title: Alternative lengthening of telomeres is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors.
abstract: Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Mangerel
authors.forename: Aryeh
authors.initials: A
authors.lastname: Price
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: Jack
authors.initials: J
authors.lastname: Brzezinski
authors.forename: Pawel
authors.initials: P
authors.lastname: Buczkowicz
authors.forename: Patricia
authors.initials: P
authors.lastname: Rakopoulos
authors.forename: Diana
authors.initials: D
authors.lastname: Merino
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wasserman
authors.forename: Matthew
authors.initials: M
authors.lastname: Mistry
authors.forename: Mark
authors.initials: M
authors.lastname: Barszczyk
authors.forename: Daniel
authors.initials: D
authors.lastname: Picard
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Hava
authors.initials: H
authors.lastname: Starkman
authors.forename: Cynthia
authors.initials: C
authors.lastname: Elizabeth
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.forename: Noa
authors.initials: N
authors.lastname: Alon
authors.forename: Jodi
authors.initials: J
authors.lastname: Lees
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Donna L
authors.initials: DL
authors.lastname: Johnston
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Annie
authors.initials: A
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000293:Adolescent; D001932:Brain Neoplasms / Q000235:genetics* / Q000503:physiopathology; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology; D016545:Choroid Plexus Neoplasms / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D060787:Neoplasm Grading; D018242:Neuroectodermal Tumors, Primitive / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D011379:Prognosis; D016615:Telomere / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein