Romain Appay1,2, Caroline Dehais3, Claude-Alain Maurage3, Agusti Alentorn3, Catherine Carpentier4, Carole Colin2, François Ducray5,6, Fabienne Escande7, Ahmed Idbaih3,4, Aurélie Kamoun8, Yannick Marie4, Karima Mokhtari4,9, Emeline Tabouret2,10, Nesrine Trabelsi4, Emmanuelle Uro-Coste11,12, Jean-Yves Delattre2,4, Dominique Figarella-Branger1,2. 1. Department of Pathological Anatomy and Neuropathology, Timone Hospital, Public Assistance-Marseille Hospitals (APHM), Marseille, France. 2. Aix-Marseille University, Scientific Research National Center (CNRS), Institute of Neurophysiopathology, Marseille, France. 3. Department of Neurology 2-Mazarin, Public Assistance-Paris Hospitals (APHP), University Hospital Pitié Salpêtrière-Charles Foix, Paris, France. 4. Sorbonne University, National Institute of Health and Medical Research (Inserm), CNRS, Brain and Spinal Cord Institute, University Hospitals of Pitié Salpêtrière-Charles Foix, Department of Neurology 2-Mazarin, Paris, France. 5. Department of Neuro-Oncology, Civil Hospices of Lyon, Pierre Wertheimer Hospital, Bron, France. 6. Department of Cancer Cell Plasticity, Cancer Research Center of Lyon, Lyon, France. 7. Department of Pathology, Lille University Hospital, Lille, France. 8. Tumor Identity Card Program, National League Against Cancer, Paris, France. 9. Department of Neurology, Raymond Escourolle Neuropathology Service, University Hospitals of Pitié Salpêtrière-Charles Foix, APHP, Paris, France. 10. Department of Neuro-Oncology, Timone Hospital, APHM, Marseille, France. 11. Department of Pathological Anatomy and Histology-Cytology, Rangueil Hospital, Toulouse, France. 12. Center for Research in Cancerology, Inserm U1037, University of Toulouse, Toulouse, France.
Abstract
BACKGROUND: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. METHODS: In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. RESULTS: CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. CONCLUSIONS: Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
BACKGROUND: The 2016 World Health Organization (WHO) classification of central nervous system tumors stratifies isocitrate dehydrogenase (IDH)-mutant gliomas into 2 major groups depending on the presence or absence of 1p/19q codeletion. However, the grading system remains unchanged and it is now controversial whether it can be still applied to this updated molecular classification. METHODS: In a large cohort of 911 high-grade IDH-mutant gliomas from the French national POLA network (including 428 IDH-mutant gliomas without 1p/19q codeletion and 483 anaplastic oligodendrogliomas, IDH-mutant and 1p/19q codeleted), we investigated the prognostic value of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene homozygous deletion as well as WHO grading criteria (mitoses, microvascular proliferation, and necrosis). In addition, we searched for other retinoblastoma pathway gene alterations (CDK4 amplification and RB1 homozygous deletion) in a subset of patients. CDKN2A homozygous deletion was also searched in an independent series of 40 grade II IDH-mutant gliomas. RESULTS: CDKN2A homozygous deletion was associated with dismal outcome among IDH-mutant gliomas lacking 1p/19q codeletion (P < 0.0001 for progression-free survival and P = 0.004 for overall survival) as well as among anaplastic oligodendrogliomas, IDH-mutant + 1p/19q codeleted (P = 0.002 for progression-free survival and P < 0.0001 for overall survival) in univariate and multivariate analysis including age, extent of surgery, adjuvant treatment, microvascular proliferation, and necrosis. In both groups, the presence of microvascular proliferation and/or necrosis remained of prognostic value only in cases lacking CDKN2A homozygous deletion. CDKN2A homozygous deletion was not recorded in grade II gliomas. CONCLUSIONS: Our study pointed out the utmost relevance of CDKN2A homozygous deletion as an adverse prognostic factor in the 2 broad categories of IDH-mutant gliomas stratified on 1p/19q codeletion and suggests that the grading of these tumors should be refined.
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