Beta‐catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/β‐catenin pathway occurs in 10‐15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for β‐catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of β‐catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all β‐catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/β‐catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear β‐catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/β‐catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow‐up of 75.7 months (range 27.5–121.2 months) from diagnosis. All three patients with focal nuclear staining of β‐catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1‐mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de‐escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.