Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma

Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear beta-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of beta-catenin Ser37 residue (Delta S37). The Delta S37 beta-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type beta-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of Delta S37 beta-catenin contributed to early medulloblastoma tumorigenesis.

Automated summary

In this study, we analyzed the histology, molecular characteristics, and functional properties of 88 pediatric medulloblastoma tumor samples. We identified a subset of patients with WNT activation, characterized by CTNNB1 mutations and nuclear beta-catenin staining. We also discovered a novel CTNNB1 mutation resulting in the deletion of beta-catenin Ser37 residue. Functional analysis showed that the Delta S37 beta-catenin variant exhibited higher protein expression levels and increased TCF/LEF transcriptional activity in cells.