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.
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