Early studies of the genomic landscape of HNSCC led by our group and others and confirmed by The Cancer Genome Atlas (TCGA), demonstrated that mutations and deletions of the TP53 and CDKN2A are the tumor suppressor genes most frequently altered somatically in HNSCC, as TP53 and CDKN2A alterations are seen in up to 85% and 58% respectively of non-human papilloma virus associated (HPV negative) HNSCC (61–63). Here, CDKN2A is linked to head and neck squamous cell carcinoma.