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Smoke exposure, histologic type and geography‐related differences in the methylation profiles of non‐small cell lung cancer
Author(s) -
Toyooka Shinichi,
Maruyama Riichiroh,
Toyooka Kiyomi O.,
McLerran Dale,
Feng Ziding,
Fukuyama Yasuro,
Virmani Arvind K.,
ZochbauerMuller Sabine,
Tsukuda Kazunori,
Sugio Kenji,
Shimizu Nobuyoshi,
Shimizu Kenji,
Lee Huei,
Chen ChihYi,
Fong Kwun M.,
Gilcrease Michael,
Roth Jack A.,
Minna John D.,
Gazdar Adi F.
Publication year - 2002
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10787
Subject(s) - methylation , lung cancer , adenocarcinoma , gstp1 , dna methylation , oncology , histology , carcinoma , lung , biology , pathology , medicine , cancer , cancer research , gene , genetics , gene expression , genotype
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.