CYLD Mutations, PD-L1 and HPV; A Pan-Cancer Landscape Analysis

Background CYLD , a tumor suppressor gene encoding a deubiquitinase enzyme, regulates tumorigenesis via NF-κB signaling. CYLD mutations are linked to immune evasion and PD-L1 upregulation, particularly in virus-associated cancers. We evaluated CYLD alterations across cancers and their correlation with PD-L1 expression. Given the established link between CYLD dysfunction and viral oncogenesis, we also assessed the co-occurrence of CYLD alterations and human papillomavirus (HPV) status. Methods We conducted a real-world data analysis of CYLD alterations in 145,991 tumor samples that underwent clinical-grade comprehensive genomic profiling during routine care; PD-L1 expression via immunohistochemistry (IHC) was assessed in 10,053 specimens. The relationship between CYLD alterations and high-risk HPV across cancers was also evaluated. Results CYLD mutations occurred in 0.57% (836/145,991) of tumors, with the highest rates in thymic carcinomas (15.4%, 34/220), anal carcinomas (11.4%, 55/479), and head and neck cancers (6.4%, 154/2,423). Among 10,053 samples with PD-L1 IHC evaluated, 62 (0.6%) harbored CYLD alterations. Overall, 61% (38/62) of CYLD -altered tumors were positive for PD-L1 IHC expression (≥ 1%), with 29% (18/62) exhibiting high PD-L1 expression (≥ 50%). In addition, 27.5% (230/836) of CYLD -altered tumors were HPV+, with strong enrichment in head and neck cancers (odds ratio [OR] = 7.4; p < 0.0001). Conclusions We highlight the rarity of CYLD mutations across most cancers but underscore their relatively elevated prevalence in thymic carcinomas, anal carcinomas, and head and neck cancers. The observed associations between CYLD alterations, PD-L1 expression, and HPV positivity suggest that CYLD status, combined with immune and viral biomarkers, may merit exploration as a predictor of immunotherapy benefits.