Craniopharyngiomas (CPs) are sellar tumours comprising adamantinomatous (ACP) and papillary (PCP) subtypes.  Potential therapies may depend on establishing and exploiting the molecular pathogenesis of these tumors (1, 2).

The wingless (Wnt) pathway influences embryonic development, including cell orientation and fate. β-catenin is constitutively synthesized and degraded by a cytosolic destruction complex. Upon Wnt pathway activation, phosphorylation at S45, S33, S37 and T41 prevents degradation, allowing β-catenin to enter the nucleus and mediate transcription of Wnt pathway target genes. Mutations at these loci in exon 3 prevent destruction in the absence of Wnt pathway activation. Such mutations are implicated in the tumorigenesis of ACPs (3-5) but have not been reported in PCPs.   β-catenin also participates in the adherens junction complex, with E-cadherin, a-catenin, plakoglobin and p120.  The role of the adherens junction has not been defined in CPs. We  characterized the largest cohort to date in the literature.

Nuclear β-catenin was found in discrete clusters or isolated epithelial cells in all of ACPs, but no PCPs, suggesting nuclear β-catenin could aid differential diagnosis of these subtypes. Mutations at S45, S33, S37 or T41 of CTNNB1 were found in only 50% of ACPs. Thus nuclear translocation of b-catenin occurs in the absence of CTNNB1 mutations, suggesting that other events can activate Wnt signalling in ACPs.  We found mutations in some PCPs defined by classical morphological criteria. 

Loss of expression of E-cadherin is associated with invasion and metastasis in neoplasia.  Previous reports show cleavage of E-cadherin and nuclear translocation of the cytoplasmic domain in other sellar tumours (6).  We sought to determine whether E-cadherin cleavage occurs in CPs. No translocation was observed. Validation of the antibody used in previous reports (clone 36/E-cadherin) showed it to be non-specific to E-cadherin.  In all cases, immunohistochemistry revealed no re-distribution of other adherens junction complex members linked with β-catenin translocation.

We conclude that while mutations in exon 3 of β-catenin are seen in 50% of ACPs, nuclear β-catenin translocation occurs in all ACPs, suggesting mutation is neither necessary nor sufficient for nuclear translocation. Redistribution of other adherens junction components is not linked with β-catenin translocation.