Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

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.

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Clinical Relevance of Microsatellite Instability in Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.0652 ◽

2010 ◽

Vol 28 (20) ◽

pp. 3380-3387 ◽

Cited By ~ 182

Author(s):

Albert de la Chapelle ◽

Heather Hampel

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Stage Ii ◽

Stage Iii ◽

Mismatch Repair Genes ◽

Almost All ◽

Deficient Mismatch Repair ◽

Detection Strategies ◽

Repair Genes

Microsatellite instability (MSI) is a clonal change in the number of repeated DNA nucleotide units in microsatellites. It arises in tumors with deficient mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. In order to determine the MSI status of a tumor, microdissection and polymerase chain reaction–based detection strategies are required. For practical purposes, MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes since both signify an abnormality in mismatch repair. Of all colorectal cancers (CRCs), 15% to 20% display MSI or abnormal IHC (often referred to as microsatellite instability [MIN] pathway). The remaining 80% to 85% of CRCs are microsatellite stable but most are characterized by chromosomal instability (CIN pathway). Almost all Lynch syndrome tumors have MSI or abnormal IHC and they account for up to one third of all MIN CRCs (3% to 5% of all CRCs). The remaining MIN tumors are sporadic as a result of somatic inactivation of the MLH1 gene caused by methylation of its promoter. Thus, the presence of a MSI/IHC abnormality prompts further investigations to diagnose Lynch syndrome, whereas its absence excludes Lynch syndrome. We recommend screening all CRC tumors for IHC or MSI. MIN tumors have a more favorable outcome than CIN tumors, and fluorouracil-based adjuvant chemotherapy does not improve the outcome of stage II or stage III MIN tumors. More data are needed to determine how best to treat patients with stage II and stage III MIN CRCs.

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