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

Research output: Contribution to journalArticle

  • Hayley P Ellis
  • C. E. McInerney
  • D Schrimpf
  • A Stupnikov
  • M Wadsley
  • C Wragg
  • P White
  • Kevin M Prise
  • D. G. McArt
  • Kathreena M Kurian
Original languageEnglish
Article number4878547
Number of pages15
JournalJournal of Oncology
Volume2019
DOIs
DateAccepted/In press - 25 Oct 2019
DatePublished (current) - 31 Dec 2019

Abstract

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.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Hindawi at https://doi.org/10.1155/2019/4878547 . Please refer to any applicable terms of use of the publisher.

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