DNA methylation and survival differences associated with the type of IDH mutation in 1p/19q non-codeleted astrocytomas
DNA methylation and survival differences associated with the type of IDH mutation in 1p/19q non-codeleted astrocytomas
Abstract Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. This high prevalence is important as IDH1R132H is presumed to be relatively poor at producing D-2-hydroxyglutarate (D-2HG) whereas high concentrations of this oncometabolite are required to inhibit TET2 DNA demethylating enzymes. Indeed, patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of site of origin. For 1p/19q non-codeleted glioma patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring non-R132H mutated tumours have better outcome (HR 0.41, 95% CI [0.24, 0.71], p=0.0013). Non-R132H mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p<0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H mutated 1p/19q non-codeleted gliomas have a more favourable prognosis than their IDH1R132H mutated counterpart is clinically relevant and should be taken into account for patient prognostication. Single sentence summaryAstrocytoma patients with tumours harbouring IDH mutations other than p.R132H have increased DNA methylation levels and longer survival
Enting Roelien H、Gill Sanjeev、Rogers Leland、Reijneveld Jaap、Aldape Ken、Jenkins Robert B、French Pim J、Bov¨|e Judith VMG、Erridge Sara、Lesimple Thierry、Clenton Susan、Gijtenbeek Anja、de Vos Filip、Mulholland Paul J、Taphoorn Martin J B、Boggiani Lorenzo、Golfinopoulos Vassilis、van den Bent Martin、Wick Wolfgang、Brandes Alba Ariela、Kros Johan M、Gorlia Thierry、Tesileanu C Mircea S、Griffin Matthew、Vogelbaum Michael A、Wheeler Helen、Sanson Marc、Caparrotti Francesca、Baurain Jean Francais、Lim Elisabeth、McBain Catherine、Nowak Anna K、Clement Paul M、Wesseling Pieter、Oosting Jan、Venneker Sanne、Chinot Olivier L、Taal Walter、Hoogstrate Youri、Baumert Brigitta、Mason Warren P、Rud¨¤ Roberta、de Heer Iris、Vallentgoed Wies R、de Wit Maurice、Weller Michael、Dubbink Hendrikus J
Department of Neurology, UMCG, University of Groningen, GroningenDept Medical Oncology, Alfred HospitalDepartment of Radiation Oncology, Barrow Neurological InstituteBrain Tumor Center Amsterdam & Department of Neurology, Amsterdam University Medical CenterPrincess Margaret Cancer Centre, University of TorontoDepartment of Laboratory Medicine and Pathology, Mayo ClinicDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDepartment of Pathology, Leiden University Medical CenterEdinburgh Centre for Neuro-Oncology, Western General Hospital, University of EdinburghDepartment of Clinical Oncology, Comprehensive Cancer Center Eug¨¨ne MarquisWeston Park HospitalDepartment of Neurology, Radboud University Medical CentreDepartment of Medical Oncology, UMC Utrecht Cancer CenterUniversity College HospitalMC HaaglandenDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamEORCT HQDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamNeurologische Klinik und Nationales Zentrum f¨1r Tumorerkrankungen Universit?tsklinikMedical Oncology Department, AUSL-IRCCS Scienze NeurologicheDepartment of Pathology, Erasmus University Medical CenterEORCT HQDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDepartment of Clinical Oncology, Nottingham University Hospitals NHS TrustDepartment of NeuroOncology, Moffitt Cancer CenterNorthern Sydney Cancer Centre University of SydneySorbonne Universit¨|s UPMC Univ Paris 06, Inserm, CNRS, APHP, Institut du cerveau et de la moelle (ICM)- H?pital Piti¨|-salp¨otri¨¨re, Boulevard de l?ˉh?pitalDepartment of Radiation Oncology, University Hospital of GenevaMedical Oncology Department, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Universit¨| Catholique de LouvainDepartment of Clinical Oncology, PLYMOUTH HOSPITALS NHS TRUSTDepartment of Clinical Oncology, The Christie NHS FTSchool of Medicine and Pharmacology, University of Western Australia||CoOperative Group for NeuroOncology, University of Sydney||Department of Medical Oncology, Sir Charles Gairdner HospitalDepartment of Oncology, KU Leuven and Department of General Medical OncologyDepartment of Pathology, VU University Medical CenterDepartment of Pathology, Leiden University Medical CenterDepartment of Pathology, Leiden University Medical CenterAix-Marseille University, AP-HM, Neuro-Oncology divisionDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDept. Radiation-Oncology (MAASTRO), Maastricht University Medical Center (MUMC) and GROW (School for Oncology)||Institute of Radiation-OnologyPrincess Margaret Cancer Centre, University of TorontoDepartment of Neuro-Oncology, City of Health and Science Hospital and University of TurinDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDept Neurology, Brain Tumor Center at Erasmus MC Cancer Institute RotterdamDepartment of Neurology and Brain Tumor Center, University Hospital and University of ZurichDepartment of Pathology, Erasmus University Medical Center
肿瘤学基础医学分子生物学
AstrocytomaD-2-hydroxyglutarateoligodendrogliomaacute myeloid leukemiachondrosarcomagenome wide DNA methylationgene expressionsurvivalIDH1IDH2p.R132H
Enting Roelien H,Gill Sanjeev,Rogers Leland,Reijneveld Jaap,Aldape Ken,Jenkins Robert B,French Pim J,Bov¨|e Judith VMG,Erridge Sara,Lesimple Thierry,Clenton Susan,Gijtenbeek Anja,de Vos Filip,Mulholland Paul J,Taphoorn Martin J B,Boggiani Lorenzo,Golfinopoulos Vassilis,van den Bent Martin,Wick Wolfgang,Brandes Alba Ariela,Kros Johan M,Gorlia Thierry,Tesileanu C Mircea S,Griffin Matthew,Vogelbaum Michael A,Wheeler Helen,Sanson Marc,Caparrotti Francesca,Baurain Jean Francais,Lim Elisabeth,McBain Catherine,Nowak Anna K,Clement Paul M,Wesseling Pieter,Oosting Jan,Venneker Sanne,Chinot Olivier L,Taal Walter,Hoogstrate Youri,Baumert Brigitta,Mason Warren P,Rud¨¤ Roberta,de Heer Iris,Vallentgoed Wies R,de Wit Maurice,Weller Michael,Dubbink Hendrikus J.DNA methylation and survival differences associated with the type of IDH mutation in 1p/19q non-codeleted astrocytomas[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.12.10.419333.点此复制
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