Genomic profiling of IDH-wildtype and IDH-mutant initial and matched recurrent glioblastomas reveals clinically actionable mutations (e.g. BRCA1/2) and resistance signatures

McInerney, C E; Ellis, H P; Schrimpf, D; Sahm, F; Stupnikov, A; Wadsley, M; Wragg, C; White, P; Prise, K M; McArt, D G; Kurian, K M

Abstract

Abstract:
Background: Glioblastomas account for 90% of all adult brain tumours. Patient survival remains low because treatments are ineffective against this lethal disease. Understanding the genes and pathways altered in subtypes is necessary for therapeutic intervention.

Material and Methods: Tumours from 41 patients, 8 with matched initial and recurrent glioblastomas were genomically profiled.

Some 130 clinically relevant neuro-oncology genes were assessed using an NGS-based diagnostic panel. Single nucleotide variants (SNVs), copy number variations (CNVs) and potentially clinically actionable mutations were described for initial and recurrent IDH-wildtype (n=38) and IDH-mutant glioblastomas (n=3).

Results: The mutational landscape revealed discrete differences and similarities between subtypes. TSC2, MSH6, TP53, CREBBP and IDH1 were co-mutated and putatively pathogenic in both subtypes, suggesting they are driver mutations.

Recurrent tumours were not hypermutated and matched analysis revealed inter-tumour heterogeneity.

IDH-wildtype: SNVs (145) impacted 55 genes in the RTK/Ras/PI(3)K (82%), p53 (63%), WNT (58%), SHH (13%), NOTCH (11%),
Rb (5%) and G-protein (8%) pathways. SNV burden was a predictor of overall survival (P=0.003) but no particular pathway was individually responsible. SNVs (40) in BRAF, DAXX, EGFR, FGFR2, JAK2, MYB, PIK3CA, PIK3R1, PTEN, ATM, BRCA1, CHEK2, PPM1D, PTCH1 and SMO were also putatively pathogenic. Many initial tumours had BRCA1 (21%) and BRCA2 (18%) variants, including previously confirmed somatic mutations in haemangioblastoma, and also WNT variants (58%).

Recurrent tumours had fewer pathways (RTK/Ras/PI(3)K, p53, WNT, G-protein) impacted by genetic alterations. Possible tumour resistance signatures included a private SNV in PIK3C2G and CNV gains (BRCA2, GNAS, EGFR) and losses (TERT, SMARCA4). Survival analysis suggested GNAS variation was prognostic (P

• Journal Article Type: Article
• Acceptance Date: Sep 19, 2018
• Publication Date: Sep 19, 2018
• Deposit Date: Sep 21, 2018
• Journal: Neuro-Oncology
• Print ISSN: 1522-8517
• Electronic ISSN: 1523-5866
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Not Peer Reviewed
• Volume: 20
• Issue: 3
• Pages: iii215-iii216
• DOI: https://doi.org/10.1093/neuonc/noy139.003
• Public URL: https://uwe-repository.worktribe.com/output/860460
• Publisher URL: https://doi.org/10.1093/neuonc/noy139.003
• Related Public URLs: https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_3/iii215/5100907?redirectedFrom=fulltext
• Additional Information: Additional Information : Conference publication: European Association of Neuro-Oncology, October 10 - 14, Stockholm, Sweden published online https://academic.oup.com/neuro-oncology/article-abstract/20/suppl_3/iii215/5100907?redirectedFrom=fulltext
• Contract Date: Sep 21, 2018