Ras Mutations in Cancer

Mutations affecting the three isoforms of the RAS gene – KRAS, HRAS and NRAS – represent the most common oncogenic event in several cancer types. RAS mutations lead to constitutive activation of the corresponding protein and contribute to different hallmarks of cancers, including increased proliferation and resistance to apoptosis. Activating mutations in KRAS are currently used in the clinic to exclude colorectal cancer patients from treatment with ineffective epidermal growth factor receptor targeted-based therapies. Future studies are needed to fully elucidate the role of all RAS oncogenic variants in cancer biology, as well as to assess the potential prognostic and predictive value of individual RAS genetic alterations in clinical settings other than colorectal cancer. Key Concepts: • RAS in human consists in 4 isoforms (KRAS4A, KRAS4B, NRAS, and HRAS) encoded by 3 genes (KRAS, NRAS, and HRAS). • Isoforms of the RAS gene (KRAS, NRAS, HRAS) are the major oncogenes mutated in several cancer types. • Mutations in RAS family genes lead to constitutive protein activation by inhibition of the catalytic reaction which converts active RAS–GTP to inactive RAS–GDP. • Different types of mutations occur in different cancers. • Mutations in RAS family genes may differ in terms of biochemical effectors, biological activities and prognostic or predictive value. Keywords: RAS; cancer; oncogenic mutation; KRAS; HRAS; NRAS