Nuclear Localization and Mutation of β-Catenin in Medulloblastomas

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Abstract
The adenomatous polyposis coli (APC) gene, a member of the Wingless/Wnt signal transduction pathway, has been implicated in the development of medulloblastomas in Turcot's syndrome. β-catenin also functions in this highly conserved signaling pathway and is instrumental in growth and development. Mutations in either APC or β-catenin can stabilize β-catenin protein. Stabilized β-catenin complexes with Tcf/Lef transcription factors and moves from the cytoplasm into the nucleus where it regulates the transcription of c-Myc and other genes. Nuclear localization of β-catenin therefore implies activation of the signaling pathway. We have analyzed the subcellular localization of β-catenin in 51 sporadic medulloblastomas and in 1 medulloblastoma arising in a patient with Turcot's syndrome. Nuclear β-catenin staining was present in 9 of the sporadic tumors (18%) and in the 1 medulloblastoma from a Turcot's patient. The remaining 41 cases did not show nuclear staining. This confirms earlier observations that Wingless/Wnt signaling is involved in a subset of sporadic medulloblastomas. We also examined 48 glial and meningeal CNS tumors, all of which were negative for nuclear β-catenin. Exon 3 of β-catenin was sequenced in 6 of the 9 sporadic medulloblastomas with nuclear β-catenin staining. Five of the 6 tumors sequenced had mutations affecting highly conserved β-catenin phosphorylation sites involved in protein stability. These data suggest a simple immunohistochemical method to screen for β-catenin mutations in medulloblastomas.