title: DNA methylation profiles of lung tumors.
abstract: Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. We determined the frequency of aberrant promoter methylation of the p16, adenomatous polyposis coli (APC), H-cadherin (CDH13), glutathione S-transferase P1 (GSTP1), O6-methylguanine-DNA-methyltransferase (MGMT), retinoic acid receptor beta-2 (RAR beta), E-cadherin (CDH1), and RAS association domain family 1A (RASSF1A) genes in 198 tumors consisting of small cell lung cancers [SCLCs (n = 43)], non-small cell lung cancers [NSCLCs (n = 115)], and bronchial carcinoids (n = 40). The profile of methylated genes in the two neuroendocrine tumors (SCLC and carcinoids) were very different from that of NSCLC. However, whereas the overall pattern of aberrant methylation of carcinoids was similar to that of SCLC, carcinoids had lower frequencies of methylation for some of the genes tested. There were also significant differences in the methylation profiles between the two major types of NSCLC, adenocarcinoma and squamous cell carcinoma. We performed cluster analysis and found that SCLCs clustered with other SCLCs and carcinoids but not with NSCLCs, whereas the NSCLCs tended to cluster together. Within NSCLCs, adenocarcinomas and squamous cell carcinomas clustered with their respective histological types. Finally, we compared the methylation profiles of SCLC and NSCLC tumors and their respective cell lines (n = 44). In general, methylation frequencies were higher in tumor cell lines, but these differences were seldom significant. Thus, tumor cell lines appear to be suitable models to study aberrant DNA methylation. We conclude that SCLC, carcinoids, squamous cell carcinomas, and adenocarcinomas of the lung have unique profiles of aberrant methylation. Our findings should help us understand differences in the pathogenetic mechanisms of lung cancers.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8563, USA.
authors.forename: S
authors.initials: S
authors.lastname: Toyooka
authors.forename: K O
authors.initials: KO
authors.lastname: Toyooka
authors.forename: R
authors.initials: R
authors.lastname: Maruyama
authors.forename: A K
authors.initials: AK
authors.lastname: Virmani
authors.forename: L
authors.initials: L
authors.lastname: Girard
authors.forename: K
authors.initials: K
authors.lastname: Miyajima
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: Y
authors.initials: Y
authors.lastname: Ariyoshi
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Sugio
authors.forename: E
authors.initials: E
authors.lastname: Brambilla
authors.forename: M
authors.initials: M
authors.lastname: Gilcrease
authors.forename: J D
authors.initials: JD
authors.lastname: Minna
authors.forename: A 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; D001984:Bronchial Neoplasms / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D002276:Carcinoid Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins
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