Individuals with germline mutations in the tumour-suppressor gene CYLD are at 
high risk of developing disfiguring cutaneous appendageal tumours, the defining 
tumour being the highly organised cylindroma. Here, we analysed CYLD mutant 
tumour genomes by array comparative genomic hybridisation and gene expression 
microarray analysis. CYLD mutant tumours were characterised by an absence of 
copy-number aberrations apart from LOH chromosome 16q, the genomic location of 
the CYLD gene. Gene expression profiling of CYLD mutant tumours showed 
dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB 
and TRKC in tumours when compared with perilesional skin. Immunohistochemical 
analysis of a tumour microarray showed strong membranous TRKB and TRKC staining 
in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 
expression. Membranous TRKC overexpression was also observed in 70% of sporadic 
BCCs. RNA interference-mediated silencing of TRKB and TRKC, as well as treatment 
with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and 
proliferation in 3D primary cell cultures established from CYLD mutant tumours. 
These results suggest that TRK inhibition could be used as a strategy to treat 
tumours with loss of functional CYLD.