Ras Mutations in Cancer

Abstract

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

Figure 1.

Primary structure of RAS proteins and hotspot of mutations. Blue and green boxes refer to the region responsible for interaction with guanine nucleotides. The purple box represents the area of interaction with downstream effectors. Switch I and Switch II (red striped boxes) undergo conformational changes depending on RAS binding to GDP or GTP. The yellow box corresponds to the HVRC‐terminal. Mutation graphics were drawn from data downloaded from COSMIC database using only tumour samples as tumour source.

Figure 2.

The RAS GTP–GDP cycle and its downstream effectors with biological consequences. GEFs catalyse the intrinsic exchange factor (GDP to GTP) reaction causing a GTP‐binding protein to release GDP and bind GTP. GAPs cause a GTP‐binding protein to hydrolyse its bound GTP to GDP+Pi.

Figure 3.

Distribution of oncogenic mutations on RAS in tumour. Data were obtained from COSMIC database. For each individual tissue the most prevalent mutated isoform was selected and mutational profiles were downloaded after filtering on tumour samples. Mutations with representation higher or equal to 5% were individually displayed. Mutations with representations between 1% and 5% were pooled by site. Finally, mutations with representations lower than 1% were pooled under ‘others’ category.

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Barault, Ludovic, Lamba, Simona, and Di Nicolantonio, Federica(Oct 2013) Ras Mutations in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025010]