β-Catenin Status Predicts a Favorable Outcome in Childhood Medulloblastoma: The United Kingdom Children's Cancer Study Group Brain Tumour Committee

TLDR

Nuclear accumulation of β‑catenin is linked to activation of the Wnt/Wg pathway, with pathway‑related mutations present in about 15 % of sporadic medulloblastomas. The study aimed to determine whether nuclear β‑catenin immunoreactivity predicts prognosis in medulloblastoma and to examine its association with CTNNB1 and APC mutations. The authors examined 109 pediatric medulloblastoma samples from the SIOP/UKCCSG PNET3 trial for β‑catenin immunoreactivity and CTNNB1/APC mutations, then correlated these findings with clinical outcomes. Nuclear β‑catenin positivity was associated with markedly improved 5‑year overall (92.3 % vs 65.3 %) and event‑free (88.9 % vs 59.5 %) survival, CTNNB1 mutations were found only in these tumors, and all nucleopositive large‑cell/anaplastic and metastatic cases survived at least five years.

Abstract

Purpose Identifying pathobiological correlates of clinical behavior or therapeutic response currently represents a key challenge for medulloblastoma research. Nuclear accumulation of the β-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 β-catenin is a prognostic marker in medulloblastoma, and assessed the relationship between nuclear β-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 β-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 β-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 β-catenin immunoreactivity or no immunoreactivity (P = .0015 and P = .0026, respectively). For β-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 β-catenin immunoreactivity, but no evidence of APC mutation was found in these cases. All children with β-catenin nucleopositive large cell/anaplastic medulloblastomas and β-catenin nucleopositive medulloblastomas presenting with metastatic disease are alive at least 5 years postdiagnosis. Conclusion Nuclear accumulation of β-catenin appears to be a marker of favorable outcome in medulloblastoma, and should be investigated further in large group-wide trials.