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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.


ABSTRACT: 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.

SUBMITTER: Barresi V 

PROVIDER: S-EPMC6770353 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Barresi Valeria V   Simbolo Michele M   Mafficini Andrea A   Piredda Maria Liliana ML   Caffo Maria M   Cardali Salvatore Massimiliano SM   Germanò Antonino A   Cingarlini Sara S   Ghimenton Claudio C   Scarpa Aldo A  

Cancers 20190830 9


<h4>Background</h4>Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (<i>IDH</i>) mutants and IDH wild-types (<i>IDH</i>-wt). This study aimed at identifying the mutational assets of <i>IDH</i>-wt GBMs in patients aged 18-54 years for which limited data are available.<h4>Methods</h4>Sixteen <i>IDH</i>-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.<h4>Results</h  ...[more]

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