Lookup NU author(s): Professor David Ellison,
Dr Janet Lindsey,
Dr Meryl Lusher,
Professor Andrew Pearson,
Professor Steven Clifford
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PURPOSE: 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. PATIENTS AND 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. CONCLUSION: 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.
Author(s): Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, Pearson ADJ, Clifford SC
Publication type: Article
Journal: Journal of Clinical Oncology
ISSN (print): 0732-183X
ISSN (electronic): 1527-7755
PubMed id: 16258095
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