OBJECTIVE To investigate the mechanism of hMLH1 deregulation in non-small cell lung cancer (NSCLC). METHODS A genetic and epigenetic study of the hMLHl gene was performed using surgical primary tumors from 40 NSCLC patients and their corresponding noncancerous tissues. The molecular alterations ex- amined included promoter methylation by Hpa Il/Msp I- based PCR anal- ysis, loss of heterozygosity (LOH) by D3S1621 locus PCR-electrophore- sis-silver staining, as well as the loss of protein expression by immuno- histochemical analysis. RESULTS The frequencies of hypermethylation, LOH and loss of protein expression of hMLHl were 67.5% (27/40) , 65% (26/40) and 72.5% (29/ 40), respectively. Among 26 hMLHl gene LOH (+) cases, 21 (80.8%) showed hypermethylation, which was significantly higher than the group of LOH (-). The frequency of the double inactivation of the hMLHl gene by hypermethylation and LOH related to a loss of protein expression of 72.4% (21/29). CONCLUSION Biallelic inactivation of the hMLHl gene by hypermethyla- tion and LOH most likely will cause loss of hMLHl protein expression and play an important role in the development of NSCLC. Therefore, control- ling and monitoring for hypermethylation of the hMLHl gene may be par- tially useful for treatment and early diagnosis of NSCLC.
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