We show that start-gain mutation frequency is influenced by background mutational signature, being favoured in MMR deficiency (Signatures 6, 14, 15, 20 and 21) or POLE mutations (Signatures 10 and 14) which can be found in colorectal and endometrial cancers, as well as age (Signature 1A/B) and tobacco smoking (Signature 4) (42). This evidence concerns the gene POLE and mismatch repair cancer syndrome 1.