title: TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.
abstract: Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
authors.affiliation: The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.forename: David J H
authors.initials: DJ
authors.lastname: Shih
authors.forename: Christian
authors.initials: C
authors.lastname: Koelsche
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Nadia
authors.initials: N
authors.lastname: Hill
authors.forename: Florence M G
authors.initials: FM
authors.lastname: Cavalli
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.forename: Mark
authors.initials: M
authors.lastname: Barszczyk
authors.forename: A Sorana
authors.initials: AS
authors.lastname: Morrissy
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.forename: Betty
authors.initials: B
authors.lastname: Luu
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Livia
authors.initials: L
authors.lastname: Garzia
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Nataliya
authors.initials: N
authors.lastname: Zhukova
authors.forename: Robert
authors.initials: R
authors.lastname: Vanner
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
authors.forename: Karel
authors.initials: K
authors.lastname: Zitterbart
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: László
authors.initials: L
authors.lastname: Bognár
authors.forename: Almos
authors.initials: A
authors.lastname: Klekner
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Lach
authors.forename: Shin
authors.initials: S
authors.lastname: Jung
authors.forename: Ali G
authors.initials: AG
authors.lastname: Saad
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
authors.forename: Michael K
authors.initials: MK
authors.lastname: Cooper
authors.forename: Reid C
authors.initials: RC
authors.lastname: Thompson
authors.forename: Oliver O
authors.initials: OO
authors.lastname: Delattre
authors.forename: Franck
authors.initials: F
authors.lastname: Bourdeaut
authors.forename: François F
authors.initials: FF
authors.lastname: Doz
authors.forename: Miklós
authors.initials: M
authors.lastname: Garami
authors.forename: Peter
authors.initials: P
authors.lastname: Hauser
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Carlotti
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Van Meter
authors.forename: Luca
authors.initials: L
authors.lastname: Massimi
authors.forename: Daniel
authors.initials: D
authors.lastname: Fults
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kumabe
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ra
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.forename: Samer K
authors.initials: SK
authors.lastname: Elbabaa
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Faria
authors.forename: Sidney E
authors.initials: SE
authors.lastname: Croul
authors.forename: Annie
authors.initials: A
authors.lastname: Huang
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Hawkins
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.forename: David
authors.initials: D
authors.lastname: Meyronet
authors.forename: Anne
authors.initials: A
authors.lastname: Jouvet
authors.forename: Michelle
authors.initials: M
authors.lastname: Fèvre-Montange
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Marta
authors.initials: M
authors.lastname: Perek-Polnik
authors.forename: Wieslawa A
authors.initials: WA
authors.lastname: Grajkowska
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
chemical_list: D019098:Telomerase