title: Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer.
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, RARbeta, 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 RARbeta 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.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas TX 75390-8593, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Riichiroh
authors.initials: R
authors.lastname: Maruyama
authors.forename: Kiyomi O
authors.initials: KO
authors.lastname: Toyooka
authors.forename: Dale
authors.initials: D
authors.lastname: McLerran
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Fukuyama
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Virmani
authors.forename: Sabine
authors.initials: S
authors.lastname: Zochbauer-Muller
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugio
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Kwun M
authors.initials: KM
authors.lastname: Fong
authors.forename: Michael
authors.initials: M
authors.lastname: Gilcrease
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm; D005260:Female; D016147:Genes, Tumor Suppressor; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D007564:Japan; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate; D013624:Taiwan; D025521:Tumor Suppressor Proteins; D014481:United States
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D007527:Isoenzymes; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D019853:O(6)-Methylguanine-DNA Methyltransferase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase