HPV-positive SCCHN is characterized by 56% of activating mutations and/or amplifications of the PIK3CA gene that encodes for the p100α unit of PI3kinase (PI3K), and a low incidence of tumor suppressor gene (TSG) alterations such as TP53 mutations (3%) (13), and no CDKN2A deletions. The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.