Comparative analysis of deeply phenotyped GBM cohorts of ‘short-term’ and ‘long-term’ survivors

Archita Biswas, Manuela Salvucci, Kate Connor, Heiko Düssmann, Steven Carberry, Michael Fichtner, Ellen King, Brona Murphy, Alice C. O’Farrell, Jane Cryan, Alan Beausang, Josephine Heffernan, Mattia Cremona, Bryan T. Hennessy, James Clerkin, Kieron J. Sweeney, Steve MacNally, Francesca Brett, Philip O’Halloran, Orna BaconSimon Furney, Maite Verreault, Emie Quissac, Franck Bielle, Mohammed H. Ahmed, Ahmed Idbaih, Sieger Leenstra, Ioannis Ntafoulis, Federica Fabro, Martine Lamfers, Anna Golebiewska, Frank Hertel, Simone P. Niclou, Romain Tching Chi Yen, Andreas Kremer, Gonca Dilcan, Francesca Lodi, Ingrid Arijs, Diether Lambrechts, Manasa Kalya Purushothama, Alexander Kel, Annette T. Byrne, Jochen H.M. Prehn*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Background: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). Methods: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. Results: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. Conclusion: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM. Graphical abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)327-338
Number of pages12
JournalJournal of Neuro-Oncology
Volume163
Issue number2
Early online date26 May 2023
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Apoptosis
  • Cell cycle
  • Cilium
  • Glioblastoma
  • Long term survivors
  • Reverse phase protein array
  • RNA-sequencing
  • Short term survivors
  • Transcriptomics

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