Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability

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.

Keywords: deficient mismatch repair; gynecological cancers; microsatellite instability.

Figure 1

The mismatch repair (MMR) pathway that functions to correct errors in microsatellites. Schematic of the MMR pathway describing the three vital steps. (i) recognition of the mismatch by MutS complex, followed by recruitment of proliferating cell nuclear antigen and replication factor C, (ii) excision of the mismatched base(s) by MutL, and, finally, (iii) re-synthesis of the strand. The MMR system functions to correct errors introduced in microsatellites. Proliferating cell nuclear antigen (PCNA), replication protein A (RPA), replication factor C (RFC), and exonuclease I (ExoI).

Figure 2

Steps in MMR deficiency (dMMR)/MSI cancer development leading to tumorigenesis. Evidence propose that MSI and the initial mutations cause a cascade of additional mutation in secondary genes in onco-, regulatory, tumor-suppressor, and repair genes. Genes affected are cancer-specific and examples are indicated in the diagram. A cascade etiology would also explain the high mutation rate in dMMR/MSI gynecological cancers. In addition, identifying the genes affected in each specific cancer types will help in understanding better cancer progression and developing markers for effective and timely screening.

Figure 3

Illustration of effect of the anti-programmed cell death-1 (anti-PD-1) antibody used for treatment of MSI/MMR gynecological cancer: In human cells the DNA polymerase can slip and insert or delete nucleotides at the repetitive DNA sequences, such as microsatellites. If these replication errors are not repaired by the repair machinery due to a defective MMR, it can lead to MSI. Translation of such genes with MSI can result in creation of novel peptide sequences, such as neoantigens (e.g., PD-ligands). Thus, these ligands on the tumor cell can trigger cell death of T cells and so evade an immune response. The anti-PD-1 antibodies bind programmed cell death-1 (PD-1) receptor and can prevent activation of programmed cell death by the PD-1 ligand.