MRC1 and colorectal carcinoma: We reasoned that subclonal incremental MMR mutations are common in the context of MMRd CRC (Fig. 1d,e) and thus multiregion-sampled a sporadic MLH1meth/BRAFV600E (hereafter MLH1−/−) MMRd CRC to obtain bulk PDO lines carrying incremental MMR mutations (Fig. 4a).