MOLECULAR GENETICS OF LUNG TUMOR PROMOTION IN MICE

摘要

ABSTRACT Genetic linkage studies using various strains of inbred mice have mapped pulmonary adenoma susceptibility (Pas) and pulmonary adenoma resistance (Par) loci [1,2]. Recently, quantitative trait locus (QTL) mapping also identified specific loci that regulate genetic susceptibility to pulmonary inflammation using inbred mouse strains [3]. Interestingly, common chromosomal locations were found to regulate both pulmonary inflammation and carcinogenesis suggesting a causal role of pulmonary inflammation in lung tumor susceptibility [3]. We hypothesize that genetic modifiers of pulmonary inflammation can be identified using F2 linkage mapping in mice followed by fine mapping strategies. Four specific aims are proposed to accomplish our goal. In Specific Aim 1, we will conduct genetic linkage mapping of pulmonary inflammation QTL in mice exposed to the lung irritant, butylated hydroxytoluene (BHT). In combination with the carcinogen 3-methylcholanthrene (MCA), BHT promotes MCA-induced lung tumorigenesis. We propose to use the F2 progeny of two strains of mice (BALB/cByJ and C57BL6/J) with extreme inflammation and inflammation-induced tumor promotion phenotypes. In Aim 2, we will conduct haplotype and whole-genome linkage disequilibrium analyses to guide discover new QTLs and guide and inform which loci to target in Aim 3. We have recently demonstrated the feasibility of association analysis in the fine mapping and identification of candidate susceptibility genes for lung adenocarcinomas [4]. Aim 3 will fine map the major QTL related to genetic susceptibility to pulmonary inflammation and tumor promotion by the production of congenic strains of mice in which the inflammation susceptible allele is substituted onto the genetic background of the inflammation resistant mice. 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. Aim 4 will identify the candidate gene(s) by positional cloning. DNA sequences of the fine mapped region will be obtained through comparison of completed mouse genomic databases. Candidate genes will be identified based on identified functional polymorphisms and differences in expression between the two parental strains of mice at different stages of disease progression. The significance of these studies is that they will identify candidate pulmonary inflammation susceptibility genes that may also contribute to genetic susceptibility to lung cancer in humans.