Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Despite aggressive treatment of HNSCC patients, which entails surgery, chemo- and radio-therapy, the five-year survival is only 40-50%. Tobacco, alcohol, microbial factors (high-risk human papillomaviruses, hrHPVs), systemic factors (immunosuppression, micronutrient deficiency) and UV-radiation are common risk factors for development of HNSCC. HNSCC patients with HPV infection were found to have better prognosis and treatment response. Besides the HPV status, no adequate biomarkers have been found so far to predict the poor/good clinical outcome nor is the mechanism of how HPV modulates therapy response fully understood. Epigenetic changes such as DNA methylation of specific gene promoters and posttranscriptional modification of gene expression by specific microRNA (miRNA) seems to be promising biomarkers of disease occurrence and progression. Therefore, the primary objective of this project is to identify novel specific epigenetic biomarkers to predict early-stage of HNSCC, notably oral and oropharyngeal cancer, patients at greater risk for developing invasive cancer, and finally understand treatment response in patient with HPV-associated cancers. State-of-the-art technologies, wide-genome microarray assay and types-specific validation of DNA methylation and miRNA profiles (methylome and mirome, respectively) will be used on subsets of healthy tissue, HPV-related and HPV-unrelated precancerous oral lesions, oral and oropharyngeal cancer, and metastasis. The integration of all findings should yield ideal epigenetic biomarkers. This project is a comprehensive interdisciplinary research, which includes basic and clinical research, and will enable the improvement of existing knowledge, development of new technological approaches in diagnostics and prognostics, and possible new treatment approach for oral and oropharyngeal cancer.