Skip to main content
Download PDF

Microsatellite instability: a review of what the oncologist should know

Cancer Cell International volume 20, Article number: 16 (2020) Cite this article

Abstract

The patients with high microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) tumors recently have been reported that can benefit from immunotherapy, and MSI can be used as a genetic instability of a tumor detection index. However, many studies have shown that there are many heterogeneous phenomena in patients with MSI tumors in terms of immunotherapy, prognosis and chemotherapy sensitivity. Here we mainly review the research results of MSI detection methods, the mechanisms of MSI occurrence and its relationship with related tumors, aiming to make a brief analysis of the current research status of MSI and provide comparable reference and guidance value for further research in this field.

Background

Microsatellite (MS), also called Short Tandem Repeats (STRs) or Simple Sequence Repeat (SSRs), consists of repeated sequences of 1–6 nucleotides [1]. The distribution characteristics are different from 15 to 65 nucleotides tandem repeats of small satellite DNA, which is mainly located near the ends of chromosomes. MS are widely distributed and mostly is located near the coding region and may be located others region like intron or non-coding region. Each MS specific site is composed of two parts: the central core and the peripheral flanks, and the specificity of MS is mainly due to the change in the number of core repeating units.

The mechanism of MS generation is generally believed to be DNA slippage in the process of replication, or mismatch of the basic group of slippage strand and complementary strand in the process of DNA replication and repair, resulting in one or more of the repeating units missing or insert. The normal tissue DNA repair system, called mismatch repair (MMR), can correct in the process of DNA replication errors. However, due to the lack of MMR genes in tumor cells or defects in the process of replication repair, the possibility of gene mutation is increased [2]. It can be seen that MSI is an important factor in the occurrence and development of tumors.

In line with the frequency of MSI, it can be distinguished into three types: high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) and microsatellite stability (MSS) [3]. At present, clinical research tends to classify MSS-L and MSS as one kind. According to the different molecular mechanisms of MSI in colorectal cancer, it can be divided into colorectal cancer (CRC) with no obvious family genetic history and Lynch syndrome with non-polyposis with family genetic history. Early findings by researchers showed that most of the MSI cases are sporadic colorectal cancer, which is caused by epigenetic inactivation of gene expression in offspring on account of the methylation of hMLH1 promoter without the gene mutation. Lynch syndrome is an autosomal dominant tumor syndrome caused by mutations in MMR strains, and it can also cause tumors in other parts of the colon and rectum [4].

Because of the limitation of early MSI detection and the ambiguity of early MSI mechanism, only some specific chemotherapy drugs can be used to treat MSI patients, and the results are not ideal. With the recent development of MSI detection technology and immunosuppressant in tumor therapy, researchers found that MSI-H tumors respond well to immunotherapy. FDA approved PD-L1 (programed cell death ligand 1) blockade Keytruda to treat MSI-H/MMR patients. Scholars began to conduct more in-depth research on MSI detection methods, MSI mechanism, and the relationship between MSI and tumor.

Methods and progress of microsatellite instability detection

With the implementation of the human genome project, scientists began to further study the genes related to human diseases, found the microsatellite instability associated with it, and sought to detect the relevant methods (Table 1).

Table 1 Summary of microsatellite instability detection methods
Full size table

Next-generation sequencing (NGS)

Owing to errors in the function of MMR during DNA replication, MSI can be liable to emerge. Clinically, MSI can be detected by detecting changes in microsatellite sequences, or by detecting whether four MMR proteins are missing to determine whether there are MMR functional defects. However, some studies have found that only one detection method may lead to misjudgment, but using two detection methods at the same time faces the problems of high sample demand and high detection cost [5]. In order to solve these problems, micro samples for MSI detection by NGS can be used for disposable detection to get the acquaintance with MSI and whether MMR—related genes and Tumor mutational burden (TMB) alter [6]. NGS detection is directly targeted to one hundred known genes for genome sequencing, to test microsatellite instability in tumor tissues. In 2017, MSK’s IMPACT products were approved to detect microsatellite instability in cancer tissues. In comparison with traditional methods, the uniformity of check results of IMPACT can reach more than 92% [7]. The next year, FMI’s NGS product F1CDX was approved by the FDA and can also be used for MSI [8].

