TY - JOUR
T1 - Telomerase activation in posterior fossa group A ependymomas is associated with dismal prognosis and chromosome 1q gain
AU - Gojo, Johannes
AU - Lötsch, Daniela
AU - Spiegl-Kreinecker, Sabine
AU - Pajtler, Kristian W.
AU - Neumayer, Katharina
AU - Korbel, Pia
AU - Araki, Asuka
AU - Brandstetter, Anita
AU - Mohr, Thomas
AU - Hovestadt, Volker
AU - Chavez, Lukas
AU - Kirchhofer, Dominik
AU - Ricken, Gerda
AU - Stefanits, Harald
AU - Korshunov, Andrey
AU - Pfister, Stefan M.
AU - Dieckmann, Karin
AU - Azizi, Amedeo A.
AU - Czech, Thomas
AU - Filipits, Martin
AU - Kool, Marcel
AU - Peyrl, Andreas
AU - Slavc, Irene
AU - Berger, Walter
AU - Haberler, Christine
N1 - Publisher Copyright:
© The Author(s) 2017.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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 fusionpositive (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.
AB - 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 fusionpositive (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.
KW - Chromosome 1q
KW - Ependymoma
KW - Promoter methylation
KW - RelA fusion
KW - Telomerase
UR - http://www.scopus.com/inward/record.url?scp=85031813982&partnerID=8YFLogxK
U2 - 10.1093/neuonc/nox027
DO - 10.1093/neuonc/nox027
M3 - Article
C2 - 28371821
AN - SCOPUS:85031813982
SN - 1522-8517
VL - 19
SP - 1183
EP - 1194
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 9
ER -