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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 71-77

Review of the application of dMMR and microsatellite instability in the diagnosis and treatment of endometrial cancer

1 Department of Pathology, Red Cross Hospital of Yulin, Yulin, Guangxi, China
2 Department of Pathology; Department of Obstetrics and Gynecology, Red Cross Hospital of Yulin, Yulin, Guangxi, China
3 Department of Pathology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Date of Submission01-Oct-2021
Date of Decision19-Oct-2021
Date of Acceptance20-Oct-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Prof. Guangjie Liao
Department of Pathology, Red Cross Hospital of Yulin, No. 1, Jin Wang Road, Yuzhou, Yulin City, Guangxi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aort.aort_20_21

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Mismatch repair genes are responsible for discovering and repairing base mismatches during DNA replication in cells. Defects in mismatch repair function will lead to accumulation of gene mutations, microsatellite instability, and ultimately tumorigenesis. Mismatch repair genes are closely related to the biological behavior, patient prognosis, and related treatments of endometrial cancer. This article reviews the research progress of mismatch repair defect (dMMR) in the diagnosis and treatment of endometrial cancer.

Keywords: Endometrial cancer, immune cells, microsatellite instability, mismatch repair, programmed death ligand

How to cite this article:
Liao G, Yang J, Zhang X. Review of the application of dMMR and microsatellite instability in the diagnosis and treatment of endometrial cancer. Ann Oncol Res Ther 2021;1:71-7

How to cite this URL:
Liao G, Yang J, Zhang X. Review of the application of dMMR and microsatellite instability in the diagnosis and treatment of endometrial cancer. Ann Oncol Res Ther [serial online] 2021 [cited 2022 Aug 8];1:71-7. Available from: http://www.aort.com/text.asp?2021/1/2/71/333304

  Introduction Top

Endometrial cancer (EC) is a common gynecological malignancy, and its incidence is second only to cervical cancer. In 2018, the United States reported about 63,230 new cases of EC and 11,315 deaths of EC. In total, more than 727,000 people suffered from EC that year.[1] According to statistics from the National Cancer Center in 2015, the incidence of EC in China was about 63.4/100,000, and the fatality rate was about 21.8/100,000, and the incidence of EC was increasing year by year and tended to be younger,[2] and the incidence rate was also at the second place in gynecological malignancies. The recognized risk factors leading to EC are represented by the triad of metabolic syndrome, such as obesity, diabetes, hypertension, and high estrogen factors.[3] At present, EC is divided into Type I EC (endometrioid carcinoma) and Type Ⅱ EC (mainly serous carcinoma and clear cell carcinoma). EC is a hormone-dependent tumor, which occurs in perimenopausal or postmenopausal women, accounting for about 80% of EC.[2] The overall prognosis of high-grade EC is poor, and the 5-year survival rate is <50%. It includes a variety of histological types, mainly high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mixed adenocarcinoma, dedifferentiated carcinoma, and undifferentiated Cancer.[4] Its treatment is limited to surgery, radiotherapy, and chemotherapy.

With the increasing progress of the research on the mechanism of cancer occurrence and development, molecular typing of EC is of great significance for understanding its etiology, precise treatment or prognosis. In 2014, based on the Cancer Genome Atlas, combined with microsatellite instability (MSI) and copy number analysis, EC was divided into 4 molecular subtypes, as low copy number/p53 wild type, high copy number/p53 mutant, polymerase E mutant (POLE mutant) type and mismatch repair defect (dMMR/MSI) type. dMMR/MSI is an important pathogenic factor of EC found after continuous estrogen stimulation and other genetic abnormalities. Tumors with POLE mutations, MSI, and p53 abnormalities are usually highly malignant tumors.[5] The objective of this review is to understand the application of dMMR and MSI in the diagnosis and treatment of EC.

