Craniopharyngiomas are epithelial, sellar tumours comprising two subtypes: adamantinomatous (aCP) and papillary (pCP). The adamantinomatous form occurs predominantly during childhood whereas the papillary form is more common in adults. aCPs often contain mutations in CTNNB1, encoding β-catenin: a component of the adherens junction and mediator of Wnt signaling. The tumorigenic mechanism underlying pCPs is not well understood. In a large series of craniopharyngiomas (61 aCP, 25 pCP) we show that the adamantinomatous subtype harbours mutations in CTNNB1 in 44% of cases sequenced, while the papillary subtype has BRAF V600E mutations in 91% of cases sequenced, indicating that these lesions are genetically distinct with differing tumorigenic mechanisms, namely Wnt pathway (aCP) and MAPK pathway activation (pCP). An antibody to the BRAF V600E mutation (clone VE1) proved less reliable than sequencing for detection of BRAF V600E mutation, but for specimens with little epithelium, immunohistochemistry may prove useful. While CTNNB1 mutation - when present - is found throughout aCPs, 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. There was no disruption of the adherens junction in these tumours indicating that loss of junction integrity is not associated with β-catenin translocation or mutation. Translocation of β-catenin from membrane to cytosol and nucleus in aCPs and mutation in V600E in pCPs offers a potential marker for differential diagnosis. Furthermore the availability and clinical efficacy of mutant BRAF inhibitors presents an opportunity for directed therapy in patients with pCPs. While mutations in CTNNB1 and BRAF underlie tumorigenesis in the majority of craniopharyngiomas, the tumorigenic event in the remaining population is unknown.
|Published - 2014
|International Congress of Endocrinolgy / ENDO 2014 - Chicago, United States
Duration: 21 Jun 2014 → 24 Jun 2014
|International Congress of Endocrinolgy / ENDO 2014
|21/06/14 → 24/06/14