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

International Journal of Cancer - Tập 103 Số 2 - Trang 153-160 - 2003
Shinichi Toyooka1,2, Riichiroh Maruyama2, Kiyomi O. Toyooka2, Dale McLerran3, Ziding Feng3, Yasuro Fukuyama2, Arvind K. Virmani4,2, Sabine Zöchbauer‐Müller2, Kazunori Tsukuda1, Kenji Sugio5, Nobuyoshi Shimizu1, Kenji Shimizu6, Huei Lee7, Chih‐Yi Chen8, Kwun M. Fong9, Michael Z. Gilcrease10, Jack A. Roth11, John D. Minna12,13,2, Adi F. Gazdar4,2
1Department of Surgical Oncology and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
2Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
3Cancer Prevention Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
4Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
5Department of Surgery 2, Kyushu University Faculty of Medicine, Fukuoka, Japan
6Department of Molecular Genetics, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan
7Institute of Toxicology, Chung Shan Medical and Dental College, Taichung, Taiwan, Republic of China
8Department of Thoracic Surgery, Veterans General Hospital, Taichung, Taiwan, Republic of China
9The Prince Charles Hospital, Chermside, Brisbane, Australia
10Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
11Department of Thoracic Surgery, University of Texas, MD Anderson Cancer Center, Houston TX, USA
12Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
13Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX USA

Tóm tắt

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, 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.

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International Journal of Cancer

Tập 103 Số 2

153-160

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