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Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment

Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH-wt GBMs from adults &l...

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Autores principales: Barresi, Valeria, Simbolo, Michele, Mafficini, Andrea, Piredda, Maria Liliana, Caffo, Maria, Cardali, Salvatore Massimiliano, Germanò, Antonino, Cingarlini, Sara, Ghimenton, Claudio, Scarpa, Aldo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770353/
https://www.ncbi.nlm.nih.gov/pubmed/31480372
http://dx.doi.org/10.3390/cancers11091279
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author Barresi, Valeria
Simbolo, Michele
Mafficini, Andrea
Piredda, Maria Liliana
Caffo, Maria
Cardali, Salvatore Massimiliano
Germanò, Antonino
Cingarlini, Sara
Ghimenton, Claudio
Scarpa, Aldo
author_facet Barresi, Valeria
Simbolo, Michele
Mafficini, Andrea
Piredda, Maria Liliana
Caffo, Maria
Cardali, Salvatore Massimiliano
Germanò, Antonino
Cingarlini, Sara
Ghimenton, Claudio
Scarpa, Aldo
author_sort Barresi, Valeria
collection PubMed
description Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel. Results: Eight (50%) IDH-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (p = 0.04). Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy.
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spelling pubmed-67703532019-10-30 Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment Barresi, Valeria Simbolo, Michele Mafficini, Andrea Piredda, Maria Liliana Caffo, Maria Cardali, Salvatore Massimiliano Germanò, Antonino Cingarlini, Sara Ghimenton, Claudio Scarpa, Aldo Cancers (Basel) Article Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutants and IDH wild-types (IDH-wt). This study aimed at identifying the mutational assets of IDH-wt GBMs in patients aged 18–54 years for which limited data are available. Methods: Sixteen IDH-wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel. Results: Eight (50%) IDH-wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs (p = 0.04). Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy. MDPI 2019-08-30 /pmc/articles/PMC6770353/ /pubmed/31480372 http://dx.doi.org/10.3390/cancers11091279 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barresi, Valeria
Simbolo, Michele
Mafficini, Andrea
Piredda, Maria Liliana
Caffo, Maria
Cardali, Salvatore Massimiliano
Germanò, Antonino
Cingarlini, Sara
Ghimenton, Claudio
Scarpa, Aldo
Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title_full Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title_fullStr Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title_full_unstemmed Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title_short Ultra-Mutation in IDH Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment
title_sort ultra-mutation in idh wild-type glioblastomas of patients younger than 55 years is associated with defective mismatch repair, microsatellite instability, and giant cell enrichment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770353/
https://www.ncbi.nlm.nih.gov/pubmed/31480372
http://dx.doi.org/10.3390/cancers11091279
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