Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer

Shinichi Toyooka, Riichiroh Maruyama, Kiyomi O. Toyooka, Dale McLerran, Ziding Feng, Yasuro Fukuyama, Arvind K. Virmani, Sabine Zochbauer-Muller, Kazunori Tsukuda, Kenji Sugio, Nobuyoshi Shimizu, Kenji Shimizu, Huei Lee, Chih Yi Chen, Kwun M. Fong, Michael Gilcrease, Jack A. Roth, John D. Minna, Adi F. Gazdar

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Abstract

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, RASSFIA (RAS association domain family I), APC, RARβ, CDHI3, MGMT and GSTPI]. 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, CDHI3 and RARβ were significantly higher in adenocarcinomas than in squamous cell carcinomas; e) methylation rates of MGMT and GSTPI 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.

Original languageEnglish
Pages (from-to)153-160
Number of pages8
JournalInternational Journal of Cancer
Volume103
Issue number2
DOIs
Publication statusPublished - Jan 10 2003
Externally publishedYes

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Keywords

  • Histology
  • Methylation
  • Non-small cell lung cancer
  • Smoking

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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., & Gazdar, A. F. (2003). Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. International Journal of Cancer, 103(2), 153-160. https://doi.org/10.1002/ijc.10787