title: The hypermethylation of the O6-methylguanine-DNA methyltransferase gene promoter in gliomas--correlation with array comparative genome hybridization results and IDH1 mutation.
abstract: The use of molecular markers in the diagnostics of gliomas aids histopathological diagnosis and allows their further classification into clinically significant subgroups. The aim of this study was to characterize the methylation pattern of the O(6) -methylguanine-DNA methyltransferase (MGMT) promoter, gene copy number aberrations, and isocitrate dehydrogenase I (IDH1) mutation in gliomas. We studied 51 gliomas (15 oligodendrogliomas, 18 oligoastrocytomas, 3 astrocytomas, and 15 glioblastomas) by pyrosequencing, array comparative genome hybridization (CGH), and immunohistochemistry. MGMT hypermethylation was observed in 100% of oligoastrocytomas, 93% of oligodendrogliomas, and 47% of glioblastomas. The most frequently altered chromosomal regions were deletions of 1p31.1/21.1-22.2 and 19q13.3qter in oligodendroglial tumors, and losses of 9p21.3, 10q25.3qter, and 10q26.13-26.2 in glioblastomas. Deletions on 9p and 10q, and gain of 7p were associated with the unmethylated MGMT phenotype, whereas deletion of 19q and oligodendroglial morphology was associated with MGMT hypermethylation. IDH1 mutation showed positive correlation with MGMT hypermethylation and loss of 1p/19q. Our results suggest that MGMT promoter methylation, analyzed by pyrosequencing, is a frequent event in oligodendroglial tumors, and it correlates with IDH1 mutation and 19q loss in gliomas. Pyrosequencing proved a good method for assessing the degree of MGMT methylation in formalin-fixed paraffin-embedded glioma samples. However, further studies are needed to confirm a clinically relevant cut-off point for MGMT methylation in gliomas.
authors.affiliation: Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Katja
authors.initials: K
authors.lastname: Tuononen
authors.forename: Olli
authors.initials: O
authors.lastname: Tynninen
authors.forename: Virinder Kaur
authors.initials: VK
authors.lastname: Sarhadi
authors.forename: Anne
authors.initials: A
authors.lastname: Tyybäkinoja
authors.forename: Mikael
authors.initials: M
authors.lastname: Lindlöf
authors.forename: Miia
authors.initials: M
authors.lastname: Antikainen
authors.forename: Juha
authors.initials: J
authors.lastname: Näpänkangas
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
authors.forename: Hanna
authors.initials: H
authors.lastname: Mäenpää
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
mesh_terms: D000328:Adult; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D005910:Glioma / Q000145:classification / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D055815:Young Adult
chemical_list: D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D019853:O(6)-Methylguanine-DNA Methyltransferase