate genes will be sought based on known or deduced function and/or differences in expression between the two parental strains of mice. The significance of these studies is that they will identify the candidate lung cancer susceptibility genes whose human homologue may predispose some individuals to lung cancer.

描述（由申请人提供）：使用各种近交小鼠菌株的遗传连锁研究具有绘制肺腺瘤易感性（PAS）和肺腺瘤耐药性（PAR）基因座。但是，尚无关于肺鳞状细胞癌敏感位点的映射的报道。我们假设可以使用F2映射来鉴定用于肺鳞状细胞肿瘤发生的遗传修饰剂，然后进行QTL区域的精细映射策略。提出了四个具体目标来实现我们的目标。在特定的目标1中，我们将在暴露于N-硝基三氯 - 氯乙烯（NTCU）的小鼠中进行肺肿瘤QTL的遗传图，这是一种导致小鼠鳞状细胞癌的致癌物。我们建议将两种小鼠菌株的F2后代使用极端的肺肿瘤表型（最易感性和最具耐药性）用于NTCU。 AIM 2将通过产生与小鼠的先天性菌株的产生相对于小鼠肺鳞状细胞癌的遗传易感性量的主要QTL，其中将肿瘤易感性等位基因取代在抗性小鼠的遗传背景上。通过产生亚综合小鼠菌株将其缩小到约0.5 -1 cm的大小，QTL将通过逐渐减少QTL区域进行细化。与AIM 2结合使用，我们将进行单倍型和全基因组链接不平衡分析，以详细绘制AIM 3中的主要QTL。我们最近证明了这种方法在对肺腺瘤/腺癌候选易感基因的精细映射和鉴定中的可行性。 AIM 4将通过位置克隆确定候选基因。狭窄区域的DMA序列将通过完成的小鼠基因组数据库获得。将根据已知或推导的功能和/或小鼠两种父母菌株之间表达的差异来识别目标区域中的新基因和候选基因。这些研究的意义在于，它们将确定人类同源物可能使某些个体患有肺癌的候选肺癌敏感性基因。