Maiden molecular differences between HPV-positive and HPV-negative HNSCC emerged from studies on p53, pRB and p16 that served as direct cellular targets of viral oncoproteins, E6 and E7 of high-risk HPVs (Van Houten et al., 2001; Hafkamp et al., 2003). This evidence concerns the gene CDKN2A and head and neck squamous cell carcinoma.