Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples
Yi-Ching Wang, … , Chuen-Ming Shih, Chih-Yi Chen
Yi-Ching Wang, … , Chuen-Ming Shih, Chih-Yi Chen
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):887-895. https://doi.org/10.1172/JCI15475.
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Article Genetics

Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples

Abstract

We performed a genetic and epigenetic study of the hMLH1 and hMSH2 mismatch repair genes in resected primary tumors from 77 non-small cell lung cancer (NSCLC) patients. The molecular alterations examined included the loss of mRNA and protein expression as well as promoter methylation, and the allelic imbalance of the chromosomal regions that harbor the genes. We found that 78% and 26% of patients showed at least one type of molecular alteration within the hMLH1 and hMSH2 genes, respectively. Promoter methylation of the hMLH1 gene was present in 55.8% of tumors, and was significantly associated with the reduction in mRNA and protein expression (P = 0.001). A 72% concordance of aberrant methylation in sputum samples with matched resected tumors was found. In addition, a 93% consistency between the promoter methylation and the mRNA expression of the hMSH2 gene was found in 14 female NSCLC patients. However, no correlation was found between the expression of hMLH1 and hMSH2 proteins and the allelic imbalance of five microsatellite markers closely linked to the genes. Our results suggest that hMLH1 is the major altered mismatch repair gene involved in NSCLC tumorigenesis, and that promoter methylation is the predominant mechanism in hMLH1 and hMSH2 deregulation. In addition, promoter methylation of the hMLH1 gene may be identified in sputum samples to serve as a potential diagnostic marker of NSCLC.

Authors

Yi-Ching Wang, Yung-Pin Lu, Ruo-Chia Tseng, Ruo-Kai Lin, Jer-Wei Chang, Jung-Ta Chen, Chuen-Ming Shih, Chih-Yi Chen

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Concordance analysis between protein expression, mRNA expression, and pr...
Concordance analysis between protein expression, mRNA expression, and promoter methylation of hMLH1 (a) and hMSH2 (b). The percentage of cases is indicated on the y axis, whereas the type of comparison is shown on the x axis. + indicates positive protein expression (protein), positive mRNA expression (RNA), and hypermethylation (methyl) of the promoter. Numbers above bars indicate percentages of the total concordant group (gray sections) and nonconcordant group (white sections). P = 0.001 for association between protein expression, mRNA expression, and promoter methylation in the hMLH1 gene; P = 0.002 for association between protein expression and mRNA expression in the hMSH2 gene.