title: Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma.
abstract: OBJECTIVE
  Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
  
  
  METHODS
  We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.
  
  
  RESULTS
  TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.
  
  
  CONCLUSIONS
  Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
authors.affiliation: University of Toronto, Toronto, Canada.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Zhukova
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Elke
authors.initials: E
authors.lastname: Pfaff
authors.forename: David J H
authors.initials: DJ
authors.lastname: Shih
authors.forename: Dianna C
authors.initials: DC
authors.lastname: Martin
authors.forename: Pedro
authors.initials: P
authors.lastname: Castelo-Branco
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.forename: Stefan
authors.initials: S
authors.lastname: Rutkowski
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bognar
authors.forename: Almos
authors.initials: A
authors.lastname: Klekner
authors.forename: Byung-Kyu
authors.initials: BK
authors.lastname: Cho
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kim
authors.forename: Kyu-Chang
authors.initials: KC
authors.lastname: Wang
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Michelle
authors.initials: M
authors.lastname: Fevre-Montange
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
authors.forename: Max
authors.initials: M
authors.lastname: Kros
authors.forename: Wieslawa A
authors.initials: WA
authors.lastname: Grajkowska
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Peter
authors.initials: P
authors.lastname: Hauser
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Anne
authors.initials: A
authors.lastname: Jouvet
authors.forename: Shin
authors.initials: S
authors.lastname: Jung
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Lach
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.forename: Linda M
authors.initials: LM
authors.lastname: Liau
authors.forename: Luca
authors.initials: L
authors.lastname: Massimi
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Young
authors.initials: Y
authors.lastname: Shin Ra
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Karel
authors.initials: K
authors.lastname: Zitterbart
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Hill
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindsey
authors.forename: Ed C
authors.initials: EC
authors.lastname: Schwalbe
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
mesh_terms: D000293:Adolescent; D000328:Adult; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D055815:Young Adult