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Acta Neuropathol. 2018 Aug;136(2):239-253. doi: 10.1007/s00401-018-1865-4. Epub 2018 May 15.

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.

Author information

1
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany.
2
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
3
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
5
Department of Neuropathology, Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital of Tübingen, Tübingen, Germany.
6
Department of Pediatric Hematology/Oncology, Children's University Hospital, Tübingen, Germany.
7
Division of Pediatric Neurosurgery, Department of Neurosurgery, University Hospital Tübingen, Tübingen, Germany.
8
Department of Neuropathology, Institute of Pathology, University of Würzburg, Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany.
9
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany.
10
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
11
KiTZ Clinical Trial Unit (ZIPO), 69120, Heidelberg, Germany.
12
Department of Neuropathology, Hannover Medical School, Hannover, Germany.
13
Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
14
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
15
Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University of Göttingen Medical Center, Göttingen, Germany.
16
Department of Neuropathology, University of Göttingen Medical Center, Göttingen, Germany.
17
Institute of Pathology, Klinikum Karlsruhe, Karlsruhe, Germany.
18
Department of Pediatrics, Klinikum Karlsruhe, Karlsruhe, Germany.
19
Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK.
20
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
21
Department of Neurodegeneration, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
22
IRCCS Neuromed, Pozzilli, Italy.
23
Department of Radiological, Oncological and Anatomo-pathological Science, Sapienza University of Rome, Rome, Italy.
24
Pathology Unit, Istituto Giannina Gaslini, Genoa, Italy.
25
Department of Pediatric Hemato-Oncology, Hospital Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain.
26
Department of Paediatrics, Children's Cancer Centre, Royal Children's Hospital, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia.
27
Institute of Neuropathology, Brain Tumor Reference Center of the Society for Neuropathology and Neuroanatomy, University of Bonn Medical Center, Bonn, Germany.
28
Institute of Neuroradiology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
29
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
30
Department of Neuropathology, Charité Universitätsmedizin, Corporate Member of Freie Universität Berlin, Humboldt Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.
31
Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany.
32
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
33
Clinical Cooperation Unit Neuropathology, German Cancer Consortium, German Cancer Research Center, 69120, Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de.
34
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany. felix.sahm@med.uni-heidelberg.de.
35
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany. david.jones@kitz-heidelberg.de.
36
Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. david.jones@kitz-heidelberg.de.

Abstract

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.

KEYWORDS:

Brain tumor; Diffuse leptomeningeal glioneuronal tumor; Methylation; Pediatric; Prognostic; Subgroup

PMID:
29766299
DOI:
10.1007/s00401-018-1865-4

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