CYLD Alterations Are Associated With Metastasis and Poor Prognosis in Human Papilloma Virus-Positive Head and Neck Cancer

Head Neck. 2025 Feb;47(2):606-614. doi: 10.1002/hed.27944. Epub 2024 Sep 30.

Abstract

Background: Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an emerging epidemic and a subset of HPV-positive patients experience aggressive disease with metastases. The CYLD gene is frequently altered in HPV-positive HNSCC, but the role of these alterations in disease progression is poorly understood.

Methods: We identified 11 HPV-positive HNSCC patients with CYLD alterations and assessed their clinical course. We also characterized a unique, HPV-positive, metastatic, HNSCC patient-derived xenograft (PDX).

Results: All 11 patients developed metastasis with reduced overall survival when compared with metastatic HPV-positive patients with wild-type CYLD. The metastatic PDX harbored a CYLD mutation (S371*) and exhibited reduced expression of connexin 43, a potentially antimetastatic protein. We also investigated the functional impact of the S371* mutation, as well as 2 CYLD mutations from our 11-patient cohort.

Conclusion: Our findings indicate that alterations in CYLD in HPV-positive HNSCC are associated with metastasis and poor prognosis.

Keywords: CYLD; HNSCC; HPV; metastasis; prognosis.

MeSH terms

  • Aged
  • Animals
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Deubiquitinating Enzyme CYLD* / genetics
  • Female
  • Head and Neck Neoplasms* / genetics
  • Head and Neck Neoplasms* / mortality
  • Head and Neck Neoplasms* / pathology
  • Head and Neck Neoplasms* / virology
  • Human Papillomavirus Viruses
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Mutation*
  • Neoplasm Metastasis
  • Papillomaviridae / genetics
  • Papillomavirus Infections* / complications
  • Papillomavirus Infections* / genetics
  • Papillomavirus Infections* / virology
  • Prognosis
  • Squamous Cell Carcinoma of Head and Neck* / genetics
  • Squamous Cell Carcinoma of Head and Neck* / mortality
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Squamous Cell Carcinoma of Head and Neck* / virology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Deubiquitinating Enzyme CYLD
  • CYLD protein, human
  • Tumor Suppressor Proteins