The pathological mutations identified in a set of HNSCC and potentially premalignant (oral) lesion-derived cell lines and primary cells derived from potentially premalignant (oral) lesions predominantly involved a relatively small set of genes reported previously (TP53, KMT2D, CDKN2A, PIK3CA, NOTCH1, and FAT1) but also other predicted cancer drivers (MGA, PABPC3, NR4A2, NCOR1, and MACF1). Here, PIK3CA is linked to head and neck squamous cell carcinoma.