"Inherited cutaneous tumour syndromes: The CYLD story"
Rare genetic skin disease can offer new insights into common skin disease. My research group focusses on patients with germline mutations in the tumour suppressor gene CYLD, who develop disfiguring, cutaneous hair follicle tumours. Curiously, the phenotypic consequences of mutations in this lysine-63 specific ubiquitin hydrolase encoding gene are almost exclusively restricted to the skin.
The defining tumour of this syndrome is called “cylindroma”, and up to 1 in 4 patients with multiple cylindromas undergo total scalp removal. To improve this outcome, we have characterised the genomic and transcriptomic changes in cylindromas and related “CYLD-defective”tumours obtained from these patients. We discovered dysregulated tropomyosin kinase signaling (TRK) in the tumour tissue, that proved to be an oncogenic dependency in primary cultures of these tumours. As TRK dependency has not been previously explored in other common cutaneous tumours, we investigated expression in a panel of common skin cancers, and found aberrant expression of TRK in sporadic basal cell carcinoma, the commonest skin cancer. Further research on cylindromas has highlighted mechanisms of histological tumour patterning and deregulated oncogenic signalling, suggesting that this fascinating model will continue to inform our understanding of common skin tumours.