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

Authors

  • Shinichi Toyooka,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
    2. Department of Surgical Oncology and Thoracic Surgery, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan
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  • Riichiroh Maruyama,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Kiyomi O. Toyooka,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Dale McLerran,

    1. Cancer Prevention Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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  • Ziding Feng,

    1. Cancer Prevention Research, Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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  • Yasuro Fukuyama,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Arvind K. Virmani,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
    2. Departments of Pathology, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Sabine Zochbauer-Muller,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Kazunori Tsukuda,

    1. Department of Surgical Oncology and Thoracic Surgery, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan
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  • Kenji Sugio,

    1. Department of Surgery 2, Kyushu University Faculty of Medicine, Fukuoka, Japan
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  • Nobuyoshi Shimizu,

    1. Department of Surgical Oncology and Thoracic Surgery, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan
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  • Kenji Shimizu,

    1. Department of Molecular Genetics, Okayama University, Graduate School of Medicine and Dentistry, Okayama, Japan
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  • Huei Lee,

    1. Institute of Toxicology, Chung Shan Medical and Dental College, Taichung, Taiwan, Republic of China
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  • Chih-Yi Chen,

    1. Department of Thoracic Surgery, Veterans General Hospital, Taichung, Taiwan, Republic of China
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  • Kwun M. Fong,

    1. The Prince Charles Hospital, Chermside, Brisbane, Australia
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  • Michael Gilcrease,

    1. Department of Pathology, University of Texas, MD Anderson Cancer Center, Houston TX, USA
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  • Jack A. Roth,

    1. Department of Thoracic Surgery, University of Texas, MD Anderson Cancer Center, Houston TX, USA
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  • John D. Minna,

    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
    2. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas TX, USA
    3. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas TX, USA
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  • Adi F. Gazdar

    Corresponding author
    1. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX, USA
    2. Departments of Pathology, University of Texas Southwestern Medical Center, Dallas TX, USA
    • Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593
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    • Fax: +214-648-4940


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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