The origins and genetic interactions of KRAS mutations are allele- and tissue-specific

Mutational activation of <em>KRAS</em> promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant <em>KRAS</em> alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic <em>KRAS</em> mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of <em>KRAS</em> activating mutations. However, there was are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of K-RAS, our genetic analysis reveals that each <em>KRAS</em> allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant <em>KRAS</em> alleles. Overall, this analysis demonstrates that the genetic interactions associated with oncogenic <em>KRAS</em> mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences.<br>