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

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

Authors

H. P. Ellis

C. E. McInerney

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

© 2019 H. P. Ellis et al. 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.

Citation

Ellis, H. P., McInerney, C. E., Schrimpf, D., Sahm, F., Stupnikov, A., Wadsley, M., …Kurian, K. M. (2019). Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches. Journal of Oncology, 2019, https://doi.org/10.1155/2019/4878547

Journal Article Type Article
Acceptance Date Oct 25, 2019
Publication Date Dec 31, 2019
Deposit Date Nov 8, 2019
Publicly Available Date Jan 30, 2020
Journal Journal of Oncology
Print ISSN 1687-8450
Electronic ISSN 1687-8469
Publisher Hindawi
Peer Reviewed Peer Reviewed
Volume 2019
Article Number 4878547
DOI https://doi.org/10.1155/2019/4878547
Public URL https://uwe-repository.worktribe.com/output/4159239
Additional Information PDF version of text submitted has been uploaded

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Licence
http://creativecommons.org/licenses/by/4.0/

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright © 2019 H. P. Ellis et al. 0is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.







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