  The Research and Application of DNA Mismatch Repair Defect (dMMR) and Microsatellite Instability in Endometrial Cancer Top

The MMR system can detect and correct base mismatches during DNA replication and avoid mutations in genetic material. The mechanism is achieved by correcting single-base and insertion/deletion mismatches during DNA replication and preventing heterologous recombination. DMMR caused by DNA damage and genetic recombination would lead to tumorigenesis.[6] Researches have shown that the MMR system consists of a series of gene products that specifically repair DNA base mismatches. At present, 9 human mismatch repair proteins (MMRPs) have been discovered, of which MSH2, MSH3, MSH6, MLH1, MLH3, PMS1, and PMS2 were the main participants in human DNA MMR. Among them, the functions of MSH2 and MLH1 were more important.[7] When a mismatch is detected, MSH2 forms a complex MutSα or MutSβ with MSH6 and MSH3, respectively. MLH1 and PMS2 or PMS1, MLH3 form a complex MutLα or MutLβ, MutLγ. When MutLα gathers at the mismatch, it combines with hMutSα or hMutSβ to form a complex and initiate repair. Studies have found that MSH2 deletion was related to the occurrence of colorectal cancer, gastric cancer, EC, breast cancer, primary liver cancer, and other malignant tumors. MSH6 is mainly involved in the DNA base mismatch repair process, which reduces the spontaneous mutation rate of genes.[8] Its mutation is also related to the occurrence of colorectal cancer, EC, ovarian cancer, and so on. Germline mutations or abnormal methylation of any of the aforementioned hMLH1, hPMS2, hMSH2, and hMSH6 genes may cause dMMR, and errors such as base mismatches accumulate and pass on from generation to generation, ultimately causing genetic mutations and cancerous. In the literature, the proportion of tumors caused by MMR mutations was hMLH1 (50%), hMSH2 (40%), and hMSH6 (10%).[9] In other researches, the loss rate of MLH1 protein expression was 24%~28%, MLH2 was 7%~8%, MLH6 was 6%~21%, and PMS2 was 28%~40%.[10]

In 1980, Wyman and White[11] first proposed the MS sequence. MS is a simple tandem DNA sequence with repeating units of 2 or 3 nucleotides in the genome. MS plays a role in chromatin formation, regulation of gene activation, cell cycle gene recombination, DNA replication, MMR, and so on.[12] In 1981, MSI was proposed. MSI suggested that the size of normal genes in tumor tissues has changed or there are insertions or deletions of repetitive sequences, which may be a new mechanism for the formation in malignant tumors. MS is prone to slippage during DNA replication. If the mismatch repair function is defective (dMMR), the error “DNA ring structure” generated by its slippage would accumulate with the replication, which will change the length or base composition of MS repeats,[12] the risk of malignant tumors is significantly increased. Most of the tumor tissues of patients with hereditary nonpolyposis colorectal cancer (HNPCC) are MSI positive (about 80%), and there are MMR gene mutations, confirming the correlation between MSI and MMR functional defects. But so far, germ cell line mutations were rarely seen in MSI cases, accounting for 71% to 92% of MSI tumors. dMMR was mainly caused by somatic gene mutations and gene expression silencing caused by promoter methylation.[13] The deletion of hMLH1 in some tumors was related to hypermethylation of gene exons and their promoters, resulting in no expression of gene products, and often accompanied by BRAFV600E mutations, which may exist in sporadic malignant tumors, without germline mutations of MLH1 gene.[7] A large deletion at the upstream 3'end of EpCAM adjacent to MSH2 caused MSH2 silencing.[10] The above studies all indicated that dMMR was closely related to MSI [Table 1]. Currently, immunohistochemical detection of MMR protein is commonly used to screen patients with Lynch syndrome-associated EC (LS-EC). However, the expression of MMR protein is only a screening method, and the diagnosis of LS must be combined with various clinical data. The loss of expression of MMRP is mainly caused by germline mutation, somatic biallelic mutation and methylation of MMR gene. At present, some people have put forward a new theory of heterogeneous expression of MMR protein.[14],[15] Heterogeneous expression loss of MMR is relatively rare, which means that there is a clear positive expression area of MMR protein in the region of tumor tissue where MMR protein expression is lacking. Such lesions are different from the uneven immunohistochemical staining caused by technical reasons such as tissue fixation and pretreatment, and they have specific molecular pathological mechanisms and significance. According to the distribution characteristics of the lesions, heterogeneous expression of MMR protein can be divided into four types: Clonal type, glandular mixed type, and isolated type. MMR positive tumor cells in heterogeneous expression region may also have MMR gene mutation and methylation, manifested as msi-h; Some mutation types of tumor cells in MMR negative region showed MSS.
Table 1: The relationship between mismatch repair protein and microsatellite status

