Transition from cylindroma to spiradenoma in CYLD-defective tumours is associated with reduced DKK2 expression.

Patients carrying heterozygous germline truncating mutations in the CYLD gene develop multiple primary hair follicle-related tumours. A highly patterned tumour, termed cylindroma, and a highly disorganized tumour, termed spiradenoma, may both develop in the same patient. Furthermore, histological features of both tumour types have been described within the same tumour specimen. We used three-dimensional computer-aided reconstruction of these tumours to demonstrate contiguous growth of cylindromas into spiradenomas, thus suggesting a transition between the two tumour types. To explore factors that may influence cutaneous tumour patterning, genome-wide transcriptomic analysis of 32 CYLD-defective tumours was performed. Overexpression of the Wnt/β-catenin signalling pathway was observed relative to normal perilesional tissue. Morphometric analysis was used to investigate the relationship between Wnt pathway-related gene expression and tumour organization. This revealed an association between reduced Dickkopf 2 (DKK2-a negative regulator of the Wnt/β-catenin signalling pathway) expression and loss of tumour patterning. Reduced DKK2 expression was associated with methylation of the DKK2 gene promoter in the majority of tumour samples assayed. RNA interference-mediated silencing of DKK2 expression in cylindroma primary cell cultures caused an increase in colony formation, cell viability, and anchorage-independent growth. Using these data, we propose a model where epigenetic programming may influence tumour patterning in patients with CYLD mutations.