Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency

Defects of mismatch repair are thought to be responsible for carcinogenesis in hereditary non-polyposis colorectal cancer and about 15% of sporadic co lon cancers. The phenotype is seen as microsatellite instability and is kno wn to be caused either by mutations in mismatch repair genes or by aberrant methylation of these genes stabilizing their downregulation. Lack of repai r of microsatellite sequence errors, created during replication, leads to a mutation-prone phenotype, Where mutations occur within mononucleotide trac ts within exons they cause translation frameshifts, premature cessation of translation and abnormal protein expression. Such mutations have been obser ved in the TGF beta RII, BAX, IGFIIR, MSH3 and MSH6 genes in colon and othe r cancers, We describe here frameshift mutations affecting the gene for the methyl-CpG binding thymine glycosylase, MBD4, in over 40% of microsatellit e unstable sporadic colon cancers. The mutations all appear heterozygous bu t their location would ensure truncation of the protein between the methyl- CpG binding and glycosylase domains, thus potentially generating a dominant negative effect. It is thus possible that such mutations enhance mutation frequency at other sites in these tumours, A suggestion has been made that MBD4 (MED1) mutations may lead to an increased rate of microsatellite insta bility but this mechanism appears unlikely due to the nature of mutations w e have found.