DNA Methylation and HPV-Associated Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC), especially oropharyngeal squamous cell carcinoma (OPSCC), has recently been found to be significantly associated with human papillomavirus (HPV) infection. The incidence of OPSCC has been increasing and surpassed the number of cervical cancer cases in the United States. Although HPV-associated OPSCC has a relatively better prognosis than HPV-negative cancer, approximately 20% of HPV-associated HNSCC patients show a poor prognosis or therapeutic response, and the molecular mechanism behind this outcome in the intermediate-risk group is yet to be elucidated. These biological differences between HPV-associated HNSCC and HPV-negative HNSCC are partly explained by the differences in mutation patterns. However, recent reports have revealed that epigenetic dysregulation, such as dysregulated DNA methylation, is a strikingly common pathological feature of human malignancy. Notably, viral infections can induce aberrant DNA methylation, leading to carcinogenesis, and HPV-associated HNSCC cases tend to harbor a higher amount of aberrantly methylated DNA than HPV-negative HNSCC cases. Furthermore, recent comprehensive genome-wide DNA-methylation analyses with large cohorts have revealed that a sub-group of HPV-associated HNSCC correlates with increased DNA methylation. Accordingly, in this review, we provide an overview of the relationship between DNA methylation and HPV-associated HNSCC.

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements

“…Among the more than 200 existing HPVs, high-risk genotype (such as HPV16 and HPV18) persistent infections progress into cancer, and in the majority of HPV-driven carcinomas, type 16 is involved [ 9 ]. Most of the HPV16-induced head and neck cancers affect the palatine tonsils, that often metastasize to nearby lymph nodes [ 10 , 11 ]. Crucial in the pathogenesis of HPV-driven carcinomas is the expression of early genes-encoded E6 and E7 oncoproteins which, by targeting host cell tumor suppressors p53 and pRB, provide the infected keratinocyte with a growth advantage, with enhanced proliferation rate, impaired apoptosis and progressive immune evasion [ 12 , 13 ].…”

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma

“…At present, nine FDA-approved agents, representing four epigenetic targets (DNMT, HDAC, IDH, and EZH2), are used for the treatment of a variety of cancers, and several drugs that target epigenetic mechanisms are currently in clinical trials [ 113 ]. Many studies have reported that HPV-negative HNSCC has lower DNA methylation levels than HPV-positive HNSCC, which harbors distinctly hypermethylated genomes [ 114 ]. Thus, researchers expect that HPV-positive HNSCC will have a more robust response to epigenetic targeted therapy.…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Methylome analyses of HPV-positive cancers revealed differences in DNA methylation compared to matching normal tissue or HPV-negative tumors and transfection studies have confirmed that the E6 and E7 oncoproteins provoked hypermethylation tumor suppressor genes and hypomethylation of proto-oncogenes [ 31 , 32 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ]. Both these viral proteins have been shown to upregulate the expression of DNMT1.…”