Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers

Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of tumor suppressor and tumor-related genes. To determine the clinicopathological significance of gene promoter methylation in non-small cell lung cancer (NSCLC), we examined the promoter methylation status of the APC, DAP-kinase, E-cadherin, GSTP1, hMLH1, p16, RASSF1A and RUNX3 genes in 75 NSCLCs and corresponding non-neoplastic lung tissues by methylation-specific PCR (MSP). The frequencies of methylation in NSCLCs and corresponding non-neoplastic lung tissues were: 37% (28 of 75) and 48% (36 of 75) for APC , 28% (21 of 75) and 13% (10 of 75) for DAP-kinase , 29% (22 of 75) and 15% (11 of 75) for E-cadherin , 1% (1 of 75) and 0% (0 of 75) for GSTP1 , 7% (5 of 75) and 0% (0 of 75) for hMLH1 , 31% (23 of 75) and 0% (0 of 75) for p16 , 43% (32 of 75) and 4% (3 of 75) for RASSF1A , and 20% (15 of 75) and 3% (2 of 75) for RUNX3 , respectively. Methylation of p16 was more frequent in squamous cell carcinomas than in adenocarcinomas ( P <0.05), and was associated with tobacco smoking ( P <0.05). On the contrary, methylation of APC and RUNX3 was more frequent in adenocarcinomas than in squamous cell carcinomas ( P <0.05). Thus, a different set of genes is thought to undergo promoter methylation, which leads to the development of different histologies. In addition, methylation of p16, RASSF1A and RUNX3 was mostly cancer-specific ( P <0.05), and may be utilized as a molecular diagnostic marker of NSCLCs.