DNA mismatch repair (
MMR) deficiency is associated with increased risk of developing several types of
cancer and is the most common cause of hereditary
ovarian cancer after BRCA1 and BRCA2 mutations. While there has been extensive investigation of
MMR deficiency in
colorectal cancer, MMR in
ovarian cancer is relatively under-investigated. This review summarizes the mechanism of MMR, the ways in which
MMR deficiency can promote
carcinogenesis in general and then assesses the available studies regarding
MMR deficiency in
ovarian cancers with specific emphasis on implications for disease incidence and
therapy. The incidence of germline MMR gene mutations in
ovarian cancer is only 2% but other mechanisms of gene inactivation mean that loss of expression of one of the seven main genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS1 and PMS2) occurs in up to 29% of cases. Both mutational and expression data suggest that
MMR deficiency is more common in non-serous
ovarian cancer. Some studies suggest an improved survival for patients with
MMR deficiency compared to historical controls but these do not account for the preponderance of non-serous
tumors. A number of in vitro studies have suggested that
MMR deficiency is a cause of
platinum resistance. To date this has not been categorically demonstrated in the clinic. Larger studies that account for stage of presentation and immunohistochemical subtype are required to assess the effect of
MMR deficiency on survival and chemosensitivity. Investigation of MMR related synthetic lethality in
colorectal cancer has identified
dihydrofolate reductase,
DNA polymerase β and
DNA polymerase γ and
PTEN-induced putative kinase 1 as synthetic lethal to certain MMR defects by causing accumulation of oxidative DNA damage. These synthetic lethal targets require tested and others should be sought within the context of MMR deficient
ovarian cancer in an attempt to provide novel therapeutic strategies for these patients.