Mutational variants upstream follow this pattern, as observed early on in knockin PIK3CA mutants,18–21 and RTKs such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2, also known as ErbB2), and mesenchymal epithelial transition factor (MET, also known as hepatocyte growth factor receptor HGFR).22,23 The higher the number of the oncogenic proteins, the more undifferentiated the population, and the more aggressive the tumor.24–26 Undifferentiated, aggressive cancer states relate to the cargo of conformationally active, oncogenic molecules.27–33. The gene discussed is PIK3CA; the disease is cancer.