Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches

Abstract

Glioblastoma is the most common primary adult brain tumour, and despite optimal treatment, the median survival is 12–15 months. Patients with matched recurrent glioblastomas were investigated to try to find actionable mutations. Tumours were profiled using a validated DNA-based gene panel. Copy number variations (CNVs) and single nucleotide variants (SNVs) were examined, and potentially pathogenic variants and clinically actionable mutations were identified. The results revealed that glioblastomas were IDH-wildtype (IDHWT; n = 38) and IDH-mutant (IDHMUT; n = 3). SNVs in TSC2, MSH6, TP53, CREBBP, and IDH1 were variants of unknown significance (VUS) that were predicted to be pathogenic in both subtypes. IDHWT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, WNT, SHH, NOTCH, Rb, and G-protein pathways. Many tumours had BRCA1/2 (18%) variants, including confirmed somatic mutations in haemangioblastoma. IDHWT recurrent tumours had fewer pathways impacted (RTK/Ras/PI(3)K, p53, WNT, and G-protein) and CNV gains (BRCA2, GNAS, and EGFR) and losses (TERT and SMARCA4). IDHMUT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, and WNT pathways. VUS in KLK1 was possibly pathogenic in IDHMUT. Recurrent tumours also had fewer pathways (p53, WNT, and G-protein) impacted by genetic alterations. Public datasets (TCGA and GDC) confirmed the clinical significance of findings in both subtypes. Overall in this cohort, potentially actionable variation was most often identified in EGFR, PTEN, BRCA1/2, and ATM. This study underlines the need for detailed molecular profiling to identify individual GBM patients who may be eligible for novel treatment approaches. This information is also crucial for patient recruitment to clinical trials.

A Custom DNA-Based NGS Panel for the Molecular Characterization of Patients With Diffuse Gliomas: Diagnostic and Therapeutic Applications

“…Hence, looking at the identified alterations, sequencing data indicate an actionability rate of 37% (22/60) in our cohort. These results are in line with previous evidence in different cohorts of glioma patients, which report a rate of actionability ranging from 18 to 55% ( 58 , 59 ). Several ongoing clinical trials investigating targeted treatments directed against actionable genetic alterations in newly diagnosed or recurrent GBM are reported in Table 2 .…”

Aberrations of Genomic Imprinting in Glioblastoma Formation

“…Due to its frequency and lethality, several studies have been carried out in order to characterize different human GBM subtypes based on genome and transcriptome changes. For example, the epidermal growth factor receptor (EGFR) is altered in almost 50% of GBM and represents one of the most promising therapeutic targets (50). Other mutations affecting TP53, PTEN, RB1, ERBB2, PIK3R1 or PIK3CA pathways have been identified in different GBM patients (51).…”