Author:
Biswas Archita,Salvucci Manuela,Connor Kate,Düssmann Heiko,Carberry Steven,Fichtner Michael,King Ellen,Murphy Brona,O’Farrell Alice C.,Cryan Jane,Beausang Alan,Heffernan Josephine,Cremona Mattia,Hennessy Bryan T.,Clerkin James,Sweeney Kieron J.,MacNally Steve,Brett Francesca,O’Halloran Philip,Bacon Orna,Furney Simon,Verreault Maite,Quissac Emie,Bielle Franck,Ahmed Mohammed H.,Idbaih Ahmed,Leenstra Sieger,Ntafoulis Ioannis,Fabro Federica,Lamfers Martine,Golebiewska Anna,Hertel Frank,Niclou Simone P.,Yen Romain Tching Chi,Kremer Andreas,Dilcan Gonca,Lodi Francesca,Arijs Ingrid,Lambrechts Diether,Purushothama Manasa Kalya,Kel Alexander,Byrne Annette T.,Prehn Jochen H.M.
Abstract
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
Funder
Royal College of Surgeons in Ireland
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Neurology (clinical),Neurology,Oncology