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  dMMR, Microsatellite Instability and Endometrial Cancer Top

Epidemiological investigations show that the risk of EC in dMMR patients is 40%–60%, and that of the normal population is only about 2.3%.[16] González et al.[8] found that the incidence of dMMR in EC patients was 15% for MLH1 and 10% for hMSH2, and MSH6 mutations were more common than MLH1 and MSH2 in multiple familial EC members. In another study, the missing rate of MHL1 or MSH2 in MSI-related EC was 44%~93%, while it was only 7%~27% in sporadic EC.[17] In the study of 138 cases of sporadic EC, the expression loss rates of MHL1, MSH2, and MSH6 were 14%, 19%, and 12.3%, respectively.[18] Ramsoekh et al.[19] found that LS familial members with MSH6 gene mutations have a higher risk of developing EC than colorectal cancer. The probability of these women developing EC at the age of 70 is 61%, and the median age is 56 years. The probability of carrying hMSH2 is 49%, the median age is 46 years, the MLH1 mutation is 25%, and the median age is 51 years old. In comparison, it can be found that the risk of EC with MSH6 mutation is higher and the age of the disease is older. Similar results, the study by Bing et al.[20] also found that the mutation rate of MSH6 in EC patients was 9.77%, and that of patients with EC family history was 14.29%, and the age of onset was similar to the above-mentioned study. Hirai et al.[21] detected 18 gene mutations (15%) in 120 patients with EC family genetic susceptibility, and the MSH6 mutation rate was 7.5%. The above studies have shown that MSH6 mutations have a higher risk of EC and older in the age of onset, especially in family members of familial EC patients the risk of cancer is also higher.

LS is caused by the loss of expression of any MMRP due to genetic mutations in the MMR system, with an incidence of about 5%. EC is the tumor with the highest incidence in female LS patients, and the risk of developing EC is about 40% to 60%.[22] About 13%–25% of dMMR-type ECs are related to pathogenic germline variants in MMR genes, and 62%–73% of which are caused by somatic methylation in the promoter region of MLH1.[23] It is currently recommended to include EpCAM in the MMR detection reagent combination, and BRAF IHC is also recommended for sporadic mutations in tumors.

Studies have found that dMMR is related to different clinical states of EC. Research by Rabban et al.[24] had clearly associated certain histological features (mainly tumor-infiltrating lymphocytes and tumor morphology) with LS-EC. Qian et al.[25] studied 134 patients with high-grade EC and found that the dMMR rate of nontype II high-grade EC patients was significantly higher than that of type II. It is recommended to detect MMRP deficiency (dMMRP) for nontype II high-grade EC, and make clear whether it has MMR gene mutation. Wei et al.[26] showed that EC patients with high FIGO staging, deep uterus muscle infiltration, and positive lymph node metastasis had a higher dMMRP rate. Wenliang et al.[22] found that dMMRP was concentrated in patients with significantly poorly differentiated EC patients, patients with a high age of onset, and patients with positive lymph node metastasis. The study of González et al.[8] also found that EC patients <50 years old and other factors such as familial hypertrophic cardiomyopathy, low BMI index, will increase the probability of dMMR. The NRG tumor/gynecology team found in 1024 EC cases that dMMR was associated with higher grades, myometrial invasion, lymphatic vascular invasion, and other adverse prognostic factors, but there was no significant difference in the survival rate of these patients. They believed that it was related to dMMR. Immune surveillance may offset the adverse prognostic factors of these patients.[27]

In short, the above studies showed that the MMR gene is closely related to the occurrence and development mechanism and related prognosis of EC, which needs to be further clarified.