Fluorescent multiplex PCR and CE

The method of Polymerase Chain Reaction (PCR) is to compare the microsatellite loci detected in tumor tissues with normal DNA. And the National Cancer Institute recommended two single nucleotide repeat loci BAT-25 and BAT-26 and three multi-nucleotide repeat loci D2S123, D5S346 and D17S250 as microsatellite markers to determine the status of MSI [9]. The instability of one site is called low microsatellite instability (MSI-L), and the instability of two or more sites is called high microsatellite instability (MSI-H). The instability of all five sites is called microsatellite instability (MSS). This method can directly reflect the status of MSI, but only the MSI genotype can be obtained [10]. By now, fluorescent multiplex PCR and capillary electrophoresis (CE) is used to detect MSI status on DNA molecular chains in normal tissues and tumor tissues of the same patient. Fluorescence multiplex PCR and CE is used to detect genes after amplification after fluorescence labeled PCR amplification. Due to the characteristics of high efficiency, high sensitivity and reliable analysis results, this detection method has become the gold standard for MSI detection. At present, based on fluorescence multiplex PCR and CE, researchers design MSI analysis system [11] to detect MSI in human cells. This method can detect 5 quasi monomorphic sites BAT-26, NR-21, BAT-25, MONO-27 and NR-24 at one time.

Immunohistochemistry (IHC)

Detection of MMR gene deletion can indirectly reflect the status of MSI. IHC, a method, is adopted to detect the expression of MMR protein which consists of hMLH1, hPMS2, hMSH2 and hMSH6 [12]. If the result shows that any of the above MMR protein expression is absent, it means MMR deficient (dMMR). If all four MMR proteins are expressed, it means Proficient Mismatch Repair (pMMR). In general, dMMR is equivalent to MSI-H [13]. IHC is so simple and practical that some people think it can be used to replace PCR [14, 15]. But in some cases, dMMR and MSI-H could not be detected at the same time. For example, dMMR caused by MSH6 mutation could not meet the criteria of MSI-H diagnosis, and MSI-H positive tumor may come from MMR pathway protein which could not be detected by current technology. Therefore, some studies suggest that the application of molecular analysis to IHC and MSI analysis can reduce the incompatibility of results [16].

Single-molecule molecular inversion probes (smMIPs)

Recently, the Academy of Sciences published a method to detect microsatellite instability by using smMIPs, which are accurate and do not require patients to match normal materials. This method can accurately diagnose pan cancer microsatellite instability by single molecule reverse probe capture and high-throughput sequencing. According to this study, smMIPs can only accurately identify microsatellite instability in colorectal, prostate and endometrial cancers to determine the presence of MSI [17, 18].

MSI calculation method

MANTIS is to take the average value as MSI score after calculating the allele distribution difference value of each microsatellite site by comparing tumor and normal samples. MANTIS can detect more MS sites and maintain high accuracy. At present, MANTIS is widely used in the MSI detection of pan cancer [19]. Recently, researchers have built a binary classifier with the core of convolutional neural network (CNN). By developing a deep learning algorithm, resnet18, the researchers used tumor cell detection and he stained histological section images to predict MSI status. Compared with the existing tumor detection data set, resnet18 has the advantages of short training time and good classification performance, but it also has the disadvantages of small amount of training data and single representativeness of training samples. It has not been widely popularized at present [20].

Mechanism of MSI

Slipped strand mispairing

In addition to point mutation, MS can also be caused slipped strand mispairing (SSM) [21]. SSM is that in the process of DNA replication and synthesis, the allele region of MS repeat sequence between new chain and template chain may be mismatched, resulting in the instantaneous separation of new chain and template chain or the formation of stable single chain structure by several repeat units. Lai et al. [22] found that the MS sliding mutation rate increased exponentially with the number of repeat units. When slip mutation occurs, MS with small number of repeat units expands more frequently, while MS with large number of repeat units contracts more frequently.

MMR deficient

The mismatch repair (MMR), can repair errors during DNA replication. For example, in the above slip mechanism, when the mutated MS is paired with another chain, the redundant structure that may be formed after the slip chain can be restored to the level before replication if it is cut by nuclease and repaired, and remain in the new chain if it is not repaired. MMR deficient (dMMR) makes the errors produced during DNA replication impossible to repair, which leads to nucleotide mutation and changes in the length of simple repeat MS sequence [2, 23].

Characteristics of gene mutation in MSI-H patients

Researchers have found that mutations in MSI-H patients had commonalities. For example, the germline mutations of MMR gene, POLE (polymerase E)/POLD1 (human DNA polymerase δ) are more common in patients with MSI-H than in patients with MSS. It is also found that the tumors with polar MSI-H can improve the translation level of oncogenes by shortening 3 ‘UTRs (3′-untranslated regions), which may cause frequent MSI, but may lead to the loss of miRNA (microRNA) mediated regulation [24]. This could be used to explain the results of a 2015 study. According to the research results, a class of noncoding RNA molecules similar to cancer cell pathogens can trigger human immune response and accelerate the development of cancer. It also found that these noncoding RNA are transcribed by a class of satellite DNA, although they do not produce proteins, their regulatory role is closely related to the growth of tumor [25, 26].

