Before the knowledge of HPV infections and widespread use of (next generation) sequencing, HNSCC progression was also seen as an accumulation of stepwise (epi)-genetic alterations such as loss of chromosome 9p21 (CDKN2A loss), acquisition of TP53 mutations, 11q13 amplification (CCDN1), EGFR overexpression and PTEN inactivation [31]. The gene discussed is CDKN2A; the disease is head and neck squamous cell carcinoma.