Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes.

Autor: Hoffmann L; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany., Coras R; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany., Kobow K; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany., López-Rivera JA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, USA.; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.; Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA., Lal D; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.; Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, 02142, USA.; Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, University Hospital of Cologne, 50931, Cologne, Germany., Leu C; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.; Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, 02142, USA.; Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, University Hospital of Cologne, 50931, Cologne, Germany., Najm I; Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, USA., Nürnberg P; Cologne Center for Genomics (CCG), Medical Faculty of the University of Cologne, University Hospital of Cologne, 50931, Cologne, Germany., Herms J; Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany., Harter PN; Center for Neuropathology and Prion Research, LMU Munich, Munich, Germany., Bien CG; Department of Epileptology (Krankenhaus Mara), Medical School, Bielefeld University, Bielefeld, 33617, Germany., Kalbhenn T; Department of Epileptology (Krankenhaus Mara), Medical School, Bielefeld University, Bielefeld, 33617, Germany.; Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School, Bielefeld University, Bielefeld, 33617, Germany., Müller M; Department of Epileptology (Krankenhaus Mara), Medical School, Bielefeld University, Bielefeld, 33617, Germany., Pieper T; Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, 83569, Rosenheim, Germany., Hartlieb T; Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, 83569, Rosenheim, Germany., Kudernatsch M; Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, 83569, Rosenheim, Germany., Hamer H; Epilepsy Center, EpiCARE Partner, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany., Brandner S; Department of Neurosurgery, EpiCARE Partner, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany., Rössler K; Department of Neurosurgery, EpiCARE Partner, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany.; Department of Neurosurgery, EpiCARE Partner, Medical University of Vienna, Vienna General Hospital, Vienna, Austria., Blümcke I; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany., Jabari S; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, FAU Erlangen-Nürnberg, Erlangen, 91054, Germany. Samir.jabari@uk-erlangen.de.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Jun; Vol. 145 (6), pp. 815-827. Date of Electronic Publication: 2023 Mar 27.
DOI: 10.1007/s00401-023-02561-5
Abstrakt: Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
(© 2023. The Author(s).)
Databáze: MEDLINE
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