Using whole exome sequencing (WES) in primary and recurrent HR-HPV-positive squamous anal cell carcinoma tumors, Mouw et al. (2017) reported four recurrent mutations in the FBXW7 gene, an E3 ubiquitin ligase that targets protooncogenes such as c-MYC and cyclin E; mutations in PIK3CA; alterations in the KEAP-1 binding domain; and mutations in TP63 and EP300, both of which are involved in squamous cell differentiation [160]. The gene discussed is PIK3CA; the disease is anal squamous cell carcinoma.