In:
Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2021-12)
Kurzfassung:
Giant cell glioblastoma (GC-GBM) is a rare variant of IDH -wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH -wt and IDH -mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30–49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content ( 〈 50% or ≥ 50%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival ( P = 0.004 ) . Sixteen (41%) cases had a TMB 〉 10 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type ( P 〈 0.0001; P = 0.0003; P 〈 0.0001) and 26 IDH -mutant ( P 〈 0.0001; P = 0.0227; P 〈 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.
Materialart:
Online-Ressource
ISSN:
2051-5960
DOI:
10.1186/s40478-021-01304-5
Sprache:
Englisch
Verlag:
Springer Science and Business Media LLC
Publikationsdatum:
2021
ZDB Id:
2715589-4
