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 (aCGH) and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy number aberrations apart from loss-of-heterozygosity at chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours revealed dysregulated tropomyosin kinase (TRK) signalling with overexpression of TRKB and TRKC in tumours when compared to perilesional skin. Immunohistochemical analysis of a tumour microarray demonstrated 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 basal cell carcinomas. 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 three-dimensional 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.
Objective
To comprehensively ascertain the extent and severity of clinical features in multiple affected individuals from two large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the three appendageal tumor predisposition syndromes, familial cylindromatosis (FC), Brooke-Spiegler syndrome (BSS), and multiple familial trichoepitheliomas (MFT) known to be associated with such germline mutations.
Design
Inter- and intra-familial observational study.
Setting
Tertiary genetic and dermatology referral centre.
Participants
32 individuals were recruited from two large multigenerational families with CYLD mutations. Clinical details, history and tumor maps were obtained from all participants whilst 18 were further corroborated with detailed clinical examination.
Main outcome measures
Severity of tumor density, distribution and histology, associated medical conditions, patient symptoms and impact of disease on quality of life.
Results
We demonstrate a wide variation in clinical presentation seen in individuals from the same family. In addition, we provide clinical evidence that correlates with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction.
Conclusion
In view of our findings, we propose that the burden of disease at sites other than the head and neck is underreported in the literature, but impacts greatly on quality of life. The differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counselling even within individuals from the same family. Thus, we suggest an encompassing diagnosis of “CYLD cutaneous syndrome”. Finally, our results relating to the clinical distribution of tumors suggest hormonal factors may play an important role in tumor induction in these patients.
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