International genome analysis studies have now cataloged mutations in thousands of human cancers. An assessment of these studies using cBioPortal^1,2 and by Tamborero et al³ shows that the phosphatidylinositol 3-kinase (PI3K) pathway genes, including PIK3CA, PTEN, and AKT1, are among the most commonly mutated in human cancers of all types. Only TP53 is mutated more frequently. PI3K signaling typically is activated by signaling from tyrosine kinases and other receptors and proceeds through recruitment of a regulatory subunit (eg, p85α encoded by PIK3R1) and a catalytic subunit (eg, p110α, encoded by PIK3CA) to produce phosphatidylinositol-3,4,5-trisphosphate (PIP₃). PIP₃ recruits protein kinase B (AKT) that, in turn, stimulates growth and cell survival. This process is negatively regulated by PIP₃ dephosphorylation by the tumor suppressor, PTEN. PI3K pathway mutations enhance signaling along the pathway directly in the case of PIK3CA and AKT1 or by inactivating the negative regulator, PTEN.⁴