RHOA takes the RHOad less traveled to cancer.

RAS and RHO GTPases function as signaling nodes that regulate diverse cellular processes. Whereas RAS mutations were identified in human cancers nearly four decades ago, only recently have mutations in two RHO GTPases, RAC1 and RHOA, been identified in cancer. RAS mutations are found in a diverse spectrum of human cancer types. By contrast, RAC1 and RHOA mutations are associated with distinct and restricted cancer types. Despite a conservation of RAS and RAC1 residues that comprise mutational hotspots, RHOA mutations comprise highly divergent hotspots. Whereas RAS and RAC1 act as oncogenes, RHOA may act as both an oncogene and a tumor suppressor. Thus, while RAS and RHO each take different mutational paths, they arrive at the same biological destination as cancer drivers.