LONGITUDINAL WGS AND WES OF GLIOBLASTOMA REVEAL POTENTIAL PATHWAY TARGETS

Abstract

Abstract AIMS Treating glioblastoma (GBM) patients remains challenging as the current regimens result in the recurrence of a treatment-resistant and fatal tumour. We aimed to identify candidate pathways that, when mutated, confer treatment resistance. Targeting these pathways may improve GBM treatment effcacy. METHOD We performed WGS and WES on 46 matched primary and recurrent GBMs (the Discovery cohort) and used data from additional 188 samples from the Glioma Longitudinal AnalySiS consortium (GLASS: Validation cohort). First, we identified variants that were shared between primary and recurrent GBMs. We then highlighted those most likely to be involved in treatment resistance, i.e. with: 1) low allele fractions at primary and high in recurrent, 2) high allele fractions in both primary and recurrent. Finally, we performed enrichment analysis using these variants to identify pathways that may drive clonal expansion from primary to recurrent. RESULTS The analysis of variants that increased from primary to recurrent revealed three significant disrupted path- ways in the Discovery cohort; “Activation of BH3 Only Proteins” (Reactome), “P53 pathway” (BIOCARTA), and “Intrinsic Pathway for Apoptosis” (REACTOME). Six distinct genes caused the aberration of these pathways. The same pathways were significantly disrupted in the recurrent variants group of the Validation cohort but were solely caused by TP53 alterations. In the Discovery cohort, “Activation of BH3 Only Proteins” was altered in 24% of the patients. CONCLUSIONS Investigating how pathway mutations alter in GBM through treatment has led to identifying potential candidate mechanisms to be further studied in the laboratory.