A Comprehensive Survey of Ras Mutations in Cancer

Abstract

All mammalian cells express three closely related Ras proteins: H-Ras, K-Ras and N-Ras that promote oncogenesis when mutationally activated at codons 12, 13 or 61. Despite a high degree of similarity between the isoforms, K-Ras mutations are far more frequently observed in cancer and each isoform displays preferential coupling to particular cancer types. We have examined the mutation spectra of Ras isoforms curated from large-scale tumour profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino acid substitution biases. These were unexpected given that these mutations occur in regions that share 100% amino acid sequence identity between the three isoforms. Importantly, many of the mutational biases were not due to differences in exposure to mutagens because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms together with isoform-specific differences in protein structure and signalling that may promote these distinct mutation patterns and differential coupling to specific cancers.

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

“…Activating mutations occur at codons 12, 13, and 61, which are within the GTPase catalytic domain, in all three RAS isoforms [14] . Approximately 80% of KRAS mutations are found in codon 12, whereas approximately 60% of NRAS mutations are found in codon 61, with 35% in codon 12 [2,14] .…”

The Ras–Membrane Interface: Isoform-Specific Differences in the Catalytic Domain

“…Ras must be membrane bound to promote signal transduction, and altering the normal time scale and details of this interaction dramatically affects signal output, leading to a multitude of disease states, including some of the most aggressive forms of cancers (5). For example, about 60% of pancreatic cancers have a point mutation at residue G12 in K-Ras, whereas about 30% of melanomas are found with mutations at residue Q61 in N-Ras (5).…”

“…K-Ras is by far the most oncogenic isoform, showing extensive prominence in pancreatic and colorectal cancers, while melanomas have a high incidence of N-Ras mutations (5). Codon mutation bias among the isoforms at 100% conserved effector lobe sites indicates that the allosteric features of Ras cannot be ignored.…”

“…Here, many effector and regulator proteins interact with the effector lobe (residues 1-86) of GTP-bound Ras to promote signaling cascades that translate to changes in gene expression, controlling cellular outcomes, such as cell proliferation, differentiation, and apoptosis (4). Point mutations occur most frequently at residue positions 12, 13, and 61, leading to constitutive Ras activation and hyperproliferation traditionally associated with cancer and developmental disorders (5). Although GAPs stimulate GTP hydrolysis by stabilizing both switch regions and inserting a positively charged arginine finger to neutralize negative charges that develop during the transition state of the reaction, oncogenic mutations often promote insensitivity to this regulation (6).…”

“…1). Interestingly, although the effector lobe containing G12, G13, and Q61 is 100% conserved across the three isoforms, an isoform-specific codon mutation profile indicates allosteric lobe influence over oncogenicity (5).…”