title: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee.
abstract: OBJECTIVE
  Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the beta-catenin protein is associated with activation of the Wnt/Wg signaling pathway, and mutations affecting components of this pathway have been reported in approximately 15% of sporadic medulloblastomas. We tested the hypothesis that nuclear immunoreactivity for beta-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear beta-catenin immunoreactivity and mutations of CTNNB1 and APC.
  
  
  METHODS
  Medulloblastomas from children entered onto the International Society for Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group (UKCCSG) PNET3 trial (n = 109) were examined for beta-catenin immunoreactivity, and where tissue was available, evidence of CTNNB1 and APC mutations. The results were correlated with clinicopathologic variables, principally outcome.
  
  
  RESULTS
  Children with medulloblastomas that showed a nucleopositive beta-catenin immunophenotype (27 of 109; 25%) had significantly better overall (OS) and event-free (EFS) survivals than children with tumors that showed either membranous/cytoplasmic beta-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For beta-catenin nucleopositive and nucleonegative medulloblastomas, 5-year OS was 92.3% (95% CI, 82% to 100%) versus 65.3% (95% CI, 54.8 to 75.7%), and 5-year EFS was 88.9% (95% CI, 77% to 100%) versus 59.5% (95% CI, 48.8 to 70.2%), respectively. Mutations in CTNNB1 were found exclusively among medulloblastomas that demonstrated nuclear beta-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with beta-catenin nucleopositive large cell/anaplastic medulloblastomas and beta-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis.
  
  
  CONCLUSIONS
  Nuclear accumulation of beta-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, UK. D.W.Ellison@ncl.ac.uk
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Olabisi E
authors.initials: OE
authors.lastname: Onilude
authors.forename: Janet C
authors.initials: JC
authors.lastname: Lindsey
authors.forename: Meryl E
authors.initials: ME
authors.lastname: Lusher
authors.forename: Claire L
authors.initials: CL
authors.lastname: Weston
authors.forename: Roger E
authors.initials: RE
authors.lastname: Taylor
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Pearson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000293:Adolescent; D002467:Cell Nucleus / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D015996:Survival Rate; D006113:United Kingdom; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D051176:beta Catenin