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Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability
Madhura Deshpande1, Phillip A Romanski1, Zev Rosenwaks1
1The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
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.
Insights
Mismatch repair deficiency (dMMR) and microsatellite instability (MSI) are common in gynecologic cancers, particularly endometrial cancer. Understanding these markers is crucial for diagnosis and developing new immunotherapies.
Area of Science:
- Gynecologic Oncology
- Cancer Genetics
- Immunotherapy
Background:
- Mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) are implicated in gynecologic malignancies, especially endometrial carcinoma (30%).
- Somatic mutations cause 90% of dMMR/MSI in endometrial cancer, while 5-10% result from germline mutations (Lynch syndrome), increasing risks for multiple cancers.
- Gynecologic cancers with dMMR/MSI are not well characterized, and MSI detection markers are undefined, impacting diagnosis and treatment for advanced cases.
Purpose of the Study:
- To review MMR defects and MSI in gynecologic cancers.
- To explore the prognostic value of dMMR/MSI in these cancers.
- To summarize advances in therapeutic strategies, including immunotherapy, for dMMR/MSI gynecologic malignancies.
Main Methods:
- Literature review of MMR defects and MSI in gynecologic cancers.
- Analysis of prognostic significance of dMMR/MSI.
- Summary of current and emerging therapeutic strategies, focusing on immunotherapy.
Main Results:
- dMMR/MSI is a significant factor in gynecologic cancers, with varying prevalence across types.
- Lynch syndrome, caused by germline MMR gene mutations, is associated with increased risk for multiple cancers.
- A new immunotherapy for MSI-positive solid tumors offers a promising treatment avenue.
Conclusions:
- Elucidating the mechanisms of dMMR/MSI in gynecologic cancers is vital for improved diagnosis and treatment.
- MSI status is an important prognostic indicator and a target for novel therapies.
- Advances in immunotherapy show potential for treating advanced gynecologic cancers with dMMR/MSI.
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