All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, 
and N-Ras, that promote oncogenesis when they are mutationally activated at 
codon 12, 13, or 61. Although there is a high degree of similarity among the 
isoforms, K-Ras mutations are far more frequently observed in cancer, and each 
isoform displays preferential coupling to particular cancer types. We examined 
the mutational 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 findings were unexpected given that these 
mutations occur in regions that share 100% amino-acid sequence identity among 
the 3 isoforms. Of importance, many of these 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, as well as isoform-specific differences in protein 
structure and signaling, that may promote these distinct mutation patterns and 
differential coupling to specific cancers.