title: Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors.
abstract: Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP- tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP-), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP- subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP-) prognosis. Furthermore, transcriptomic analyses revealed CIMP-specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs.
authors.affiliation: Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, Avda. Barber 30, 45004, Toledo, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Mur
authors.forename: Manuela
authors.initials: M
authors.lastname: Mollejo
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Ruano
authors.forename: Ángel Rodríguez
authors.initials: ÁR
authors.lastname: de Lope
authors.forename: Concepción
authors.initials: C
authors.lastname: Fiaño
authors.forename: Juan Fernando
authors.initials: JF
authors.lastname: García
authors.forename: Javier S
authors.initials: JS
authors.lastname: Castresana
authors.forename: Aurelio
authors.initials: A
authors.lastname: Hernández-Laín
authors.forename: Juan A
authors.initials: JA
authors.lastname: Rey
authors.forename: Bárbara
authors.initials: B
authors.lastname: Meléndez
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D019175:DNA Methylation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D009837:Oligodendroglioma / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human