title: TERT Promoter Mutations but not the Alternative Lengthening of Telomeres Phenotype Are Present in a Subset of Ependymomas and Are Associated With Adult Onset and Progression to Ependymosarcoma.
abstract: Genetic signatures related to telomere maintenance have emerged as powerful classifiers among CNS tumors. These include the alternative lengthening of telomeres (ALT) phenotype associated with mutations in the ATRX and DAXX genes and recurrent point mutations in the TERT gene promoter. We investigated a patient cohort covering the entire spectrum of childhood and adult ependymomas (n = 128), including subependymomas and myxopapillary ependymomas, for the presence of TERT promoter mutations, for loss of ATRX or DAXX expression by immunohistochemistry (as surrogates as underlying gene mutations), and for the ALT phenotype by fluorescence in situ hybridization (FISH). TERT promoter mutations were identified in 9/120 (7%) of tumors, all of which were conventional ependymomas occurring in adults. TERT promoter mutations were associated with older age and intracranial localization. Remarkably, 2 of these tumors progressed to ependymosarcoma upon recurrence. No tumors displayed an ALT phenotype by FISH or were ATRX or DAXX deficient by immunohistochemistry. In sum, TERT promoter mutations are present in a subset of mostly intracranial conventional ependymomas in adults and may be relevant for the uncommon progression to ependymosarcoma. Loss of ATRX immunoreactivity is a useful marker to rule out ependymoma in specific diagnostic settings.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brügger
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Dettmer
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Maja
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marinoni
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Hewer
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004806:Ependymoma / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics*; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: ATRX; Alternative lengthening of telomeres; DAXX; Ependymoma; Ependymosarcoma; TERT