HPV-negative HNSCC show inactivation mainly by deletion or promoter hypermethylation of the CDKN2A gene encoding p16INK4a [51] and frequently have CCND1 amplification [52], which encodes cyclin D1, with both leading to a decrease in the growth-suppressive hypo-phosphorylated RB form. Here, RB1 is linked to head and neck squamous cell carcinoma.