Promoter Hypermethylation Is the Predominant Mechanism in hMLH1 and hMSH2 Deregulation and Is a Poor Prognostic Factor in Nonsmoking Lung Cancer

• Published in: Clinical cancer research Vol. 11; no. 15; pp. 5410 - 5416
• Main Authors: Hsu, Han-Shui, Wen, Chiao-Kai, Tang, Yen-An, Lin, Ruo-Kai, Li, Wing-Yin, Hsu, Wen-Hu, Wang, Yi-Ching
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2005
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - genetics; DNA Methylation; DNA Restriction Enzymes - chemistry; DNA Restriction Enzymes - pharmacology; Female; gene; Gene Expression Regulation, Neoplastic; hMLH1; hMSH2; Humans; Immunohistochemistry; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Medical sciences; Middle Aged; Neoplasm Metastasis; NSCLC; Pharmacology. Drug treatments; Pneumology; Polymerase Chain Reaction; Prognosis; promoter hypermethylation; Promoter Regions, Genetic; Smoking; Time Factors; Treatment Outcome; Tumors of the respiratory system and mediastinum; Lung disease; Prognosis; Respiratory disease; Transcription promoter; Lung cancer; Mechanism of action; Methylation; Bronchopulmonary; Repair gene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0601

Purpose and Experimental Design: The etiologic association and prognostic significance of mismatch repair gene/protein alterations have never been examined in nonsmoking lung cancer. Therefore, we investigated protein expression and promoter hypermethylation of hMLH1 and hMSH2 genes in the tumor specimens from 105 nonsmoking female non–small cell lung cancer (NSCLC) patients. Immunohistochemistry and restriction enzyme–based multiplex PCR were used to examine the protein expression and promoter hypermethylation, respectively. The occurrence of gene/protein alteration for each gene was compared with the patients' clinicopathologic variables as well as the overall survival and cancer-specific survival rates. Results: Protein expression alteration and promoter hypermethylation were observed in 66% to 67% and 30% to 34% of tumor specimens for hMLH1 and hMSH2 genes, respectively. Loss of hMLH1 and hMSH2 protein expression was significantly associated with their promoter hypermethylation ( P < 0.0001 and P = 0.049). The overall survival and cancer-specific survival rates were significantly lower in patients with promoter hypermethylation of hMSH2 gene than in those without hypermethylation ( P = 0.038 and P = 0.004). The poor prognosis was still especially significant in adenocarcinoma ( P = 0.035 and P = 0.061) and early-stage NSCLC patients ( P = 0.067 and P = 0.041). Conclusion: Our data suggest that hMLH1 is the major altered mismatch repair gene involved in nonsmoking NSCLC tumorigenesis and that promoter methylation is the predominant mechanism in hMLH1 and hMSH2 deregulation. In addition, promoter methylation of the hMSH2 gene may be a potential prognostic factor in nonsmoking female lung cancer.