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Acta Neuropathol Commun. 2018 Dec 4;6(1):134. doi: 10.1186/s40478-018-0630-1.

Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.

Author information

1
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
2
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
3
Department of Biomedical Research and Innovation, Institute for Clinical Research, Osaka National Hospital, National Hospital Organization|, Osaka, Japan.
4
Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
5
Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
6
Department of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan.
7
Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
8
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
9
Department of Pathology, Saitama Medical University, Saitama, Japan.
10
Department of Pathology, Gunma University Hospital, Maebashi, Gunma, Japan.
11
Department of Diagnostic Pathology, Hyogo Cancer Center, Kobe, Hyogo, Japan.
12
Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
13
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
14
Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan.
15
Department of Neurosurgery, Graduate School of Medicine, Yokohama City University, Fukuura, Kanagawa, Japan.
16
Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
17
Department of Neurosurgery and Neurooncology, National Cancer Center Hospital, Tokyo, Japan.
18
Department of Neurosurgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
19
Department of Neurosurgery, Faculty of Life Sciences, Kumamoto University Graduate School, Kumamoto, Japan.
20
Department of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan.
21
Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
22
Department of Pediatric Neurosurgery, Osaka City General Hospital, Osaka, Japan.
23
Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
24
Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
25
Department of Pathology, Kurume University, Kurume, Fukuoka, Japan.
26
Department of Neurosurgery, Fujita Health University, Toyoake, Aichi, Japan.
27
Department of Neurosurgery, Showa University School of Medicine, Tokyo, Japan.
28
Department of Neurological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.
29
Department of Neurological Surgery, Wakayama Medical University, Wakayama, Japan.
30
Department of Neurosurgery, Nagano Children's Hospital, Nagano, Japan.
31
Department of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan.
32
Department of Neurosurgery, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan.
33
Department of Pathology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan.
34
Department of Neurosurgery, Tazuke Kofukai Foundation, Medical Research Institute and Kitano Hospital, Osaka, Japan.
35
Department of Neurosurgery, Shizuoka Children's Hospital, Shizuoka, Japan.
36
Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.
37
Department of Neurosurgery, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
38
Department of Neurosurgery, Kanazawa Medical University, Kanazawa, Japan.
39
Department of Neurosurgery, Toyama University Hospital, Toyama, Japan.
40
Department of Neurosurgery, Faculty of Medicine, Kinki University, Osaka, Japan.
41
Department of Neurosurgery, Kansai Medical University, Hirakata, Osaka, Japan.
42
Department of Neurosurgery, Hokkaido Medical Center for Child Health and Rehabilitation, Sapporo, Japan.
43
Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
44
Department of Pathology, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
45
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
46
Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada.
47
Department of Neurosurgery, Teikyo University Hospital, Mizonokuchi, Kanagawa, Japan.
48
Department of Pediatric Neurosurgery, Takatsuki General Hospital, Takatsuki, Osaka, Japan.
49
Department of Neurosurgery, Juntendo University, Tokyo, Japan.
50
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kichimur@ncc.go.jp.

Abstract

Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

KEYWORDS:

Ependymal tumors; Fusion gene; Gene rearrangement; Molecular classification

PMID:
30514397
PMCID:
PMC6278135
DOI:
10.1186/s40478-018-0630-1
[Indexed for MEDLINE]
Free PMC Article

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