A Korshunov1,2, B Casalini1, L Chavez2,3,4, T Hielscher5, M Sill2,3,4, M Ryzhova6, T Sharma2,3,4, D Schrimpf1, D Stichel1, D Capper7,8,9, D E Reuss1, D Sturm2,3,4,10, O Absalyamova6, A Golanov6, S Lambo2,3,4, M Bewerunge-Hudler11, P Lichter12, C Herold-Mende13, W Wick14,15, S M Pfister2,3,4,10, M Kool2,3,4, D T W Jones2,3,4, A von Deimling1, F Sahm1,2. 1. Department of Neuropathology, University Hospital Heidelberg, Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 2. Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany. 3. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. German Cancer Consortium (DKTK), Heidelberg, Germany. 5. Department of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Department of Neuropathology, NN Burdenko Neurosurgical Institute, Moscow, Russia. 7. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany. 8. Department of Neuropathology, Berlin Institute of Health, Berlin, Germany. 9. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany. 10. Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany. 11. Genomics and Proteomics Core Facility, Microarray Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. 12. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. 13. Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany. 14. Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 15. Department of Neurology and Neurooncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
Abstract
AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.
AIMS: Mutations of isocitrate dehydrogenase (IDH)1/2 affect almost all astrocytomas of WHO grade II and III. A subset of IDH-mutant astrocytic tumours progresses to IDH-mutant glioblastoma or presents with the histology of a glioblastoma at first presentation. We set out here to assess the molecular spectrum of IDH-mutant glioblastomas. METHODS: We performed an integrated molecular analysis of a mono-centric cohort (n = 97); assessed through genome-wide DNA methylation analysis, copy-number profiling and targeted next generation sequencing using a neurooncology-tailored gene panel. RESULTS: Of these 97 IDH-mutant glioblastomas, 68 had a glioblastoma at first presentation ('de novo' IDH-mutant glioblastoma) and 29 emerged from a prior low-grade lesion ('evolved' IDH-mutant glioblastoma). Unsupervised hierarchical clustering of DNA methylation data disclosed that IDH-mutant glioblastoma ('de novo' and 'evolved') formed a distinct group separate from other diffuse glioma subtypes. Homozygous deletions of CDKN2A/B were found to be associated with shorter survival. CONCLUSIONS: This study demonstrates DNA methylation patterns in IDH-mutant glioblastoma to be distinct from lower-grade astrocytic counterparts but homogeneous within de novo and evolved IDH-mutant glioblastomas, and identifies CDKN2A as a marker for possible genetic sub-stratification.
Authors: Melissa Umphlett; Khawaja Hasan Bilal; Michael L Martini; Abigail K Suwala; Sadhna Ahuja; Omid Rashidipour; Isabelle Germano; Matija Snuderl; Peter Morgenstern; Nadejda M Tsankova Journal: Neurooncol Adv Date: 2022-05-10
Authors: Sohil H Patel; Prem P Batchala; Thomas J Eluvathingal Muttikkal; Sergio S Ferrante; James T Patrie; Camilo E Fadul; David Schiff; M Beatriz Lopes; Rajan Jain Journal: J Neurooncol Date: 2021-03-04 Impact factor: 4.130
Authors: Emilie Darrigues; Benjamin W Elberson; Annick De Loose; Madison P Lee; Ebonye Green; Ashley M Benton; Ladye G Sink; Hayden Scott; Murat Gokden; John D Day; Analiz Rodriguez Journal: Front Oncol Date: 2021-04-26 Impact factor: 6.244