In a recent Commentary in Carcinogenesis, Hazra and colleagues described the discovery of a new family of mammalian enzymes for the repair of oxidatively damaged DNA and suggested thatthe multiplicity of DNA glycosylases with overlapping substrate ranges could explain why... deficiency of the base excision enzymes examined so far has not been linked to susceptibility to cancer or other pathophysiological states'(1). However, we have recently shown that inherited defects in the base excision repair (BER) DNA glycosylase MYH cause multiple colorectal adenoma and carcinoma (2, 3). 8-Oxo-7, 8-dihydro-2H-deoxyguanosine (8-oxoG) is the most stable product of oxidative DNA damage (4) and readily mispairs with A residues (5), leading to G: C 3 T: A mutations in repair-deficient bacteria and yeast (6±9). In Escherichia coli, three enzymes act synergistically to help protect cells against the mutagenic effects of guanine oxidation (7). MutM DNA glycosylase removes the oxidized base from 8-oxoG: C base pairs in duplex DNA, MutY DNA glycosylase excises A residues misincorporated opposite unrepaired 8-oxoG during replication and MutT, an 8-oxo-dGTPase, prevents the incorporation of 8-oxo-dGMP into nascent DNA. Homologues of mutM, mutY and mutT have been identified in human cells and termed OGG1 (10), MYH (11) and MTH1 (12), respectively. MYH DNA glycosylase interacts with AP endonuclease, PCNA and RPA, suggesting a role in long patch BER (13), and is associated with the replication foci, indicating a role in replication-coupled repair (14). Last year, we studied a British Caucasian family with three affected siblings with multiple colorectal adenomas and carcinoma and showed that these siblings were compound heterozygotes for the missense mutations Y165C and G382D in MYH (2). Analysis of the equivalent mutations in E. coli MutY showed that both variants significantly compromised adenine glycosylase activities (2). In a follow-up study, we identified seven further unrelated patients with> 100 colorectal adenomas (six with colorectal cancer) and biallelic germline mutations in MYH, including four patients homozygous for truncating mutations (3). As predicted from inactivation studies of the bacterial and yeast orthologues of MYH, colorectal tumours from affected individuals displayed a significant excess of somatic G: C 3 T: A mutations in APC, as compared with sporadic or familial adenomatous polyposis-associated colorectal tumours (2, 3). More recently, Sieber et al.(15) identified a further 14 unrelated patients with multiple colorectal adenomas (six cases) or polyposis (eight cases) and biallelic germline variants in MYH. Taken together, these data unequivocally confirm that germline defects in the BER DNA glycosylase MYH cause a multiple colorectal adenoma and carcinoma phenotype.