Kayhanian, Hamzeh; (2021) Role of secondary mismatch repair (MMR) frameshifts in the evolution of microsatellite instable (MSI) colorectal cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mismatch repair deficient (MMRd) cancers face a delicate balance. Whilst hypermutation fuels adaptive evolution, it also comes at the cost of immunogenic neoantigens and other deleterious mutations. How MMRd cancers navigate the costs versus benefits of hypermutation is unknown. By visualising the clonal architecture of MMRd colorectal cancer in situ I show that the mismatch repair system unfolds in reversible steps to adapt cellular mutability to immune selection. Mechanistically microsatellite instability unmasks two hypermutable homopolymers in the mismatch repair genes MSH6 and MSH3. Spontaneous frameshift mutation and reversion at these homopolymers allows them to act as a molecular switch, regulating expression of MutSα and MutSß respectively. Frameshift switching at these homopolymer sites modulates the rate and spectrum of mutations across the genome. In this manner stochastic mutation bursts combined with stringent immune selection, drive continuous adaptation. This work is supported by a bespoke clonally resolved exome sequencing dataset, validated using two large publicly available genomic datasets and tested in a mathematical model of mutation rate switching. In summary, this work identifies that adaptive mutability associates with increased immune escape and intratumour heterogeneity during mismatch repair deficient cancer evolution. Knowledge of this mechanism of adaptation may inform strategies to target resistance evolution in cancer treatment.

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