CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

• Published in: Modern pathology Vol. 34; no. 2; pp. 358 - 370
• Main Authors: Williams, Erik A., Montesion, Meagan, Alexander, Brian M., Ramkissoon, Shakti H., Elvin, Julia A., Ross, Jeffrey S., Williams, Kevin Jon, Glomski, Krzysztof, Bledsoe, Jacob R., Tse, Julie Y., Mochel, Mark C.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.02.2021; Nature Publishing Group US; Elsevier Limited
• Subjects: 45/23; 631/67/1858; 692/699/67/1536/1665; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Carcinoma, Adenoid Cystic - genetics; Cdc4 protein; Deubiquitinating Enzyme CYLD - genetics; DNA fingerprinting; DNA sequencing; Female; Gene deletion; Head & neck cancer; Head and neck; Head and neck carcinoma; Histopathology; Humans; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Mutants; Mutation; Papillomavirus Infections - complications; Pathology; PTEN protein; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - virology; Tumor cells; Tumor suppressor genes
• ISSN: 0893-3952; 1530-0285; 1530-0285
• DOI: 10.1038/s41379-020-00672-y

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p < 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p < 0.0001), KMT2D (1% vs. 16%, p < 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p < 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment.