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

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

Research output: Contribution to journalArticle

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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 bMLH1 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.

Original languageEnglish
Pages (from-to)887-895
Number of pages9
JournalJournal of Clinical Investigation
Volume111
Issue number6
DOIs
Publication statusPublished - Mar 2003
Externally publishedYes

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Sputum
Methylation
Lung
Non-Small Cell Lung Carcinoma
Genes
Allelic Imbalance
Neoplasms
DNA Mismatch Repair
Messenger RNA
Proteins
Epigenomics
Microsatellite Repeats
Carcinogenesis
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

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Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. / Wang, Yi Ching; Lu, Yung Pin; Tseng, Ruo Chia; Lin, Ruo Kai; Chang, Jer Wei; Chen, Jung Ta; Shih, Chuen Ming; Chen, Chih Yi.

In: Journal of Clinical Investigation, Vol. 111, No. 6, 03.2003, p. 887-895.

Research output: Contribution to journalArticle

Wang, Yi Ching ; Lu, Yung Pin ; Tseng, Ruo Chia ; Lin, Ruo Kai ; Chang, Jer Wei ; Chen, Jung Ta ; Shih, Chuen Ming ; Chen, Chih Yi. / Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 6. pp. 887-895.
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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 bMLH1 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.",
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