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, DAPkinase, 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. (Cancer Sci 2003; 94: 589-592) ung cancer is the leading cause of cancer deaths in the world, with over one million cases diagnosed every year.
1)Lung cancers are divided into two major histological types, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), the latter consisting of adenocarcinoma (AdC), squamous cell carcinoma (SCC) and large cell carcinoma. There is a growing body of biological and epidemiological data suggesting that AdC and SCC are distinct etiological entities.2, 3) There are no squamous cells in the normal bronchus, and SCCs are believed to arise from metaplastic cells present in the bronchi of smokers. By contrast, most AdCs may express features of Clara cells or type II pneumocytes. It is well known that the female/male occurrence ratio of AdC is significantly higher than that of SCC. SCC is more common in the central region, but AdC is more common in the peripheral region. Genetically, mutations in p53 and p16 are more common in SCC than AdC, 4,5) although K-ras mutations are more frequent in AdC.
6)Allelic imbalance is more frequent in SCC than AdC. 7, 8) Aberrant methylation of normally unmethylated CpG-rich areas (or islands) in or near the promoter region has been associated with transcriptional inactivation of tumor suppressor and tumor-related genes in human cancers, including NSCLC.9-12) Therefore, it is possible that methylation of different genes may contribute to the development of different histologies. In fact, we have recently determined that p16 methylation is mor...
