Giant cell glioblastoma is a distinctive subtype of glioma characterized by vulnerability to DNA damage

Abstract

Giant cell glioblastoma (GC-GBM) consists of large cells with pleomorphic nuclei. As a contrast to GC-GBM, we defined monotonous small GBM (MS-GBM) as GBM that consists of small cells with monotonous small nuclei, and compared the DNA damage as well as other pathological features. GC-GBM showed minimal invasion (< 2 mm) and focal sarcomatous areas. TERTp was wild type in GC-GBM but mutant in MS-GBM. OLIG2 expression was significantly higher in MS-GBM (P < 0.01) (77% in MS-GBM and 7% in GC-GBM). GC-GBM showed significantly higher DNA double-strand breaks (DSBs) compared with MS-GBM (P < 0.01) (76% in GC-GBM and 15% in MS-GBM). Nearly, all large cells in GC-GBM underwent DSBs. Thus, significant DSBs in GC-GBM might be induced by an innate lesser stemness characteristic and be followed by mitotic slippage, resulting in polyploidization and the large pleomorphic nuclei. We conclude that GC-GBM is a distinctive subtype of glioma characterized by its vulnerability to DNA damage and that wild-type TERTp and lower OLIG2 function might induce this feature. Notably, even large pleomorphic nuclei with severe DSBs demonstrated Ki67 positivity, which alerts pathologists to the interpretation of Ki67 positivity, because cells with large nuclei undergoing severe DSBs cannot be recognized as proliferating cells that contribute to tumor aggressiveness.

Near haploidization is a genomic hallmark which defines a molecular subgroup of giant cell glioblastoma

“… 7 , 8 Furthermore, certain copy number variations that occur more frequently in conventional glioblastoma, such as EGFR amplification and CDKN2A homozygous deletions, are much less frequent or absent in gcGBM. 1 , 5 , 6 While gcGBMs have been shown to be vulnerable to DNA damage due to a higher propensity for DNA double strand breaks, 9 the underlying molecular mechanisms unique to gcGBM remain unknown.…”

Pediatric Giant Cell Glioblastoma Presenting with Intracranial Dissemination at Diagnosis: A Case Report

“… 35 , 36) Furthermore, high CD133 expression is reported to be a useful predictor for GBM dissemination. 5 , 37) It was also reported that PTEN might be one of the suppressor factors in glioma cell dissemination, since PTEN mutation was significantly detected in malignant gliomas with meningeal gliomatosis. 38 , 39) However, PTEN mutation was not demonstrated in our case.…”

“…4) Giant cell glioblastoma (GCG) is an unusual GBM subtype defined by the latest classification of the World Health Organization. 5,6) GCG constitutes only 1% of adult GBMs and 3% of pediatric GBMs. 6,7) Although GCGs are diagnosed at relatively younger ages than the more common GBM, 7) they rarely develop in childhood.…”

In Vitro Glioblastoma Models: A Journey into the Third Dimension

“…These cells, reminiscent of neuronal subtype, often display specific neuronal marker expression such as synaptophysin and MYC amplification. In GBM specimens, multinucleate giant cells and other packed rhomboid-like cells with abundant cytoplasm, probably derived from epithelium, have also been found [ 17 ]. The limitations of the classical histopathological diagnosis of GBM tumors, mainly due to broad intracellular variability, could be partially overcome by the aid of DNA methylation-based classification.…”

“…Many of the invasive mechanisms utilized by GSC were found to mimic NSC motility in white matter and blood vessels [ 16 ]. Interestingly, GBM tumors display an infiltrative leading edge that disseminates into healthy tissue and orthotopic xenograft tumors derived from human GSC mimic this invasive behavior displaying GSC concentrated at the tumor edge [ 17 ]. The reported GSC resistance to radiation and conventional chemotherapeutics, including temozolomide, are currently ascribed to a number of factors: signaling pathways involved in tumor cell contacts and tumor–stroma interactions, including the Wnt/β-catenin, the Notch, PI3K, and JAK/STAT pathways [ 17 ].…”