Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors

• Published in: Acta neuropathologica Vol. 126; no. 2; pp. 277 - 289
• Main Authors: Mur, Pilar, Mollejo, Manuela, Ruano, Yolanda, de Lope, Ángel Rodríguez, Fiaño, Concepción, García, Juan Fernando, Castresana, Javier S., Hernández-Laín, Aurelio, Rey, Juan A., Meléndez, Bárbara
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2013; Springer; Springer Nature B.V
• Subjects: Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain research; Brain tumors; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Dehydrogenases; DNA methylation; DNA Methylation - genetics; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genome-Wide Association Study; Genomes; Genomics; Gliomas; Humans; Isocitrate Dehydrogenase - genetics; Kaplan-Meier Estimate; Medical prognosis; Medicine; Medicine & Public Health; Methylation; Mutation; Neurosciences; Oligodendroglioma - genetics; Oligodendroglioma - mortality; Original Paper; Pathology; Prognosis; Transcriptome; Tumor Suppressor Protein p53 - genetics; Tumors; Madrid Spain; Spain; mutation; Oligodendroglial tumors; Methylation array; 1p/19q codeletion; CIMP
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-013-1130-9

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.