  Microsatellite Instability and Endometrial Cancer Top

As mentioned above, MSI is a kind of hypermutation caused by dMMR. In many clinical applications, the two are even equivalent. After the EC molecular classification was proposed, the International Federation of Gynecology and Obstetrics (FIGO) took MSI, p21 and other biotin expressions as the prognostic indicators for Stage 1 endometrioid adenocarcinoma.[17] The detection of MSI in LS patients can detect EC early, and provide certain guidance for the chemotherapy sensitivity of patients with advanced or recurrent EC (MSI positive EC is not sensitive to pentafluorouracil), and postoperative treatment, and immunotherapy can be used. This new generation of precision treatment methods can improve the prognosis of these patients.

MSI is a simple and sensitive indicator for the early detection of gene mutations. The MSI of ECs related to HNPCC is more than 75%. Junling et al.[28] and Yan et al.[18] showed that the positive rate of MSI in EC patients over 50-year-old was higher than that in patients under 50-year-old, the positive rate of MSI in EC patients was higher than that in non-EC patients, and The positive rate of the MSI related patients with poorly differentiated EC cancer is higher than that of patients with moderately differentiated and well-differentiated EC. However, the above studies mentioned the comparison of the positive rate of MSI among EC patients with different FIGO stages, depth of invasion, and lymph node metastasis, and the differences were not statistically significant.

The incidence of MSI-H EC varies greatly in different regions, but the overall significance is the same. The positive EC expression of MSI in Pakistan was 44%, and a study of 473 ECs in the United States showed that MSI-H EC accounted for 20%.[29] They all found that although MSI-positive tumors were associated with poor prognosis histological parameters (such as tumor pathological staging and grade), they were also associated with a better prognosis. A study detected the MSI highly unstable (MSI-H) state in 15.6% of ECs, and it was associated with high TNM/FIGO staging.[30]

The above studies show that the clinical status of MSI-H and EC, including patient age, tumor stage, grade and depth of invasion, lymph node metastasis, and other recurrence factors have a certain relationship, but the current research results have certain differences, and further research is still needed.

  dMMR-type Endometrial Cancer and Related Prognostic Treatment Indicators Top

dMMR/microsatellite instability endometrial cancer and P53

P53 is a common tumor suppressor gene. Once P53 is mutated, it will promote tumorigenesis. It is reported in the literature that p53 play 耳朵 an important role in the CIN pathway in CRC following the normal mucosal-adenoma-adenocarcinoma multi-stage and multi-step progression pattern.[31] The positive expression of p53 immunohistochemistry has been widely used as an effective indicator of the prognosis and classification of cancer patients, as p53 is related to the depth of tumor invasion, distant metastasis, and Ki-67 high expression index. Under normal circumstances, the body can maintain the stability of the genome through mechanisms such as immune surveillance and DNA repair. Once MMRP is missing, chromosome deletion, duplication, inversion, ectopic, and rearrangement may occur, leading to cancerization. At present, many literatures have a negative correlation between dMMR/MSI and p53 mutation in tumors. Bond et al.[32] reported that the mutation rate of p53 in MSI-H CRC was low (17%), and other studies[33] showed the positive rate of p53 in non-MSI groups was 61.1%, while the tumor in the MSI group was 42.6%, suggesting that p53 and MSI were negatively correlated with the prognosis of patients with colorectal cancer. There were similar implications in some current EC studies.

