Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features
Por:
Deng MY, Sill M, Chiang J, Schittenhelm J, Ebinger M, Schuhmann MU, Monoranu CM, Milde T, Wittmann A, Hartmann C, Sommer C, Paulus W, Gärtner J, Brück W, Rüdiger T, Leipold A, Jaunmuktane Z, Brandner S, Giangaspero F, Nozza P, Mora J, Morales-La Madrid A, Cruz-Martínez O, Hansford JR, Pietsch T, Tietze A, Hernáiz-Driever P, Stoler I, Capper D, Korshunov A, Ellison DW, von Deimling A, Pfister SM, Sahm F and Jones DTW
Publicada:
1 ago 2018
Ahead of Print:
15 may 2018
Aceptada:
9 may 2018
Resumen:
Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
Filiaciones:
Deng MY:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
Sill M:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
Chiang J:
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Schittenhelm J:
Department of Neuropathology, Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital of Tübingen, Tübingen, Germany
Ebinger M:
Department of Pediatric Hematology/Oncology, Children's University Hospital, Tübingen, Germany
Schuhmann MU:
Division of Pediatric Neurosurgery, Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany
Monoranu CM:
Department of Neuropathology, Institute of Pathology, University of Würzburg, Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
Milde T:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120, Heidelberg, Germany
KiTZ Clinical Trial Unit (ZIPO), 69120, Heidelberg, Germany
Wittmann A:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
Hartmann C:
Department of Neuropathology, Hannover Medical School, Hannover, Germany
Sommer C:
Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
Paulus W:
Institute of Neuropathology, University Hospital Münster, Münster, Germany
Gärtner J:
Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University of Göttingen Medical Center, Göttingen, Germany
Brück W:
Department of Neuropathology, University of Göttingen Medical Center, Göttingen, Germany
Rüdiger T:
Institute of Pathology, Klinikum Karlsruhe, Karlsruhe, Germany
Leipold A:
Department of Pediatrics, Klinikum Karlsruhe, Karlsruhe, Germany
Jaunmuktane Z:
Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
Brandner S:
Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK
Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
Giangaspero F:
IRCCS Neuromed, Pozzilli, Italy
Department of Radiological, Oncological and Anatomo-pathological Science, Sapienza University of Rome, Rome, Italy
Nozza P:
Pathology Unit, Istituto Giannina Gaslini, Genoa, Italy
Mora J:
Department of Pediatric Hemato-Oncology, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain
Morales-La Madrid A:
Department of Pediatric Hemato-Oncology, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain
Cruz-Martínez O:
Department of Pediatric Hemato-Oncology, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain
Hansford JR:
Department of Paediatrics, Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia
Pietsch T:
Institute of Neuropathology, Brain Tumor Reference Center of the Society for Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany
Tietze A:
Institute of Neuroradiology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Hernáiz-Driever P:
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Stoler I:
Department of Neuropathology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Capper D:
Department of Neuropathology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Korshunov A:
Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
Ellison DW:
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
von Deimling A:
Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany
Pfister SM:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120, Heidelberg, Germany
Sahm F:
Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany.
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
Jones DTW:
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany.
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
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