Humans; Aged; Glioblastoma/pathology; Prognosis; Brain Neoplasms/pathology; Brain/pathology; Survivors; Apoptosis; Cell cycle; Cilium; Glioblastoma; Long term survivors; RNA-sequencing; Reverse phase protein array; Short term survivors; Transcriptomics
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Biswas, Archita; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Salvucci, Manuela; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Connor, Kate; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Düssmann, Heiko; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Carberry, Steven; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Fichtner, Michael; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
King, Ellen; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Murphy, Brona; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
O'Farrell, Alice C; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Cryan, Jane; Department of Neuropathology, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Beausang, Alan; Department of Neuropathology, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Heffernan, Josephine; Department of Neuropathology, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Cremona, Mattia; Department of Medicine, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin 9, Dublin, Ireland.
Hennessy, Bryan T; Department of Medicine, Royal College of Surgeons in Ireland and Beaumont Hospital, Dublin 9, Dublin, Ireland.
Clerkin, James; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland. ; Department of Neurosurgery, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Sweeney, Kieron J; Department of Neurosurgery, Beaumont Hospital, Dublin 9, Dublin, Ireland.
MacNally, Steve; Department of Neurosurgery, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Brett, Francesca; Department of Neuropathology, Beaumont Hospital, Dublin 9, Dublin, Ireland.
O'Halloran, Philip; Department of Neurosurgery, Beaumont Hospital, Dublin 9, Dublin, Ireland.
Bacon, Orna; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Furney, Simon; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Verreault, Maite; DMU Neurosciences, Service de Neurologie 2-Mazarin, Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Inserm, F-75013, Paris, France.
Quissac, Emie; DMU Neurosciences, Service de Neurologie 2-Mazarin, Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Inserm, F-75013, Paris, France.
Bielle, Franck; DMU Neurosciences, Service de Neurologie 2-Mazarin, Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Inserm, F-75013, Paris, France.
Ahmed, Mohammed H; DMU Neurosciences, Service de Neurologie 2-Mazarin, Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Inserm, F-75013, Paris, France.
Idbaih, Ahmed; DMU Neurosciences, Service de Neurologie 2-Mazarin, Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Inserm, F-75013, Paris, France.
Leenstra, Sieger; Dept of Neurosurgery Brain Tumor Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Ntafoulis, Ioannis; Dept of Neurosurgery Brain Tumor Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Fabro, Federica; Dept of Neurosurgery Brain Tumor Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
Lamfers, Martine; Dept of Neurosurgery Brain Tumor Center, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
GOLEBIEWSKA, Anna ; NORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, 6A, Rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg.
HERTEL, Frank ; University of Luxembourg ; NORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, 6A, Rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg.
NICLOU, Simone P. ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM) ; NORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, 6A, Rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg.
Yen, Romain Tching Chi; Information Technology for Translational Medicine, 27, Rue Henri Koch - House of BioHealth, L-4354, Esch-sur-Alzette, Luxembourg.
KREMER, Andreas ; Information Technology for Translational Medicine - House of BioHealth, L-4354, Esch-sur-Alzette, Luxembourg.
Dilcan, Gonca; VIB-KU Leuven Cancer for Cancer Biology, Onderwijs en Navorsing 5, Herestraat, 49, 3000, Leuven, Belgium.
Lodi, Francesca; VIB-KU Leuven Cancer for Cancer Biology, Onderwijs en Navorsing 5, Herestraat, 49, 3000, Leuven, Belgium.
Arijs, Ingrid; VIB-KU Leuven Cancer for Cancer Biology, Onderwijs en Navorsing 5, Herestraat, 49, 3000, Leuven, Belgium.
Lambrechts, Diether; VIB-KU Leuven Cancer for Cancer Biology, Onderwijs en Navorsing 5, Herestraat, 49, 3000, Leuven, Belgium.
Kel, Alexander; geneXplain GmbH, Am Exer 19b, 38302, Wolfenbüttel, Germany.
Byrne, Annette T; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland.
Prehn, Jochen H M; Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Dublin, D02 YN77, Ireland. prehn@rcsi.ie.
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