Anna Luisa Di Stefano1,2,3,4, Alberto Picca5,6, Edouard Saragoussi7, Franck Bielle8, Francois Ducray9,10, Chiara Villa11, Marica Eoli12, Rosina Paterra12, Luisa Bellu3, Bertrand Mathon13, Laurent Capelle13, Véronique Bourg14, Arnaud Gloaguen15,16, Cathy Philippe16, Vincent Frouin16, Yohann Schmitt1,2, Julie Lerond1,2,8, Julie Leclerc1,2,8, Anna Lasorella17,18,19, Antonio Iavarone17,18,20, Karima Mokhtari8, Julien Savatovsky7, Agusti Alentorn1,2,3, Marc Sanson1,2,3,21. 1. Inserm Unit 1127, Sorbonne University, Institute of the Brain and Spinal Cord, Paris, France. 2. SiRIC CURAMUS, LNCC (équipe labellisée). 3. Department of Neuropathology 2, Pitié-Salpêtrière Hospital,Paris, France. 4. Department of Neurology, Foch Hospital, Suresnes, France. 5. C. Mondino Foundation, Pavia, Italy. 6. Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. 7. Department of Radiology, Adolphe de Rothschild Ophthalmological Foundation, Paris, France. 8. Department of Neuropathology, Pitié Salpêtrière-Charles Foix, Paris, France. 9. Department of Neuro-Oncology, Civil Hospice of Lyon, University Claude Bernard Lyon 1, Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, Lyon, France. 10. POLA Network. 11. Department of Pathology, Foch Hospital, Suresnes, France. 12. Unit of Molecular Neuro-Oncology, Carlo Besta Neurological Institute, Milan, Italy. 13. Department of Neurosurgery, Pitié-Salpêtrière Hospital, Paris, France. 14. Department of Neurology, Pasteur 2 Hospital, Nice Côte D'Azur University, Nice, France. 15. Signals and Systems Laboratory, Paris-Saclay University, Gif-sur-Yvette, France. 16. Neurospin, French Atomic Energy Commission, Paris-Saclay University, Gif-sur-Yvette, France. 17. Institute for Cancer Genetics, Columbia University, New York, New York, USA. 18. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA. 19. Department of Pediatrics, Columbia University, New York, New York, USA. 20. Department of Neurology, Columbia University, New York, New York, USA. 21. OncoNeuroTek, Institute of the Brain and Spinal Cord, Paris, France.
Abstract
BACKGROUND: Actionable fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. METHODS: We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. RESULTS: We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis.F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). CONCLUSION: F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.
BACKGROUND: Actionable fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil protein 3 fusions (F3T3) are found in approximately 3% of gliomas, but their characteristics and prognostic significance are still poorly defined. Our goal was to characterize the clinical, radiological, and molecular profile of F3T3 positive diffuse gliomas. METHODS: We screened F3T3 fusion by real-time (RT)-PCR and FGFR3 immunohistochemistry in a large series of gliomas, characterized for main genetic alterations, histology, and clinical evolution. We performed a radiological and radiomic case control study, using an exploratory and a validation cohort. RESULTS: We screened 1162 diffuse gliomas (951 unselected cases and 211 preselected for FGFR3 protein immunopositivity), identifying 80 F3T3 positive gliomas. F3T3 was mutually exclusive with IDH mutation (P < 0.001) and EGFR amplification (P = 0.01), defining a distinct molecular cluster associated with CDK4 (P = 0.04) and MDM2 amplification (P = 0.03). F3T3 fusion was associated with longer survival for the whole series and for glioblastomas (median overall survival was 31.1 vs 19.9 mo, P = 0.02) and was an independent predictor of better outcome on multivariate analysis.F3T3 positive gliomas had specific MRI features, affecting preferentially insula and temporal lobe, and with poorly defined tumor margins. F3T3 fusion was correctly predicted by radiomics analysis on both the exploratory (area under the curve [AUC] = 0.87) and the validation MRI (AUC = 0.75) cohort. Using Cox proportional hazards models, radiomics predicted survival with a high C-index (0.75, SD 0.04), while the model combining clinical, genetic, and radiomic data showed the highest C-index (0.81, SD 0.04). CONCLUSION: F3T3 positive gliomas have distinct molecular and radiological features, and better outcome.
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