BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

Abstract

Epithelioid glioblastoma (E-GBM) is a rare aggressive variant of IDH-wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. Approximately 50% of E-GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E-GBM are recognized as primary/de novo lesions; however, several E-GBM with co- or pre-existing lower-grade lesions have been reported. To better understand associations between E-GBM and the lower-grade lesions, we undertook a histological and molecular analysis of 14 E-GBM, 10 of which exhibited lower-grade glioma-like components (8 E-GBM with co-existing diffuse glioma-like components, 1 E-GBM with a co-existing PXA-like component and 1 E-GBM with a pre-existing PXA). Molecular results demonstrated that the prevalence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions in E-GBM were 13/14 (93%), 10/14 (71%) and 11/14 (79%), respectively, and concurrent BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions were observed in 7/14 (50%) of E-GBM. These alterations were also frequently seen in the lower-grade lesions irrespective of the histology. Genetic analysis including array comparative genomic hybridization performed for 5 E-GBM with co- and pre-existing lower-grade components revealed that all molecular changes found in the lower-grade components were also observed in the E-GBM components, and additional changes were detected in the E-GBM components. In conclusion, E-GBM frequently exhibit BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions and these alterations tend to coexist in E-GBM. Taken together with the facts that only one PXA preceded E-GBM among these lower-grade lesions, and that co-occurrence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions have been reported to be rare in conventional lower-grade diffuse gliomas, the diffuse glioma-like components may be distinct infiltrative components of E-GBM, reflecting intratumoral heterogeneity.

A rare case of BRAF V600E‐mutated epithelioid glioblastoma with a sarcomatous component

“…Epithelioid glioblastoma is a rare aggressive variant of IDH‐wild type GBM that was newly recognized in the 2016 World Health Organization (WHO) classification . Typically, E‐GBM is predominantly composed of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm . In the case described here, the epithelioid component was not dominant and coexisted with a sarcomatous component.…”

“…Intratumoral heterogeneity of genomic alterations has been reported in E‐GBM harboring BRAF V600E . TERT promoter mutations, CDKN2A/B homozygous deletion and BRAF V600E are frequently present in E‐GBM and tend to coexist . Nobusawa et al .…”

“…Both sarcomatous and epithelioid components harbored a BRAF thymidine to adenosine transversion (T1799A), which results in the V600E mutation, as revealed by direct DNA sequencing (Fig. ) and homozygous deletion of cyclin‐dependent kinase inhibitor 2A/B (CDKN2A/B), as detected by multiplex ligation‐dependent probe amplification analysis . IDH1/2, fibroblast growth factor receptor 1 (FGFR1), histone H3.3 (H3F3A) and telomerase reverse transcriptase (TERT) promoter mutations were not detected by direct DNA sequencing.…”

“…4) and homozygous deletion of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B), as detected by multiplex ligation-dependent probe amplification analysis. 3 (TERT) promoter mutations were not detected by direct DNA sequencing. There was no discrepancy between the genetic profiles of the gliomatous and sarcomatous components.…”

Histological and genetic analysis of anaplastic pleomorphic xanthoastrocytoma suspected of malignant progression over a 12‐year clinical course

“…Although the BRAF V600E mutation is rarely found in GBM, it has been identified at a relatively high frequency (54%) in E‐GBM . E‐GBM frequently exhibits not only BRAF V600E but also TERT promoter mutation and CDKN2A/B homozygous deletions . E‐GBM is similar to anaplastic PXA which exhibits epithelioid features.…”