A common mechanism of PI3K activation in cancers is through the presence of mutations in the PIK3CA gene.61 The reported incidence of PIK3CA alterations in LSCC varies between 8 and 20% and the two main mutation types are canonical PIK3CA mutations and PIK3CA amplification.62–64 The canonical PIK3CA mutations affect two different domains of p110α, the kinase domain and the helical domain.65 These two types of mutations can activate the downstream signaling through two distinctive mechanisms. The gene discussed is PIK3CA; the disease is cancer.