The Role Of DNA Mismatch Repair Defects In Carcinogenesis Of Lung Cancer

Objective: To explore the relationship among mismatch repair gene function defects , their downstream genes BAX, TGF β RII framshift mutations, and the alteration of microsatellite DNA, their role in carcinogenesis of lung cancer, in order to provide markers in clinic diagnosis and prognosis. Method: microsatellite instability ( MSI ) and loss of heterozygosity ( LOH ) of six microsatellite markers on 3p13-26 and 2p21-22, frameshift mutations of BAX and TGF β RII genes, expression of mismatch repair ( MMR ) proteins and mRNA, mutations of MMR genes hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6, and methylation of the hMLHl promoter were examined in fifty primary lung cancer frozen samples by PCR, RT-PCR, SSCP, PAGE-silver staining and immunohistochemistry, etc. Results:1. There were midding frequent MSI and LOH in lung cancer tissues. The incidence of MSI was 6%-34.7%. The total incidence of MSI was 52% ( 26/50, ≥1 locus ) and 42% ( 21/50, ≥2 loci) respectively; LOH was detected in 8%-14%, total 44% (22/50, ≥1 locus ) and 8% ( 4/50, ≥2 loci ); The total frequency of MSI and/or LOH was 72% ( 36/50, ≥1 locus ) and 48% ( 24/50, ≥2 loci).2. The alteration of microsatellite correlated with histological type and degree of differentiation. LOH was found more frequently in squamous cell carcinoma ( 60%, 15/25 ) than thatin adenocarcinoma ( 26.3%, 5/19 ); The incidence of MSI in poorly differentiated lung cancer ( 77% ) was significantly higher than those in well, moderately differentiated ( 36% ), so as MSI and/or LOH ( 71% versus 32%).3. Negative expression of MMR proteins was detected in 19.6%-30.4%, total 63% ( 29/46, ≥1 protein ). The expression of MMR proteins did not correlate with clinicopathological characteristics of lung cancer.