Question

Why are activating mutations in Ras oncogenes confined so narrowly to a small number of nucleotides such as the 12th codon?

Answer 1

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 tumor 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 with specific cancer types.

We discuss potential genetic and epigenetic mechanisms together with isoform-specific differences in protein structure and signaling that may promote these distinct mutation patterns and differential coupling to specific cancers.