Department of Diagnostics and Public Health, Section of Anatomic Pathology, University of Verona, Verona, Italy.
Unit of Anatomic Pathology, Catholic University of Sacred Hearth, Rome, Italy.
Acta Neuropathol Commun. 2021 Dec 24;9(1):200. doi: 10.1186/s40478-021-01304-5.
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.
巨细胞胶质母细胞瘤（GC-GBM）是一种罕见的 IDH-wt GBM 变体，组织学上以存在大量多核巨细胞为特征，分子上被认为是 IDH-wt 和 IDH-突变型 GBM 之间的杂交体。由于缺乏对这种诊断所需的巨细胞百分比的客观定义，可能导致这种变体缺乏明确的分子特征。本研究旨在阐明 GC-GBM 的分子特征，通过探索 458 个与癌症相关基因的突变和拷贝数变化、肿瘤突变负担（TMB）和微卫星不稳定性（MSI），对 39 例胶质母细胞瘤进行分析，这些肿瘤根据巨细胞含量分为 30-49%（15 例）或≥50%（24 例）。在本系列中，遗传改变的类型和发生率与巨细胞含量无关（<50%或≥50%）。大多数病例（82%和 51.2%）存在 TP53/MDM2 和 PTEN/PI3K 通路的损伤，但相当一部分病例还具有 TERT 启动子突变（61.5%）和 RB1（25.6%）或 NF1（25.6%）改变。在 18%的病例中检测到 EGFR 扩增，与总生存期缩短相关（P=0.004）。16 例（41%）有 TMB>10 mut/Mb，其中 2 例（5%）存在 MSI，1 例存在 POLE 突变。与 TCGA PanCancer Atlas 队列中的 567 例 IDH 野生型（P<0.0001；P=0.0003；P<0.0001）和 26 例 IDH-突变型（P<0.0001；P=0.0227；P<0.0001）胶质母细胞瘤相比，RB1 和 NF1 改变和 TMB 计数的频率显著更高。这些发现表明，至少有 30%巨细胞的 GBM 的分子特征主要表现为 TP53/MDM2 和 PTEN/PI3K 通路的损伤，此外还具有频繁的 RB1 改变和高突变率，并在侵袭性更强的病例中出现 EGFR 扩增。高频率的高突变病例提示 GC-GBM 可能是免疫检查点抑制剂临床试验的候选者。
