Genetic Alterations in Gliosarcoma and Giant Cell Glioblastoma

Abstract

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas.

Gliosarcoma with primitive neuronal, chondroid, osteoid and ependymal elements

“…Yao et al reported a case of gliosarcoma with primitive neuronal, osseous, cartilage and adipocyte differentiation. 5 In our study, direct DNA sequencing revealed TERT promoter mutation and wild-type IDH, and immunohistochemical staining showed ATRX expression. Gliosarcoma is considered to be a rare histological variant of primary glioblastoma because of its clinical behavior and lack of a less malignant precursor lesion.…”

“…21 In our study, the ependymal component appeared as small nests, containing the formation of ependymal lining and tubules, and mitotic activity was very low. 5 Nuclear ATRX expression was observed in all 17 gliosarcomas. 22 In their study, the tumor showed various mesenchymal differentiation, and formation of Homer-Wright rosettes within the primitive neuronal component.…”

Gliosarcoma with Primary Skull Base Invasion

“…Notwithstanding, limited but stepwise discoveries are optimizing treatment protocols, as in the specific example of GS frequently lacking the overexpression of epidermal growth factor receptor (EGFR) seen in IDH-wildtype GB, which challenges the utility of anti-EGFR modalities in GS treatment [19]. Still other studies of the molecular alterations in GS have found a high incidence of TP53 mutations, as well as rare EGFR and IDH mutations [20, 21]. Further study of the molecular mechanisms underlying GS development and spread is required to better understand the natural history and optimal treatment of these lethal tumors.…”

Primary Gliosarcoma of the Optic Nerve: A Unique Adult Optic Pathway Glioma

“…21 Gene level mutations within gliosarcoma include CDKN2A deletion, TP53 mutation, and TERT promoter mutations. Cytogenetic copy number alterations include chromosome 10q loss and polysomy chromosome 7, although unlike glioblastoma the latter is not usually associated with epidermal growth factor receptor amplification.…”

“…Cytogenetic copy number alterations include chromosome 10q loss and polysomy chromosome 7, although unlike glioblastoma the latter is not usually associated with epidermal growth factor receptor amplification. 15,21 In addition to these genetic changes, gliosarcoma rarely (11.5%) shows the epigenetic change of MGMT promoter methylation. 15,21 Gliosarcoma generally lacks mutations in the genes associated with lower-grade diffuse gliomas, including IDH1/2 and ATRX.…”