Quantifying these third-order interactions allows us to propose a simple principle for tumor evolution (Fig. 5): that for some cancer types (e.g., SKCM) tumor evolution can occur via two alternative evolutionary paths—either via a cell obtaining two hits in a single driver gene (e.g., BRAF) or via a cell obtaining single hits in two different genes in the same pathway (e.g., BRAF and NRAS). The gene discussed is BRAF; the disease is neoplasm.