title: The Wnt signalling cascade and the adherens junction complex in craniopharyngioma tumorigenesis.
abstract: Craniopharyngiomas are epithelial, sellar tumours with adamantinomatous (aCP) and papillary (pCP) subtypes. The aCP type usually occurs during childhood and pCP in middle-aged adults; aCPs often contain mutations in CTNNB1, encoding β-catenin, a component of the adherens junction and a mediator of Wnt signalling. No such mutational event has been associated with pCPs, where the BRAF gene appears to be more important. In a large series of 95 craniopharyngiomas, we show that the aCP subtype harbours mutations in CTNNB1 in 52 % of cases, while the pCP subtype does not, with agreement between immunohistochemistry and sequencing methods in the majority of cases. When present, the CTNNB1 mutation is found throughout the aCP tumour, while translocation of β-catenin from membrane to cytosol and nucleus is restricted to small cell clusters near the invading tumour front. We observed translocated β-catenin in 100 % of aCPs, occurring not only in cell clusters but also in individual cells scattered throughout the tumour. We characterised the adherens junction involving α-catenin, β-catenin, γ-catenin, p120 and E-cadherin (cytosolic and membranous components). Although suggested to be important in other sellar mass tumourigenesis pathways, there was no disruption of the adherens junction in these tumours, indicating that a loss of junctional integrity is not associated with β-catenin translocation or mutation. We conclude that mutations in CTNNB1 underlie tumourigenesis in the majority of aCPs, which are distinct morphologically and at the molecular level from pCPs.
authors.affiliation: Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Rd, Headington, Oxford, OX3 7LE, UK, vpre3773@uni.sydney.edu.au.
authors.forename: Veronica
authors.initials: V
authors.lastname: Preda
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Larkin
authors.forename: Niki
authors.initials: N
authors.lastname: Karavitaki
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis; D015820:Cadherins / Q000378:metabolism; D003397:Craniopharyngioma / Q000235:genetics / Q000473:pathology*; D005091:Exons / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology*; D021381:Protein Transport; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D051176:beta Catenin