Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer
Article first published online: 31 OCT 2002
Copyright © 2003 Wiley-Liss, Inc.
International Journal of Cancer
Volume 103, Issue 2, pages 153–160, 10 January 2003
How to Cite
Toyooka, S., Maruyama, R., Toyooka, K. O., McLerran, D., Feng, Z., Fukuyama, Y., Virmani, A. K., Zochbauer-Muller, S., Tsukuda, K., Sugio, K., Shimizu, N., Shimizu, K., Lee, H., Chen, C.-Y., Fong, K. M., Gilcrease, M., Roth, J. A., Minna, J. D. and Gazdar, A. F. (2003), Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int. J. Cancer, 103: 153–160. doi: 10.1002/ijc.10787
- Issue published online: 26 NOV 2002
- Article first published online: 31 OCT 2002
- Manuscript Accepted: 12 SEP 2002
- Manuscript Revised: 4 SEP 2002
- Manuscript Received: 21 JUN 2002
- UT Specialized Program of Research Excellence in Lung Cancer. Grant Number: P50CA70907
- Early Detection Research Network National Cancer Institute, Bethesda, MD. Grant Number: 5U01CA8497102
- non-small cell lung cancer;
Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARβ, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers; analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes; b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers; c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers; d) the methylation rates of APC, CDH13 and RARβ were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan; and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors. © 2002 Wiley-Liss, Inc.