Genomic profiling of newly diagnosed glioblastoma patients and its potential for clinical utility – a prospective, translational study

Abstract

Glioblastoma (GBM) is an incurable brain tumor for which new treatment strategies are urgently needed. Next-generation sequencing of GBM has most often been performed retrospectively and on archival tissue from both diagnostic and relapse surgeries with limited knowledge of clinical information, including treatment given. We sought to investigate the genomic composition prospectively in treatment-na€ ıve patients, searched for possible targetable aberrations, and investigated for prognostic and/or predictive factors. A total of 108 newly diagnosed GBM patients were included. Clinical information, progression-free survival, and overall survival (OS) were noted. Tissues were analyzed by whole-exome sequencing, single nucleotide polymorphism (SNP) and transcriptome arrays, and RNA sequencing; assessed for mutations, fusions, tumor mutational burden (TMB), and chromosomal instability (CI); and classified into GBM subgroups. Each genomic report was discussed at a multidisciplinary tumor board meeting to evaluate for matching trials. From 111 consecutive patients, 97.3% accepted inclusion in this study. Eighty-six (77%) were treated with radiation therapy/temozolomide (TMZ) and adjuvant TMZ. One NTRK2 and three FGFR3-TACC3 fusions were identified. Copy number alterations in GRB2 and SMYD4 were significantly correlated with worse median OS together with known clinical variables like age, performance status, steroid dose, and O6-methyl-guanine-DNA-methyl-transferase status. Patients with CI-median or TMB-high had significantly worse median OS compared to CI-low/high or TMB-low/median. In conclusion, performing genomic profiling at diagnosis enables evaluation of genomic-driven therapy at the first progression. Furthermore, TMB-high or CI-median patients had worse median OS, which can support the possibility of offering experimental treatment already at the first line for this group.

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study

“…We could not evaluate MGMT promoter methylation status and IT in our study due to the low number of patients and the low incidence of MGMT promoter methylation of 20%. This is lower than the 40-50% that has been reported in other large studies [26,41,42], including the CGC cohort, that our patients were included from. The CGC had an incidence of MGMT promoter methylation of 44.4%, and we explain the lower incidence in the present study by the low number of patients.…”

“…We could not evaluate MGMT promotor methylation status and IT in our study due to the low number of patients and the low incidence of MGMT promotor methylation of 20%. This is lower than the 40-50% that has been reported in other large studies [41,42,26], including the CGC cohort, that our patients were included from.…”

Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History

“…Along with inter-tumor heterogeneity, intra-tumor heterogeneity represents a pivotal area of investigation of GB. Several genomic studies have highlighted this heterogeneity by demonstrating a difference in somatic alterations, expression subtypes, and epigenetic modifications between different GBs and within the same tumor [ 13 , 27 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Other studies have attempted to go even further by specifically examining regional heterogeneity between multiple sectors of the same primary GB, sometimes also coupled to relapsed tumor, through whole exome and transcriptome sequencing [ 2 , 3 , 41 , 42 , 43 ].…”

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

“…The recruitment of SOS to the plasma membrane by Grb2 is required for the activation of Ras, which in turn sets in motion MAPK/ERK and PI3K/Akt signaling for gene expression and cell proliferation [ 129 ] ( Figure 3 A). Given its involvement in oncogenic signaling and correlation with poor patient prognosis [ 130 , 131 , 132 ], many anti-Grb2 therapeutic strategies are under development. Antagonists that bind to the Grb2′s SH2 domain, such as NHD2–15, have shown to inhibit the proliferation and metabolism of human leukemia cells in pre-clinical studies [ 133 , 134 ].…”