Well prior to the advent of high throughput sequencing, alterations in several genes, including inactivation or deletion of the tumor suppressors CDKN2A (p16; [71]) and TP53 (p53; [72]), and overexpression (via amplification and elevated transcription) of the epidermal growth factor receptor EGFR [73] had been identified as relevant to the pathogenesis of HPV-negative HNSCC. This evidence concerns the gene EGFR and head and neck squamous cell carcinoma.