Studies have shown that the overexpression rate of p53 in patients with high-grade EC with MMRP missing is significantly lower than that in patients with high-grade EC with normal MMR.[25] Similar to other malignant tumors, the overexpression of p53 in EC patients related to Ki67 high index, high grade, and late stage. The overexpression of p53 was often accompanied by poor clinicopathological prognostic factors.[34] The overexpression of p53 and high expression of PCNA and Ki-67 can be used as important indicators of poor prognosis of EC. In recent years, studies have found that EC genotyping can help improve the diagnosis and treatment of EC. Studies[5] have shown that high-grade EC often has MMR and tumor suppressor gene (P53) mutations, and the mutations of both contribute to EC gene analysis typing.

dMMR/microsatellite instability and tumor infiltrating lymphocytes

The number and activation of lymphocytes in the tumor microenvironment, especially T lymphocytes, are closely related to tumor invasion and metastasis. Studies have found that the number of T lymphocytes in patients without early metastasis of colon cancer and without tumor thrombus is significantly higher than those with tumor thrombus.[6] With the development of immunotherapy in clinical trials and clinical practice, the impact of tumor-infiltrating lymphocytes (TILs) on the prognosis of cancer has been widely recognized and studied.

Cancer patients with a lack of MMRP expression (dMMR) often have a better prognosis. The possible mechanism is that cancer cells in dMMR patients can produce heterologous antigens recognized by T-cells, and MMRP is closely related to the production of neoantigens. The MS sequence mutation rate of dMMR tumors increases, which promotes the body to produce new peptides as new antigens that can be recognized and processed by the body's immune system, resulting in increased infiltration of immune cells, especially T lymphocytes.[35] In colorectal cancer and non-small cell lung cancer, patients with dMMR have increased lymphocyte infiltration.[5],[36] Xuehua et al.[37] and Wenliang et al.[22] found that the CD4+ and CD8+ levels of dMMR patients were significantly higher than those of patients with normal MMR. Shia et al.[38] found that high TIL counted in the EC and the presence of lymphocytes around the tumor could predict dMMR, with a sensitivity of 85% and a specificity of 46%. About 7% of ECs found POLE mutations, leading to loss of DNA polymerase and dMMR.[39] The prognosis of this group of POLE hypermutant ECs seems to have improved, Hussein et al.[40] and van Gool et al.[41] also reported POLE mutant EC has a high neoantigen load, and POLE and MSI ECs had more TILs and higher programmed death-ligand 1 (PD-L1) expression rate than MSS ECs. Intraepithelial CD8+ T-cell density has shown independent prognostic significance in preliminary studies[42],[43],[44] and interstitial CD3+ T cells may also had prognostic value.[45] Zhang et al.[46] and Willvonseder et al.[47] found that EC patients with high tumor mutation burden (TMB) and POLE mutations and MSI had higher activated CD4+ T-cells, plasma cells, CD8+ T cells and higher PD-L1 expression level than MSS ECs.

Studies have confirmed that CD103+ TRM (memory T-cells) was related to the prolonged survival time of many solid tumors, including EC.[48] Workel et al.[49] confirmed that after combining TCR stimulation and transforming growth factor-beta (TGF-β) signaling, intraepithelial CD8+ T-cells up-regulated CD103. POLE mutations and dMMR ECs were more likely to be infiltrated by immune cells including CD103+ TRM.[8],[19],[21] Webb et al.[50] and Bösmüller et al.[51] have demonstrated that the integrin CD103 that binded to E-cadherin was highly expressed in intraepithelial T-cells in ovarian cancer, suggesting that it is these CD103+ T-cells that cause high levels of TIL infiltration. CD39 is up-regulated on activated T-cells and is considered to be an immunosuppressive marker related to T-cell failure. Some scholars have proposed CD39 as an immune regulatory checkpoint and a new therapeutic target for cancer.[50],[52] CD39+ CD103+ TRM cells and CD8+ TILs in EC were responsive to reactivation.[50] It is worth mentioning that recent studies[53] have put forward inconsistent opinions. Although the number of CD8+ T-cells in EC has increased, compared with adjacent noncancerous tissues, the tumor microenvironment contains higher levels of immunosuppressive factors including TGFβ. Responsible for killing allogeneic target cells is CD103-CD8+ T-cells from adjacent tissues and cancer tissues, not CD103+CD8+ T-cells.

