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Acta Neuropathol. 2018 Aug;136(2):211-226. doi: 10.1007/s00401-018-1877-0. Epub 2018 Jun 16.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Author information

1
Hopp-Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany.
2
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
3
Department of Pediatric Oncology, Hematology and Immunology, University Hospital, 69120, Heidelberg, Germany.
4
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
5
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
6
Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
7
Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
8
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham, UK.
9
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
10
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
11
Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
12
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA.
13
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
14
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
15
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
16
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
17
Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
18
Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.
19
Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
20
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. David.Ellison@stjude.org.

Abstract

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

KEYWORDS:

CXorf67; DNA methylation profiling; Ependymoma; H3 K27-trimethylation; H3 K27M; Molecular heterogeneity; PRC2

PMID:
29909548
PMCID:
PMC6105278
DOI:
10.1007/s00401-018-1877-0
[Indexed for MEDLINE]
Free PMC Article

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