TP53 mutations and 1p19q codeletion are the main molecular abnormalities recorded, respectively, in astrocytomas and oligodendrogliomas and in mixed gliomas.
All xenograft-producing gliomas harbored "lineage-defining" mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET, or N-MYC.
Combined loss of 1p and 19q was found in 38 of 56 (67.9%) and exhibited distinct concomitant deletion (P = 0.000). p53 overexpression was observed in 17 cases (30.3%), GFAP expression in 18 cases (32.1%), and p16 loss in 40 cases (74%) of oligodendrogliomas.
Considering the p53 labeling index and the apoptosis index together, this congenital oligodendroglioma may be regarded as potentially malignant despite the benign morphological features.
Detection of chromosome 1p/19q status combined with p53 protein immunohistochemistry might be beneficial to improve the pathological diagnosis and to determine the prognosis of patients with oligodendrogliomas.
DNA sequencing, performed in 84% of cases, revealed that TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but were infrequent (13%) in oligodendrogliomas.
Histologically, those oligoastrocytomas with TP53 mutations were more often astrocytoma-predominant, while those with chromosome 19q loss were more often oligodendroglioma-predominant.
IDH1 mutations were co-present with TP53 mutations in 63% of low-grade diffuse astrocytomas and with loss of heterozygosity 1p/19q in 64% of oligodendrogliomas; they were rare in pilocytic astrocytomas (10%) and primary glioblastomas (5%) and absent in ependymomas.
Importantly, IDH and TERTp co-occurred in 75% of 1p/19q intact, TP53 wild-type oligodendrogliomas, highlighting the potential of the co-mutations in assisting diagnosis of oligodendrogliomas in tumors with clear cell morphology and non-codeleted 1p/19q status.
In conclusion, evaluation of p53 protein accumulation reflected the clinical course of oligodendrogliomas better than the mere presence of TP53 gene mutations.
In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma.
In stratified analyses by ethnicity, source of controls, and glioma subtypes, the p53 codon 72 Arg/Pro polymorphism did not alter the risk for glioma in population-based, hospital-based, astrocytoma, and oligodendroglioma studies among Caucasian.
In this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16INK4a/p15INK4b and TP53/p14ARF/MDM2 pathways.
It was more frequent in astrocytomas and oligoastrocytomas (98/256, 38%) than oligodendrogliomas (28/327, 8.6%; p < .0001) or glioblastoma multiforme (30/210, 14.3%; p < .0001), tightly associated with TP53 mutation (69/71 vs. 20/79; p = 2 × 10(-16)), and mutually exclusive with 1p19q codeletion (1/156 vs. 249/556; p < .0001).
LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation.
LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas.
Moreover two additional genetic alterations are recorded in grade II and III gliomas: TP53 mutations that characterize astrocytomas and 1p19q codeletion (as the result of t(1;19)(q10;p10) translocation) recorded in oligodendrogliomas.
None of the astrocytomas including two pediatric cases showed this alteration (P < 0.05). p53 was expressed in 57.1% of astrocytomas (8/14), 33% of mixed oligoastrocytomas (3/9) and 10% of oligodendrogliomas (2/20).
Our previous and present data show alterations of at least one of TP53 promoter methylation, p14ARF promoter methylation, and TP53 mutations in 43/49 (88%) of low-grade astrocytomas, 15/18 (83%) of oligoastrocytomas, and 35/42 (83%) oligodendrogliomas, suggesting that disruption of the TP53/p14ARF pathway is frequent in all histological types of low-grade glioma.
Recently, mutations in IDH1 and IDH2 have been reported as an early and common genetic alteration in diffuse gliomas, being possibly followed by 1p/19q loss in oligodendrogliomas and TP53 mutations in astrocytomas.
Since accumulation of wild-type and mutant p53 are both associated with a poor prognosis, it is suggested to include immunohistochemical evaluation of p53 protein in routine diagnostics of oligodendrogliomas.