At present, there are still relatively few studies on TILs in EC, and many studies focus on the value of TILs in predicting MSI status. MSI and POLE mutant ECs usually have higher immunogenicity. TILs in MSI/dMMR ECs are worthy of in-depth research in guiding treatment and judging prognosis.

dMMR/microsatellite instability and programmed death-ligand 1

Programmed death receptor 1 (PD-1) is a member of the immunoglobulin B7/CD28 family. It is an immunosuppressive receptor that maintains autoimmune tolerance. It is expressed on activated T lymphocytes, B lymphocytes, natural killer cells, and the surface of nuclear macrophages and mesenchymal stem cells. PD-L1 and PD-L2 are the ligands of PD-1 and belong to the B7 family members. PD-L1 plays a major role in regulation and is mainly expressed in tumor cells, thymic cortical epithelial cells, placental trophoblast cells, and the above-mentioned immune cells. Under normal physiological conditions, the combination of PD-1 on the surface of T cells and PD-L1 on the surface of antigen-presenting cells reduces the production of Interferon-gamma, interleukin-2, and TNF-α, and inhibits the proliferation of T cells.[54] When cells become cancerous, tumor cells can up-regulate PD-L1 molecules to activate the PD-1/PD-L1 signaling pathway, inhibit the activation of T cells, and promote tumor infiltration and growth. Immunotherapy targeting PD-1/PD-L1 can be used to treat malignant tumors. For example, blocking the combination of PD-1/PD-L1 and restoring T-cell function can promote the killing of cancer cells.[55] At present, PD-1/PD-L1 inhibitors include nivolumab, pembrolizumab, pidilizumab, ate-zolizumab, etc. Some of them have been clinically tested and applied. Le et al.[36] reported that the PD-1 inhibitor pembrolizumab had a therapeutic effect on colorectal cancer patients with dMMR. In 2017, the American Society of Clinical Oncology reported that the data of pembrolizumab combined with lenvatinib (E7080) in the treatment of EC confirmed that PD-1/PD-L1 inhibitors have great prospects for the treatment of dMMR-type EC.[56] Le et al.[57] studied EC patients with an objective response rate of 53%, and patients with MSI-H/dMMR EC seemed to respond better to inhibitor therapy. Cytotoxic T lymphocyte-associated protein (CTLA4) was the target of monoclonal antibody-based drugs (such as ipilimumab) that enhance anti-cancer immunity. In some cancers, the combined use of immune checkpoint inhibitors such as anti-PD-1 and CTLA4 antibodies had a higher therapeutic effect than monotherapy. The overexpression of PD-1 and CTLA4 was related to TILs infiltration and expression of immune markers, PD-1. The expression level of CTLA4 and CTLA4 was correlated with the expression of TMB, MSI, dMMR, and DNMT.[51] Guillotin and Martin[58] found that dMMR-type ovarian cancer was resistant to platinum drugs, and there was no relevant finding in EC patients.

The EC of MSI-H/dMMR is related to a large number of TILs and high neoantigen load, which indicates that they may respond well to immunotherapy and can induce an immune response.

  Conclusion Top

The current clinical-pathological markers are not ideal in predicting the guiding treatment of P53 mutant EC, POLE mutant EC and MSI EC and judging the prognosis. The study of dMMR/MSI will confirm its value in EC diagnosis and personalized medicine and prognosis evaluation of EC. More big data, valuable prospective and in-depth dMMR/MSI EC researches are necessary to achieve meaningful breakthroughs.

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