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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

Authors

C E McInerney

H P Ellis

D Schrimpf

F Sahm

A Stupnikov

M Wadsley

C Wragg

Paul White Paul.White@uwe.ac.uk
Associate Professor in Applied Statistics

K M Prise

D G McArt

K M Kurian



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
Publication Date Sep 19, 2018
Journal Neuro-Oncology
Print ISSN 1522-8517
Publisher Oxford University Press (OUP)
Peer Reviewed Not Peer Reviewed
Volume 20
Issue 3
Pages iii215-iii216
APA6 Citation McInerney, C. E., Ellis, H. P., Schrimpf, D., Sahm, F., Stupnikov, A., Wadsley, M., …Kurian, K. M. (2018). Genomic profiling of IDH-wildtype and IDH-mutant initial and matched recurrent glioblastomas reveals clinically actionable mutations (e.g. BRCA1/2) and resistance signatures. Neuro-Oncology, 20(3), iii215-iii216. https://doi.org/10.1093/neuonc/noy139.003
DOI https://doi.org/10.1093/neuonc/noy139.003
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.co...redirectedFrom=fulltext