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.
Increasing evidence supports a direct link between inflammation and cancer, and lung cancer in particular. Epidemiologic data in humans have shown an increased cancer risk in patients with various inflammatory diseases of the lung, including chronic obstructive pulmonary disease (COPD) and asthma among others. Inflammation was found to enhance the development of lung tumors in mice. Many of the QTLs that control genetic susceptibility to lung inflammation, also co-localize with QTLs that regulate lung tumor susceptibility in mice. Administration of budesonide and indomethacin (with anti-inflammatory activity) inhibit lung tumorigenesis in mice. Finally, inflammation biomarkers including Cox1 and Cox2 are frequently elevated in both mouse and human lung cancers. These associations between inflammation and lung cancer suggest that pulmonary inflammation appears to be a key tumor promotion step during the lung tumorigenesis process. The objective of this proposal is to identify genetic modifiers of pulmonary inflammation. 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.
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