Mutator pathways unleashed by epigenetic silencing in human cancer

Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair genes. Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancer. Many cellular pathways, including DNA repair, are inactivated by this type of epigenetic lesion, resulting in mutator pathways. In this review, we discuss the adverse consequences suffered by a cell when DNA repair genes such as the DNA mismatch repair gene hMLH1, the DNA alkyl-repair gene O(6)-methylguanine-DNA methyltransferase, the familial breast cancer gene BRCA1 and the Werner syndrome gene WRN become epigenetically silenced in human cancer.