Integrative Molecular Analysis of Skin Tumors from Patients with CYLD Cutaneous Syndrome

CYLD cutaneous syndrome (CCS) is a rare genetic disorder caused by germline CYLD mutations, leading to multiple benign skin tumors, including cylindromas, spiradenomas, and trichoepitheliomas. Although these tumors are well-characterized histologically, their molecular landscape remains unclear, and no targeted treatments exist. To comprehensively analyze the molecular features of CCS tumors, we integrated newly generated and publicly available data using multiomic approaches. We profiled 24 CCS tumors through whole-exome/genome sequencing, RNA sequencing, immunohistochemistry, and methylation arrays. To enhance statistical power, we incorporated existing CCS tumor datasets, forming a cohort of 50 tumors. CCS tumors exhibited a low mutational burden and scarce UV damage. The driver landscape was defined by mutations in CYLD, DNMT3A, and BCOR. The tumor microenvironment of cylindromas was rich in CD8⁺ T cells. Methylation profiling identified 2 groups: cylindromas, which appeared to originate from apocrine sweat glands, and trichoepitheliomas, which clustered with basal cell carcinoma. RNA sequencing revealed specific activation of the noncanonical NF-κB pathway in cylindromas, a finding confirmed by immunohistochemistry. This pathway may drive tumor formation, highlighting a potential therapeutic target for CCS. Our study provides insights into CCS tumor biology and suggests that targeting the noncanonical NF-κB pathway could be explored as a treatment strategy.