Fig. 6.

Timing of POLE-exo* and MSI events. a Frequency of MLH1 silencing as the mechanism of MMR deficiency in POLE WT vs. POLE-exo* cases. 153/160 MSI-H samples with MLH1 silencing data available are shown. b Model representing accumulation of clonal and subclonal mutations based on the order of POLE and MSI events. c Mutational spectra of the five cases displaying significant enrichment of signature E (POLE-exo*) mutations in the clonal subset of mutations, suggesting that the POLE-exo* event preceded acquisition of MSI in these samples. Stacked bars represent the relative contributions of signatures E and C to the clonal and subclonal spectra of each patient. In each case, signature E (blue) is enriched in the clonal spectra