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.

Impact on prognosis of the regional distribution of MGMT methylation with respect to the CpG island methylator phenotype and age in glioma patients

“…Patients, samples and external datasets DNA methylation profiles through the HM-450K platform were established for 46 glioma tumor samples and five non-tumoral brain tissue (NTBT) samples used as controls [7]. Tumors included 33 samples diagnosed as OD (19 WHO grade II, 14 WHO grade III) and 13 as OA (5 WHO grade II and 8 WHO grade III).…”

“…[6,7]. On the other hand, MGMT encodes a nuclear repair enzyme (alkyltransferase) that removes O(6)-alkylating binds of guanine and helps maintain the integrity of DNA from normal cells.…”

Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers

“…The pattern of CpG methylation appears to be non-random and tumour type-specific, hence G-CIMP for glioma [52]. It has also been shown that the G-CIMP profiles are different among the IDH-mutated tumours depending on the make-up of the complete genotype, i.e., astrocytomas typically having TP53/ATRX mutations (see below) and oligodendroglioma with total 1p/19q co-deletion [92,158]. Although the targets for methylation that function as driver genes for glioma are yet to be defined [96], it is widely believed that silencing of critical gene(s) by G-CIMP is the main mechanism in the pathogenesis of IDH-mutated tumours.…”

Advances in the Treatment of Primary Brain Tumors: The Realm of Immunotherapy

“…Point mutations in isocitrate dehydrogenase (IDH) 1 and 2 have been associated with improved prognosis compared to patients with wild-type IDH [10]. The combined loss of chromosomal arms 1p and 19q has been shown to occur in oligodendrogliomas and oligoastrocytomas [11], but it is associated with better response to chemotherapy and radiation therapy leading to prolonged progression-free and overall survival [12,13]. Epidermal growth factor receptor (EGFR) is a cell surface receptor involved in cell proliferation.…”