Highlights
- •Both mutational and expression data suggest that MMR deficiency is more common in non-serous ovarian cancer than in serous subtypes.
- •The effect of MMR deficiency on ovarian cancer chemosensitivity remains unproven but synthetic lethal approaches offer hope of novel therapies.
Abstract
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.
Keywords
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Article info
Publication history
Published online: December 30, 2013
Accepted:
December 2,
2013
Received:
October 7,
2013
Footnotes
☆CG is supported by the Scottish Funding Council. The Edinburgh Ovarian Cancer Database is supported by Experimental Cancer Medicine Centre (ECMC) funding from the Scottish Chief Scientist's Office and Cancer Research UK.
☆XX is supported by the China Scholarship Council and the Nicola Murray Foundation.
Identification
Copyright
© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
