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Molecular analysis of adolescent and young adult high grade gliomas in the SPECTA-AYA study: Poorly characterised tumours with frequent germline alterations

Morfouace, M.
; 
Bielle, F.
; 
Razis, E.
; 
Estrade, F.
; 
Rubio, A.
; 
Bautista, F.
; 
de Rojas, T.
; 
Vieito, M.
; 
Meade, S.
; 
Sanson, M.
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Abstract
BACKGROUND: Adolescent and young adult (AYA) high grade gliomas (HGG) have the worst survival of AYA malignancies yet are poorly represented in large-scale molecular datasets. METHODS: 50 AYAs aged 12-29 with newly diagnosed or recurrent HGG and other high risk central nervous system (CNS) tumours were prospectively recruited to the EORTC SPECTA platform study and underwent whole exome sequencing, RNA sequencing and methylation profiling, with central pathological review. Actionable mutations were reported and patients followed up for therapies and outcome. RESULTS: From 46 locally diagnosed HGGs and 4 other recurrent CNS tumours, molecular and pathology review resulted in histological grade re-classification (n = 10), diagnostic refinement (n = 9) and revised diagnoses (n = 12) in a substantial proportion. Pathogenic constitutional alterations were present in 14 % overall and were largely limited to cases with IDH-wildtype glioblastoma and paediatric-type diffuse HGGs. 91 % of HGGs had potentially actionable alterations affecting RAS/RAF/MAPK (60 %), PI3K/AKT/mTOR (27 %) and cell cycle genes (11 %). High tumour mutational burden (> 10 somatic non-synonymous mutations per Mb of genome targeted) was present in 12 % at diagnosis and 18 % at recurrence, all in histological grade 4 tumours. Ten patients' treatment was modified on the basis of molecular profile, of whom 5 remained on treatment at last follow-up. CONCLUSION: AYA HGGs comprise a diverse group of entities; accurate, molecularly-defined diagnosis is critical to direct primary treatment, determine risk of genetic predisposition and guide molecularly-directed therapy. Current services fail to routinely address diagnosis, personalised molecular profiling or investigation of therapeutic opportunities for this high risk, poor prognosis group of rare cancer patients.
Authors
Morfouace, M.
Bielle, F.
Razis, E.
Estrade, F.
Rubio, A.
Bautista, F.
de Rojas, T.
Vieito, M.
Meade, S.
Sanson, M.
Marques, A. C.
Preusser, M.
Hatcher, H.
Balasubramanian, G. P.
Pineda, E.
D'Hondt, L.
Duerinck, J.
Michotte, A.
Mawrin, C.
Ribalta, T.
Marucci, G.
Golfinopoulos, V.
Pfister, S. M.
Jones, D. T.
McCabe, M. G.
Affiliation
EORTC Headquarters, Brussels, Belgium; Gustave Roussy, Villejuif, France. Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuropathology, Paris, France. Third Medical Oncology Dept, Hygeia Hospital, Athens, Greece. Centre Eugène Marquis, Rennes, France. Hospital Niño Jesús, Department of Pediatric Oncology, Hematology and Stem Cell Transplantation, Madrid, Spain. Hospital Niño Jesús, Department of Pediatric Oncology, Hematology and Stem Cell Transplantation, Madrid, Spain; Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands. EORTC Headquarters, Brussels, Belgium. GU, Sarcoma and Neuroncology Unit, Vall d'Hebron University Hospital and Drug Development Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. UHB-Queen Elizabeth Medical Centre, Birmingham, UK. Sorbonne Université, Paris Brain Institute-ICM, Inserm, CNRS, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Department of Neuro-oncology, Paris, France. Cen.Hospitalar Vila Nova Gaia, Portugal. Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria. Department of Medical Oncology, Addenbrookes Hospital, Cambridge, UK. Hopp Children´s Cancer Center Heidelberg (KiTZ), German Consortium for Translational Cancer Research (DKTK), Germany; Division Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), Heidelberg, Germany. Hospital Clinic Universitari de Barcelona, Spain. Department of Oncology CHU UCL Namur site Godinne, Yvoir, Belgium. Department of Neurosurgery, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, Brussels 1090, Belgium. Dept of Pathology (Neuropathology), Universitair Ziekenhuis Brussel, Brussels, Belgium. Institut für Neuropathologie, Magdeburg, Germany. Pathology Department, Hospital Clinic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. National Center for Tumor Diseases (NCT), Heidelberg, Germany; Division of Pediatric Glioma Research, Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. Electronic address: martin.mccabe@manchester.ac.uk.
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2025
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Morfouace M, Bielle F, Razis E, Estrade F, Rubio A, Bautista F, et al. Molecular analysis of adolescent and young adult high grade gliomas in the SPECTA-AYA study: Poorly characterised tumours with frequent germline alterations. European journal of cancer (Oxford, England : 1990). 2025 Jun 18;223:115493. PubMed PMID: 40393126. Epub 2025/05/21. eng.
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https://christie.openrepository.com/handle/10541/627905
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