The cell cycle is compromised in most HPV-negative HNSCC and premalignant cells through loss of function of p53, p16Ink4A (mutations, methylations and focal losses of chromosomal locus 9p21) and frequent amplification of cyclin D1 (Figure 3) [3,26]. The gene discussed is CDKN2A; the disease is head and neck squamous cell carcinoma.