Hyper-mutational processes provide a head-start for weak cancer drivers: Explaining atypical KRAS variants

Michael D Nicholson and Ian Tomlinson

PLOS Computational Biology, 2026, vol. 22, issue 10, 1-20

Abstract: Hypermutant cancers frequently contain atypical driver gene variants, which may provide sub-optimal oncogenic advantages. The reason why weak cancer drivers prevail and are not outcompeted by stronger alternatives is unclear. Here, using mathematical modelling, we show that aberrant mutational processes alone can account for the detection of weak, rather than canonical, driver mutations. We find that simply increasing the mutation rate per cell division, without altering selection or mutational biases, can lead to the dominance of weak drivers due to rapidly occurring further driver events. This effect can be further enhanced by mutational biases towards specific nucleotide sequence contexts. Focusing on POLE-mutant (DNA polymerase epsilon proofreading-deficient) colorectal cancers, we quantify the mutation bias for varied KRAS drivers under both POLE-mutant and non-hypermutant mutational processes. In POLE-mutant cancers, the combination of the bias coupled with an elevated mutation rate is sufficient to explain the enrichment of atypical KRAS drivers. Furthermore, model predictions are consistent with the observed prevalence of atypical KRAS drivers observed in mismatch repair deficient colorectal cancer. Thus, differential selection across these cancer types need not be invoked to explain the variation in driver mutations. Our study clarifies the interplay of mutation and selection during the evolutionary dynamics of tumourigenesis.Author summary: Considerable variability exists in the effectiveness of cancer driving mutations to promote cancer. Mutations which are thought to be less effective, ‘weak’ driver mutations, are commonly observed in DNA repair deficient, ‘hypermutant’ cancers, for reasons that remain unclear. Through mathematical modelling, we detail conditions such that accelerated mutation rates, combined with the biassing of mutations towards certain DNA locations, leads to the dominance of weak driver mutations within a tumour. In contrast to classical mathematical models of cancer initiation, we find that heightened mutation burden alone can alter which driver mutations are to be expected. Applying our model to the canonical oncogene KRAS, we show that the occurrence of weak driver mutations is well explained by the aberrant molecular processes of hypermutant colorectal cancers. Differential effectiveness of the ‘weak’ drivers in hypermutant cancers is not required. Our study clarifies how mutation and selection interact during the evolutionary dynamics of tumourigenesis.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1014858

DOI: 10.1371/journal.pcbi.1014858

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