Nuclear β-catenin, a hallmark of active canonical Wnt signaling, can be histologically detected in a subset of cells and cell clusters in up to 94% of adamantinomatous craniopharyngioma (ACP) samples.
The genetic analysis with whole-exome sequencing studies showed no differential mutations of CTNNB1 (β-catenin) and BRAF (V600E) between TC and NC subtypes, but there was a difference between adamantinomatous craniopharyngioma and papillary craniopharyngioma.
Frequent somatic mutations of BRAF and CTNNB1 were identified in both histological subtypes of craniopharyngioma (adamantinomatous and papillary) which shed light on target therapy to cure this oncogenic disease.
All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation.
The data suggest that mutations in CTNNB1 are the major driver mutations of CCOT, and that CCOT is the genetic analog of pilomatrixoma and adamantinomatous craniopharyngioma in odontogenic tissue.
Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner.
Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors.
Since the first identification of CTNNB1 mutations in adamantinomatous craniopharyngioma (ACP), much has been learned about the molecular pathways and processes that are disrupted in ACP pathogenesis.
In addition, they play a critical role in tumor formation, specifically in the etiology of human adamantinomatous craniopharyngioma, a clinically relevant tumor that is associated with mutations in CTNNB1 (gene encoding β-catenin).
The authors have previously shown high mutation rates of BRAF V600E in papillary craniopharyngioma and of CTNNB1 in adamantinomatous craniopharyngioma.
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.
With the discovery of aberrant Wnt/β-catenin pathway signaling in the pathogenesis of the most common subtype of craniopharyngioma (adamantinomatous), the identification of candidate genes and proteins implicated in this cascade provide attractive targets for future therapies.
Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours.
Mutations or polymorphisms in pituitary transcription factors are unlikely to contribute to the adamantinomatous craniopharyngioma pathogenesis, differently of CTNNB1 mutations.
Sequenced PCR products for possible beta-catenin gene mutations showed a total of 7/43 alterations in adamantinomatous craniopharyngioma-derived DNA samples.