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

Abstract

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of highrisk (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 hrHPVpositive 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.

NF-κB over-activation portends improved outcomes in HPV-associated head and neck cancer

“…Somatic mutations or deletions in TRAF3 or CYLD identified a subset of HPV+ HNSCC associated with improved outcome [1,16,17]. Increasing evidence demonstrates these somatic mutant tumors identify a distinct clinical entity given notable molecular, histopathologic, and outcome differences [3,16,43]. Regarding function, TRAF3 is a ubiquitin ligase that regulates numerous receptor pathways, ultimately functioning to negatively regulate both canonical and non-canonical NF-κB pathways [44].…”

“…It is categorized into two discrete diseases based on etiology: human papillomavirus (HPV) negative HNSCC, which is primarily caused by exposure to ethanol and tobacco, and HPV-associated (HPV+) HNSCC [1]. These forms of HNSCC have contrasting clinical, epidemiological, and histological features [2][3][4] with HPV+ HNSCC occurring in a younger population with less or no smoking history [5, www.oncotarget.com 6]. HPV-mediated cancer arises primarily in the reticulated epithelia of the oropharynx (e.g., tonsils, base of tongue), whereas HPV-negative HNSCC is found at all subsites (e.g., oral cavity, larynx) [2].…”

KMT2 (MLL) family of methyltransferases in head and neck squamous cell carcinoma: A systematic review

“…The included studies were conducted in 16 different countries, that is Austria, 23 Brazil, 24 Canada, 25,26 China, 27,28 Denmark, 29,30 France, 31,32 Germany, 33 India, 34–36 Japan, 37 Malaysia, 38 Pakistan, 39 Poland, 40 Taiwan, 41,42 Thailand, 43 the Netherlands, 44 and the United States of America 45–55 . All of them were published in English between 2011 and 2022.…”

Recent Advances on Immunohistochemistry and Molecular Biology for the Diagnosis of Adnexal Sweat Gland Tumors

“…Similar to adenoid cystic carcinoma, CYLD-defective cylindromas, however, demonstrate upregulation and overexpression of MYB and its target genes [44], suggesting the involvement of alternative mechanisms than MYB fusion [29]. CYLD mutations have recently been described in a subset of high-risk HPV-positive head and neck squamous cell and anal carcinomas, which show histological features close to cylindroma and have been designated as CYLD-mutant cylindroma-like basaloid carcinoma [45,46].…”