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8-Oxoguanine, a common mutagenic DNA lesion, generates G:C > T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C > T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs., Graphical Abstract Image 1, Highlights • A modest mutator phenotype in MUTYH-defective colorectal cancer • Novel mutational signature of G>T mutations from persisting 8-oxoguanine:A mispair • This mutational signature is present in oncogenes/tumor suppressor associated with colorectal cancer • The mutational signature allows identifying a role for 8-oxoguanine-related mutations in other types of human cancer. Viel et al. identifies by exome-sequencing a mutational signature in colorectal cancer defective in the MUTYH DNA glycosylase, a DNA repair gene preventing 8-oxoguanine-related mutagenesis. A strong sequence dependence of G > T transversions characterizes this mutational fingerprint and unveils the contribution of persistent 8-oxoG:A mismatches in human cancer.