The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability

Most tumours arising in individuals affected with hereditary non-polyposis colorectal cancer (HNPCC) are characterized by microsatellite instability (MSI). MSI is also detected in a subset of sporadic colorectal and extracolonic carcinomas. We recently identified a new human DNA repair gene, MBD4 (also known as MED1, for methyl-CpG binding endonuclease), that encodes an MLH1 interactor. We detected MBD4 mutations in 14 of 56 (25%) primary MSI tumours, 11 of 42 (26.2%) colorectal carcinomas, 2 of 9 (22.2%) endometrial carcinomas and 1 of 5 (20%) pancreatic tumours. Analysis of the corresponding normal DNAs indicated that the mutations were somatic.Overall, these studies further illustrate that in a subset of human carcinomas a mutational process is set in motion that progressively targets DNA repair genes and steadily increases genomic instability