title: Inactivation of O6-methylguanine-DNA methyltransferase in human lung adenocarcinoma relates to high-grade histology and worse prognosis among smokers.
abstract: To evaluate the significance of O6-methylguanine-DNA methyltransferase (MGMT) activity in the development of human lung adenocarcinoma (AC), we investigated promoter hypermethylation of the MGMT gene by methylation-specific PCR, and the expression of MGMT protein by immunohistochemistry in relation to smoking history of the patients. In total, 31 of 87 AC patients (35.5%) showed hypermethylation of the MGMT gene, and no significant difference was observed between smokers (37.3%) and non-smokers (33.3%). However, hypermethylation of the MGMT gene increased in parallel with lesser differentiation grade of tumors among smokers (well, 16.7%; moderately, 42.1%; poorly, 57.1%; P = 0.022), although this trend was not observed among non-smokers. Almost all the tumors with promoter hypermethylation of the MGMT gene showed consistently negative MGMT staining by immunohistochemistry. When the prognosis of stage-I patients was compared among smokers, it was apparent that the prognosis of patients with inactivated MGMT was worse than that of MGMT-positive patients (P = 0.036). Such differences in the prognoses were not observed among non-smokers. In conclusion, MGMT inactivation is related to the differentiation grade and the prognosis of lung AC patients among smokers. Although further studies are required, we speculate that smoking may induce hypermethylation, not only of the MGMT gene, but also of other important tumor suppressor genes.
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama 236-0004, Japan. hirohaya@med.yokohama-cu.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nagai
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kanisawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kitamura
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase