TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors.

Autor:	Cantero D; Department of Pathology (Neuropathology) and Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain., Mollejo M; Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain., Sepúlveda JM; Department of Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain., D'Haene N; Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium., Gutiérrez-Guamán MJ; Department of Pathology (Neuropathology) and Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain., Rodríguez de Lope Á; Department of Neurosurgery, Virgen de la Salud Hospital, Toledo, Spain., Fiaño C; Department of Pathology, Alvaro Cunqueiro Hospital, Vigo, Spain., Castresana JS; Department of Biochemistry and Genetics, University of Navarra School of Sciences, Pamplona, Spain., Lebrun L; Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium., Rey JA; IdiPaz Research Unit, La Paz University Hospital, Madrid, Spain., Salmon I; Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium., Meléndez B; Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain.; Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium., Hernández-Laín A; Department of Pathology (Neuropathology) and Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2020 Jan 24; Vol. 2 (1), pp. vdz059. Date of Electronic Publication: 2020 Jan 24 (Print Publication: 2020).
DOI:	10.1093/noajnl/vdz059
Abstrakt:	Background: Giant cell glioblastoma (gcGBM) is a rare morphological variant of IDH-wildtype (IDHwt) GBM that occurs in young adults and have a slightly better prognosis than "classic" IDHwt GBM. Methods: We studied 36 GBMs, 14 with a histopathological diagnosis of gcGBM and 22 with a giant cell component. We analyzed the genetic profile of the most frequently mutated genes in gliomas and assessed the tumor mutation load (TML) by gene-targeted next-generation sequencing. We validated our findings using The Cancer Genome Atlas (TCGA) data. Results: p53 was altered by gene mutation or protein overexpression in all cases, while driver IDH1 , IDH2 , BRAF , or H3F3A mutations were infrequent or absent. Compared to IDHwt GBMs, gcGBMs had a significant higher frequency of TP53 , ATRX , RB1 , and NF1 mutations, while lower frequency of EGFR amplification, CDKN2A deletion, and TERT promoter mutation. Almost all tumors had low TML values. The high TML observed in only 2 tumors was consistent with POLE and MSH2 mutations. In the histopathological review of TCGA IDHwt, TP53 -mutant tumors identified giant cells in 37% of the cases. Considering our series and that of the TCGA, patients with TP53 -mutant gcGBMs had better overall survival than those with TP53wt GBMs (log-rank test, P  < .002). Conclusions: gcGBMs have molecular features that contrast to "classic" IDHwt GBMs: unusually frequent ATRX mutations and few EGFR amplifications and CDKN2A deletions, especially in tumors with a high number of giant cells. TML is frequently low, although exceptional high TML suggests a potential for immune checkpoint therapy in some cases, which may be relevant for personalized medicine. (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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