학술논문
TP53, ATRX alterations, and low tumor mutation load feature IDH-wildtype giant cell glioblastoma despite exceptional ultra-mutated tumors.
Document Type
Academic Journal
Author
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.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 101755003 Publication Model: eCollection Cited Medium: Internet ISSN: 2632-2498 (Electronic) Linking ISSN: 26322498 NLM ISO Abbreviation: Neurooncol Adv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
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.)
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.)