| Authors | Hamzeh Kayhanian, Panagiotis Barmpoutis, Eszter Lakatos, William Cross, Giulio Caravagna, Luis Zapata, Kevin Litchfield, Christopher Steele, William Waddingham, Dominic Patel, Salvatore Milite, Chen Jin, Ann-Marie Baker, Christopher Ross, Daniel Alexander, Khurum Khan, Daniel Hochhauser, Marco Novelli, Benjamin Werner, Naomi Guppy, Josep Linares, Marjolijn J.L. Ligtenberg, Iris D. Nagtegaal, Andrea Sottoriva, Trevor Graham, Nischalan Pillay, Manuel Rodriguez-Justo, Kai-Keen Shiu, Marnix Jansen and Genomics England Research Consortium |
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| Description | SUMMARY
Mutation rate optimisation drives evolution and immune evasion of bacteria and lentiviral strains, including HIV. Whether evolving cancer lineages similarly adapt mutation rates to increase tumour cell fitness is unknown. Here, by mapping the clonal topography of mismatch repair-deficient (MMRd) colorectal cancer, we show that genomic MMRd mutability co-evolves with neoantigen selection to drive intratumour diversification and immune escape. Mechanistically, we find that microsatellite instability modulates subclonal DNA repair by toggling two hypermutable mononucleotide homopolymer runs in the mismatch repair genes MSH6 and MSH3 (C8 and A8, respectively) through stochastic frameshift switching. Spontaneous mutation and reversion at these evolvability switches modulates subclonal mutation rate, mutation bias, and clonal HLA diversity during MMRd cancer evolution. Combined experimental and simulation studies demonstrate that subclonal immune selection favours incremental MMR mutations. MMRd cancers thus fuel intratumour heterogeneity by adapting subclonal mutation rate and mutation bias to immune selection, revealing a conserved co-evolutionary arms race between neoantigen selection and adaptive genomic mutability. Our work reveals layers of mutational complexity and microsatellite biology in MMRd cancer evolution previously hidden in bulk analyses. |
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