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language
eng
Author
Gojo, Johannes
Lotsch, Daniela
Spiegl-Kreinecker, Sabine
Pajtler, Kristian W
Neumayer, Katharina
Korbel, Pia
Brandstetter, Anita
Mohr, Thomas
Hovestadt, Volker
Chavez, Lukas
Kirchhofer, Dominik
Ricken, Gerda
Stefanits, Harald
Korshunov, Andrey
Pfister, Stefan M
Dieckmann, Karin
Azizi, Amedeo A
Czech, Thomas
Filipits, Martin
Kool, Marcel
Peyrl, Andreas
Slavc, Irene
Berger, Walter
Haberler, Christine
Description
Background
Ependymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma.

Methods
We determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas.

Results
In posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q.

Conclusion
Taken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.
Subject
chromosome 1q
ependymoma
promoter methylation
RelA fusion
telomerase
Journal Title
Neuro-Oncology
Volume
19
Issue
9
Start Page
1183
End Page
1194
ISSN
1522-8517
ISSN(Online)
1523-5866
Published Date
2017-5-24
DOI
Publisher
Society for Neuro-Oncology
NII Type
Journal Article
Format
PDF
Text Version
出版社版
Gyoseki ID
e34479
OAI-PMH Set
Faculty of Medicine