The clinical significance of molecular subtyping in glioblastoma
Maine Medical Center, Medical Education, Maine Medical Center Research Institute
Glioblastoma, Brain Neoplasms
Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Three molecular subtypes (Proneural; Classical; Mesenchymal) have been described based on gene expression, but the clinical significance remains unclear.
Methods: We studied 26 adult patients with GBM diagnosed between 2014 and 2019 at a single tertiary institution, for whom next generation sequencing and overall survival (OS) data were available. Genes were identified using a CLIA/CAP certified tumor panel.
Results: Among 26 patients, the median age was 67 years and 16 (62%) were male. 23 (88%) initial tumors were IDH wildtype and 10 (38%) were MGMT methylated. At diagnosis, 22 (85%) initiated standardized temozolomide chemoradiation and 15 (58%) received bevacizumab, Optune, or an experimental agent. We stratified patients into shorter (OS < 12 months, n=10) and longer (OS >12 months, n=16) survival groups. Patients with longer survival tended to be younger, with higher KPS, and more extensive surgical resection. PTEN variants were more frequent among patients with shorter survival (3/10, 30% versus 0/16, 0%, p = 0.046), as were CDKN2A deletions (5/10, 50% versus 1/16, 6%, p = 0.018); CDK4 amplifications were not informative. TP53 variants were more frequent among longer survivors (9/16, 56% versus 2/10, 20%, p = 0.11), as were PDGFRA variants (2/16, 12.5% versus 0/10, 0%, p = 0.51). Overall, there was no association between EGFR variants and OS (3/10, 30% versus 4/16, 25%, p=1.0), although EGFR vIII was only observed among longer survivors (3/16, 19% versus 0/10, 0% p = 0.26). NF1 mutations were infrequent, with 1 per survival group.
Conclusion: The Proneural subtype is associated with longer OS, mutations in TP53 and PDGFRA, and absent PTEN mutations. Our clinical data, although not always significant, were consistent with this. The Classical subtype is characterized by improved treatment sensitivity, EGFR variants, and CDKN2A deletions. Our data were not consistent with this. CDKN2A deletions were associated with shorter OS; EGFR vIII had potentially longer survival, and other EGFR variants had no relationship to OS. The Mesenchymal subtype (associated with NF1) could not be assessed due to low numbers.
Craig, Wendy; Bystrom, Rebecca; Rueter, Jens; and Lu-Emerson, Christine, "The clinical significance of molecular subtyping in glioblastoma" (2020). Costas T. Lambrew Research Retreat 2020. 37.