Alterations of DNA Mismatch Repair Genes in Lung Cancer

  • Li, Guo Min (PI)
  • Gu, Liya (CoI)

Grants and Contracts Details


Lung cancer is the most lethal cancer in the United States and Kentucky is the leading state for lung cancer death in the nation. However, the molecular basis of the deadly disease is still unknown. Previous studies have shown that lung cancer is often associated with deletion of chromosome 3p, where a mismatch repair (MMR)gene, MLH1, is located. Recently, a substantial fraction of lung cancer have been shown to manifest frequent alterations in simple repetitive sequences (also called microsatellite instability), a phenotype that was initiaJlyidentified in hereditary non-polyposis colorectal cancer and was caused by loss of function in a genome maintenance pathway called MMR. These findings strongly suggest a close association of lung cancer with MMRdefects. To test this hypothesis, this application will utilize both genetic and biochemical approaches to analyze relationship between lung cancer and MMRdeficiency. First, lung tumors willbe screened for microsatellite instability (MSI), and tumors with MSI willbe examined for expression of two important MMRgenes, MSH2 and MLH1, by immunohistochemistry. Specific alterations/mutations willbe determined in tumors lacking expression of MSH2 or MLH1 using the combined technology of PCR, single strand conformation polymorphism, and DNA sequencing analysis. Second, individual alterations identified willbe introduced into the MSH2 or MLH1 baculovirual clones by site-directed mutagenesis. To determine actual impact of these alterations on lung carcinogenesis and MMRfunction, the mutant baculovirual recombinant proteins willbe examined for their ability to restore MMRto known MSH2 or MLH1 mutant extracts using an in vitro functional assay. Finally, tumors lacking MLH1 expression willbe analyzed for hypermethylation of the MLH1 promoter, whose methylation has been shown to transcriptionally silence the MLH1 expression in other cancers. Based on our preliminarystudies, we believe that both deletions and point mutations of MMR genes will be identified in lung cancers, and this study will provide useful inforr~ation for lung cancer etiology, early detection, and treatment.
Effective start/end date7/1/026/30/05


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