An update on the biology of RAS/RAF mutations in colorectal cancer

Deaths caused by colorectal cancer (CRC) are among the leading causes of cancer-related death in the United States and around the world. Approximately 150,000 Americans are diagnosed with CRC each year nd around 50,000 will die from it. Mutations in many key genes have been identified that are important to the pathogenesis of CRC. Among the genes mutated in CRC, RAS and RAF mutations are common events. Both RAS and RAF are critical mediators of the mitogen-activated protein kinase (MAPK) pathway that is involved in regulating cellular homeostasis, including proliferation, urvival, and differentiation. In this review, we provide a historical perspective and update on RAS/RAF mutations as related to colorectal cancer. Additionally, we will review recent mouse models of RAS and RAF mutations that have an impact on CRC research. around the world. Research pertaining to the pathogenesis and treatment of CRC is therefore of utmost importance. As with other cancers, CRC is a genetic disease involving many known mutations, which are classified as tumor suppressor genes or oncogenes. Tumor suppressors act as checkpoints in the cell cycle to keep cells under strict physiological control. Mutations in genes encoding tumor suppressors result in hyperproliferation and deregulated cell cycle control. The other major mutational events in cancers are those that occur in oncogenes. These are often activating mutations in genes that are also involved in cellular homeostasis. In particular, the most common activating mutation in CRC occurs in the RAS gene. This change transpires in about 50% of most CRCs [1··]. In addition, mutations in RAF that is downstream from RAS, are gaining importance in the pathogenesis of CRC. Here we review the recent progress on the roles of RAS and RAF in CRC.