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

Abstract

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...

Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer

“…In addition, concordant results were also obtained after studying noncancerous and cancerous lung samples collected in these seven patients by a methylation-specific PCR method (data not shown). The frequency of TFPI-2 gene promoter methylation (30%) was relatively high compared to frequencies previously published for other methylated genes in primary lung tumours such as MGMT, DAPK, E-cadherin, RASSF1A, TIMP-3 and p16 (Esteller et al, 1999;Tang et al, 2000;Zochbauer-Muller et al, 2002;Yanagawa et al, 2003). Silencing of the TFPI-2 gene associated with hypermethylation of the promoter has recently been described in several cancer cell lines derived from choriocarcinoma (Hube et al, 2003b), glioma (Konduri et al, 2003), fibrosarcoma, breast and prostate cancers .…”

Aberrant methylation of the adenomatous polyposis coli promoter 1A in bronchial aspirates from patients with suspected lung cancer

“…11,13,14,16 Previous studies utilizing nonquantitative traditional MSP on resection specimens and cell lines of NSCLC and SCLC reported APC hypermethylation in 0 to 53% (median, 45%) and in 26%, respectively. 12,15,24,25 Up to now, the information about a possible basal methylation of the APC promoter is limited. Brabender et al 11 found APC hypermethylation only in 2 out of 10 histologic normal lung tissues.…”

Interferon Regulatory Factors IRF5 and IRF7 Inhibit Growth and Induce Senescence in Immortal Li-Fraumeni Fibroblasts

“…About 60% of mammalian genes have CpG islands in their promoter regions, which, under normal circumstances, are not methylated. In tumor cells, hypermethylation of the CpG islands in promoters results in transcriptional inhibition of tumor suppressor genes (17)(18)(19). Abnormal promoter hypermethylation and subsequent silencing of gene expression of p16 INK4a , p15 INK4B , p14 ARF , p73, APC, and BRCA1 has revealed that epigenetic changes are one of the common mechanisms leading to cancer (20,21).…”