Role of DNA Methylation Profiles as Potential Biomarkers and Novel Therapeutic Targets in Head and Neck Cancer

SIMPLE SUMMARY: Recent studies have shown that DNA methylation alters gene expression, which drives tumorigenesis in cancer, and also, increasing evidence has shown that DNA methylation can regulate the tumor immune microenvironment (TIME) of cancer, which can affect the response to immunotherapy. For these reasons, DNA methylation has been recently recognized as a potential therapeutic target in various cancers, including head and neck cancer. Epigenetic therapy, specifically the role of DNA methyltransferase (DNMT) inhibitors in head and neck cancer treatment, is still in a primitive stage; therefore, a review of the published evidence of known DNA methylation profiles in head and neck cancer is important to access the potential value of DNA methylation as a diagnostic, prognostic, and predictive biomarker. Ultimately, I envision the rational design of clinical trials that will target a select group of head and neck patients with DNA methylation alterations that can be targeted in combination with chemotherapy and/or radiotherapy or immunotherapy. ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with high mortality. The main reasons for treatment failure are a low rate of early diagnosis, high relapse rates, and distant metastasis with poor outcomes. These are largely due to a lack of diagnostic, prognostic, and predictive biomarkers in HNSCC. DNA methylation has been demonstrated to play an important role in the pathogenesis of HNSCC, and recent studies have also valued DNA methylation as a potential biomarker in HNSCC. This review summarizes the current knowledge on DNA methylation profiles in HPV-positive and HPV-negative HNSCC and how these may contribute to the pathogenesis of HNSCC. It also summarizes the potential value of DNA methylation as a biomarker in the diagnosis, prognosis, and prediction of the response to therapy. With the recent immunotherapy era in head and neck treatment, new strategies to improve immune responses by modulating TIMEs have been intensely investigated in early-phase trials. Therefore, this study additionally summarizes the role of DNA methylation in the regulation of TIMEs and potential predictive immunotherapy response biomarkers. Finally, this study reviews ongoing clinical trials using DNA methylation inhibitors in HNSCC.