Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

SIMPLE SUMMARY: Microsatellite instability (MSI) has been detected in multiple types of gynecologic cancers. MSI is linked to mutations in mismatch repair (MMR) genes that cause mismatch repair deficit (dMMR) in human cells. Discovery of new therapeutic approaches are needed especially for treatment of advanced endometrial and other gynecological cancers with dMMR/MSI. In addition, there is a need to identify markers for reliable detection of dMMR/MSI gynecological cancers. Determination of the mechanism leading to these malignancies would help in diagnosis and therapeutic intervention. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, and new therapeutic strategies to treat these cancers. ABSTRACT: Mutations in mismatch repair genes leading to mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) have been implicated in multiple types of gynecologic malignancies. Endometrial carcinoma represents the largest group, with approximately 30% of these cancers caused by dMMR/MSI. Thus, testing for dMMR is now routine for endometrial cancer. Somatic mutations leading to dMMR account for approximately 90% of these cancers. However, in 5–10% of cases, MMR protein deficiency is due to a germline mutation in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. These germline mutations, known as Lynch syndrome, are associated with an increased risk of both endometrial and ovarian cancer, in addition to colorectal, gastric, urinary tract, and brain malignancies. So far, gynecological cancers with dMMR/MSI are not well characterized and markers for detection of MSI in gynecological cancers are not well defined. In addition, currently advanced endometrial cancers have a poor prognosis and are treated without regard to MSI status. Elucidation of the mechanism causing dMMR/MSI gynecological cancers would aid in diagnosis and therapeutic intervention. Recently, a new immunotherapy was approved for the treatment of solid tumors with MSI that have recurred or progressed after failing traditional treatment strategies. In this review, we summarize the MMR defects and MSI observed in gynecological cancers, their prognostic value, and advances in therapeutic strategies to treat these cancers.