Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus–positive oropharyngeal squamous cell carcinoma

Sunny Haft, Shuling Ren, Guorong Xu, Adam Mark, Kathleen Fisch, Theresa W. Guo, Zubair Khan, John Pang, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Joseph A. Califano

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


Background: Human papillomavirus (HPV)–associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied. Methods: This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort. Results: There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV– counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV– HNSCC. Conclusions: This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.

Original languageEnglish
Pages (from-to)2423-2434
Number of pages12
Issue number14
Publication statusPublished - Jul 15 2019
Externally publishedYes


  • The Cancer Genome Atlas (TCGA)
  • epigenetics
  • exome sequencing
  • head and neck squamous cell carcinoma
  • human papillomavirus (HPV)
  • oropharyngeal squamous cell carcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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