#40 · Systems biology

Mutation bursts and hypermutation let weak drivers and tumors adapt

The common thread across these items is that mutation supply, not only selection, governs which somatic variants and adaptive steps arise in tumors. A mathematical model of POLE-mutant and hypermutant settings attributes the dominance of weak KRAS drivers to elevated, sequence-context-biased mutation rates rather than differential selection. A separate modelling study shows that punctuated mutagenesis, such as APOBEC-driven mutation bursts, helps tumor cells cross fitness valleys during multi-step adaptation, with TCGA patterns described as consistent with this model. The melanoma preprint addresses adaptation from a different angle: in 2D colony experiments coupled to particle-based digital twins and reinforcement learning therapy optimization, mechanical crowding drives resistance confinement and informs adaptive therapy design. What is new here is treating mutagenesis dynamics as an adaptive variable rather than background noise. The melanoma work does not analyze mutagenesis directly, so its link to the mutation-focused papers is conceptual.