IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation

Abstract

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.

Keywords: Giant cell; Glioblastoma; Mismatch repair; RB1; Tumor mutational burden.

Fig. 1

Histological aspect of giant cell enriched glioblastomas. In the upper image is a glioblastoma classified as having ≥ 50% giant cells, while in the lower is a glioblastoma classified as having 30–49% giant cells

Fig. 2

Clinical-pathological features, gene alterations and MMR status of 39 giant cells enriched GBMs. The matrix shows for each case the tumor mutational burden, mutational signature, gene alterations, immunohistochemical analysis of genes involved in DNA mismatch repair (MMR IHC) and the presence of microsatellite instability as assessed by MSI-PCR. Samples are sorted by the percentage of giant cells (30–49%; ≥ 50%) and then by ID number. Genes are grouped by pathway and then by frequencies of alterations and alphabetical order

Fig. 3

Immunostaining of MMR proteins in a GBM enriched in GCs. This case showed the loss of MSH2 and MSH6 in all tumor cells (60GL), albeit having stable microsatellites

Fig. 4

Impact of EGFR amplification and hypermutation on clinical outcome. The overall survival of patients with glioblastomas enriched in giant cells and harboring EGFR amplification (P = 0.004), or TMB < 10 mutations/Mb (P = 0.0263) was significantly shorter than that of patients with giant cells enriched glioblastoma lacking EGFR amplification or having TMB ≥ 10 mutations/Mb

Fig. 5

Comparison in the OS of patients with GBMs enriched in giant cells and TCGA GBMs IDH-wt or IDH-mutant. Patients with giant cells enriched GBM had an OS significantly shorter than patients with IDH-mutant GBM (P = 0.0127), but not significantly different from that of patients with IDH-wt GBM (P = 0.187). Patients with giant cell enriched GBM and younger than 55 years had an OS significantly longer than patients with IDH-wt GBM and similar to patients with IDH-mutant GBM, while those of 55 years or older had an OS length similar to IDH-wt GBM and significantly shorter than IDH-mutant GBM (P = 0.0013)