TY - JOUR
T1 - Comparative analysis of deeply phenotyped GBM cohorts of ‘short-term’ and ‘long-term’ survivors
AU - Biswas, Archita
AU - Salvucci, Manuela
AU - Connor, Kate
AU - Düssmann, Heiko
AU - Carberry, Steven
AU - Fichtner, Michael
AU - King, Ellen
AU - Murphy, Brona
AU - O’Farrell, Alice C.
AU - Cryan, Jane
AU - Beausang, Alan
AU - Heffernan, Josephine
AU - Cremona, Mattia
AU - Hennessy, Bryan T.
AU - Clerkin, James
AU - Sweeney, Kieron J.
AU - MacNally, Steve
AU - Brett, Francesca
AU - O’Halloran, Philip
AU - Bacon, Orna
AU - Furney, Simon
AU - Verreault, Maite
AU - Quissac, Emie
AU - Bielle, Franck
AU - Ahmed, Mohammed H.
AU - Idbaih, Ahmed
AU - Leenstra, Sieger
AU - Ntafoulis, Ioannis
AU - Fabro, Federica
AU - Lamfers, Martine
AU - Golebiewska, Anna
AU - Hertel, Frank
AU - Niclou, Simone P.
AU - Yen, Romain Tching Chi
AU - Kremer, Andreas
AU - Dilcan, Gonca
AU - Lodi, Francesca
AU - Arijs, Ingrid
AU - Lambrechts, Diether
AU - Purushothama, Manasa Kalya
AU - Kel, Alexander
AU - Byrne, Annette T.
AU - Prehn, Jochen H.M.
N1 - Funding Information:
This project was funded by the European Union’s Horizon 2020 and Horizon Europe research and innovation programme under the Marie Skłodowska-Curie ITN / Doctoral Network initiatives (Grant Agreement #s 766069 ‘GLIOTRAIN’ and 101073386 ‘GLIORESOLVE’). The authors further acknowledge the funding contribution from Brain Tumour Ireland to the Beaumont Hospital Brain Tumour Bioresource, the contribution of the Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, to the LIH Brain tumour resource and the support of L.M Houlihan and J Mythen (Beaumont Hospital).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - 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.].
AB - 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.].
KW - Apoptosis
KW - Cell cycle
KW - Cilium
KW - Glioblastoma
KW - Long term survivors
KW - Reverse phase protein array
KW - RNA-sequencing
KW - Short term survivors
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85160323853&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37237151
U2 - 10.1007/s11060-023-04341-3
DO - 10.1007/s11060-023-04341-3
M3 - Article
C2 - 37237151
AN - SCOPUS:85160323853
SN - 0167-594X
VL - 163
SP - 327
EP - 338
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 2
ER -