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1. Characteristics of IDH-mutant gliomas with non-canonical IDH mutation

Author

Poetsch, L., Bronnimann, C., Loiseau, H., Frénel, J., Siegfried, A., Seizeur, R., Gauchotte, G., Cappellen, D., Carpentier, C., Figarella‑Branger, Dominique, Eimer, S., Meyronet, D., Ducray, F., Network, POLA, Rigaud, V., CHU Bordeaux [Bordeaux], Imagerie moléculaire et thérapies innovantes en oncologie (IMOTION), Université de Bordeaux (UB), CRLCC René Gauducheau, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service d’Anatomie Pathologique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Département de neurologie 2 - Mazarin, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Anatomie Pathologique-Neuropathologique [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neuro-oncologie [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, IDH1, [SDV]Life Sciences [q-bio], Mutant, IDH2, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Glioma, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Family history, neoplasms, ComputingMilieux_MISCELLANEOUS, Brain Neoplasms, business.industry, Cancer, Prognosis, medicine.disease, Combined Modality Therapy, Isocitrate Dehydrogenase, nervous system diseases, 3. Good health, Idh mutation, Survival Rate, Neurology, Oncology, 030220 oncology & carcinogenesis, Mutation, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P

Published
2020

2. The molecular landscape of glioma in patients with Neurofibromatosis 1

Author

Dominique Vidaud, Mariona Suñol, Tala, Francesco DiMeco, John de Groot, Gaetano Finocchiaro, Fulvio D'Angelo, Luc Bauchet, Marica Eoli, Véronique Lorgis, David Meyronet, Kristin Alfaro, Luciano Garofano, John M. Slopis, Laurent Capelle, Pascale Varlet, Giulia Berzero, Mario Cangiano, Veronica Saletti, Romuald Seizeur, Jing Zhang, Carlo Efisio Marras, Veronique Frattini, Walid Farah, Cinzia Lavarino, David Cachia, Genevieve Lewis, Michele Ceccarelli, Seung-Ki Kim, David E. Reuss, Hugues Loiseau, Carlos Kamiya-Matsuoka, Do-Hyun Nam, Krishna P. Bhat, Stéphane Goutagny, Karima Mokhtari, François Ducray, Anna Lasorella, Colin Watts, Francesca Pia Caruso, Hector Salvador, Antonio Iavarone, F. Vandenbos, Ian E. McCutcheon, Susanna Ronchi, Viviane Tabar, Marc Sanson, D'Angelo, Fulvio, Ceccarelli, Michele, Tala, Garofano, Luciano, Zhang, Jing, Frattini, Veronique, Caruso, Francesca P., Lewis, Genevieve, Alfaro, Kristin D., Bauchet, Luc, Berzero, Giulia, Cachia, David, Cangiano, Mario, Capelle, Laurent, de Groot, John, Dimeco, Francesco, Ducray, Francoi, Farah, Walid, Finocchiaro, Gaetano, Goutagny, Stephane, Kamiya-Matsuoka, Carlo, Lavarino, Cinzia, Loiseau, Hugue, Lorgis, Veronique, Marras, Carlo E., Mccutcheon, Ian, Nam, Do-Hyun, Ronchi, Susanna, Saletti, Veronica, Seizeur, Romuald, Slopis, John, Sunol, Mariona, Vandenbos, Fanny, Varlet, Pascale, Vidaud, Dominique, Watts, Colin, Tabar, Viviane, Reuss, David E., Kim, Seung-Ki, Meyronet, David, Mokhtari, Karima, Salvador, Hector, Bhat, Krishna P., Eoli, Marica, Sanson, Marc, Lasorella, Anna, Iavarone, Antonio, D'Angelo, F., Ceccarelli, M., Garofano, L., Zhang, J., Frattini, V., Caruso, F. P., Lewis, G., Alfaro, K. D., Bauchet, L., Berzero, G., Cachia, D., Cangiano, M., Capelle, L., de Groot, J., Dimeco, F., Ducray, F., Farah, W., Finocchiaro, G., Goutagny, S., Kamiya-Matsuoka, C., Lavarino, C., Loiseau, H., Lorgis, V., Marras, C. E., Mccutcheon, I., Nam, D. -H., Ronchi, S., Saletti, V., Seizeur, R., Slopis, J., Sunol, M., Vandenbos, F., Varlet, P., Vidaud, D., Watts, C., Tabar, V., Reuss, D. E., Kim, S. -K., Meyronet, D., Mokhtari, K., Salvador, H., Bhat, K. P., Eoli, M., Sanson, M., Lasorella, A., Iavarone, A., Columbia University Medical Center (CUMC), Columbia University [New York], University of Sannio [Benevento], The University of Texas M.D. Anderson Cancer Center [Houston], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Medical University of South Carolina [Charleston] (MUSC), Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Milan, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Sungkyunkwan University [Suwon] (SKKU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Pasteur [Nice] (CHU), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Sainte Anne [Paris], Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], University of Birmingham [Birmingham], Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and CHU Cochin [AP-HP]

Subjects
0301 basic medicine, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X-linked Nuclear Protein, Neurofibromatosis 1, Adolescent, [SDV]Life Sciences [q-bio], T-Lymphocytes, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Germline mutation, CDKN2A, Antigens, Neoplasm, Glioma, medicine, Humans, Epigenetics, Neurofibromatosis, 10. No inequality, Child, Gene, neoplasms, ATRX, Germ-Line Mutation, Cancer, Neurofibromin 1, Brain Neoplasms, Reproducibility of Results, General Medicine, DNA Methylation, Middle Aged, medicine.disease, 3. Good health, nervous system diseases, 030104 developmental biology, 030220 oncology & carcinogenesis, Child, Preschool, DNA methylation, Cancer research, Genomics, Bioinformatic, Female, Transcriptome
Abstract

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors. An integrated analysis of glioma samples from patients with neurofibromatosis 1 annotates their mutational, epigenetic, transcriptional, and immunological features and uncovers similitudes with a subset of sporadic gliomas.

Published
2018

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