Based on analysis of the complete CRC cohort, some specific hotspot mutations tend to co-occur (Fig. 7d); typically, co-occurring mutations are predicted to arise from a similar mutational process based on mutational signatures linked to POLE mutations (predominant in MSS-htmb tumors), or likely MMR deficiency (IDT and associated signatures, found in the MT-H subset) (Fig. 7d). Here, POLE is linked to mismatch repair cancer syndrome 1.