Abstract
Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
Highlights
Oligodendroglioma is defined as a diffusely infiltrating glioma with an IDH mutation and codeletion of chromosomal arms 1p and 19q [23]
Most of the recurrent tumors with sarcomatous features showed elevated scores for “IDH glioma, subclass high-grade astrocytoma“ and some samples reached a matching score (> 0.9) for this reference set. Comparing these methylation profiles with an extensive cohort of more than 75,000 tumors from various entities, we found the profile of sarcomatous tumors to be highly distinctive while the profiles of the primary oligodendrogliomas fell together with conventional oligodendrogliomas
In restricted analyses using t-distributed stochastic neighbor embedding (t-SNE)-analysis we confirmed the distinctiveness of the DNA methylation profile of the sarcomatous tumors which were clearly separated from their primary tumor manifestations and from conventional oligodendrogliomas, as well as from IDH-wildtype glioblastomas, from high- and low-grade supra- and infratentorial IDH-mutant astrocytomas, and from primary mismatch repair deficient IDH-mutant astrocytomas (PMMRDIA) (Fig. 1, Supplementary tables, online resource)
Summary
Oligodendroglioma is defined as a diffusely infiltrating glioma with an IDH mutation and codeletion of chromosomal arms 1p and 19q [23]. In contrast to IDH-mutant astrocytomas, oligodendrogliomas typically show retained expression of ATRX and no p53 accumulation, corresponding to an absence of mutations in these genes [33, 36]. Oligodendrogliomas exhibit a typical DNA methylation profile with a high degree of global DNA methylation [11]. Oligodendrogliomas were shown to display a unique histone-modification pattern with a reduced trimethylation of lysin 27 of histone H3 (H3K27me3) in comparison to IDH-mutant astrocytomas [17, 18, 28]. Oligodendrogliomas are associated with the most favorable prognosis among all diffuse gliomas in adults with a median overall survival of more than 14 years for patients receiving combined radio-chemotherapy [44]
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