Mutational characteristics in various cancers

An analysis based on TCGA data shows that there are not only the same repeated loci in MSI-H cases, but also some tumor specific loci. For example, its transmembrane/TGFβ, cell stress response/DNA damage and chromosome/M-phase related molecular functions are abundant in the genes of recurrent MSI, and the occurrence of frameshift MSI in TGFBR2 is more common in Colon adenocarcinoma (COAD) and Stomach adenocarcinoma (STAD) than in Uterine corpus endometrial carcinoma (UCEC), indicating that specific tumor environment is conducive to the occurrence of MSI events [24]. Patil et al. [27] found that with five quasi-singlet markers (NR-21, BAT-25, MONO-27, NR-24 and BAT-26), the Promega MSI analytical reagent can accurately identify MSI-H CRC without pairing normal DNA. Hause et al. [28] suggested that MSI mainly concentrates in some tumors of functional areas. For example, MSI occurs mostly in ion-binding genes in gastric adenocarcinoma. And the study showed that tumor suppressor genes ACVR2A and RNF are the most common and effective mutation targets in MSI-H tumors.

Treatment mechanism of MSI tumors

With the development of immunosuppressive drugs, it is helpful to study the immune response caused by MSI tumor. Scientists have found that some of the mechanisms of action of drugs suitable for MSI-H treatment, such as PD-L1 (programed cell death ligand 1) immunosuppressant, can produce heteroantigens that are easy to be recognized by T cells in dMMR cancer cells, which is beneficial to a variety of MSI-H tumors [54]. At present, there are researches on specific tumor targets of MSI. After analyzing multiple sets of data through CRISPR-Cas9-mediated knockout and RNA interference, Chan et al. that RecQDNA helicase WRN (Werner syndrome, RecQ helicase-like) was an essential factor for the MSI model, but not an important factor for microsatellite stable tumors. Silencing WRN can induce DNA double-strand breakage, activate DNA damage response, induce apoptosis and cell cycle arrest MSI tumors require WRN helicases but do not cause death of their own cells, suggesting that WRN may be a target for lethal synthesis [29].

The above studies indicate that microsatellite mutation is a multi-pathway process, and the continuously updated and developed MSI mechanism will play a more important role in the diagnosis and treatment of future clinical applications.

Advances in the clinical application of microsatellite instability

MSI-H/dMMR related diseases

Understanding the classes of diseases (Table 2) associated with MSI is the basis of diagnosis and cure of illnesses with MSI-related technologies.

Table 2 Summary of MSI-H/dMMR related diseases
Full size table

Lynch syndrome

Latham et al. [30] reported that dMMR is common in patients with Lynch syndrome (LS), so patients with MSI-H or dMMR tumors can predict Lynch syndrome through MSI related tests. NCCN guidelines also recommends gene testing for Lynch syndrome, including MMR genes (hMLH1, hMSH2, hMSH6, hPMS2) and EpCAM genes. MMR IHC screening and MSI detection screening are two ways to screen for patients with Lynch syndrome (Fig. 1). The IHC test results show that the negative hMLH1 cannot directly indicate that there is no mutation in hMLH1, and the hMLH1 promoter needs to be tested to determine whether there is methylation or BRAF (v-RAF murine sarcoma viral oncogene homologB1) mutation, so as to exclude Lynch syndrome [31]. However, EpCAM (Epithelial cell adhesion molecule) gene [21] is still needed to be detected in suspected hMSH2 patients, because LS caused by hypermethylation of hMSH2 which caused by EpCAM body mutation will also lead to the loss of MMR protein expression in IHC detection, but hMSH2 mutation analysis is negative. Only when EpCAM immunostaining is negative, EpCAM abnormality indicates hMSH2 mutation [32]. MSI was detected by nucleotide markers: two of the unstable sites were MSI-H, the instability of one of the locus was MSI-L, locus-free instability was MSS [33]. But some diseases need to be identified by multiple detection methods at the same time. For example, Cosgrove et al. [34] found that the Lynch syndrome could not be recognized by IHC alone or MSI, and the evaluation of endometrial cancer by MSI, hMLH1 methylation and IHC combined application was needed. A research of Dabir et al. [35] stated MSI-H was more common in patients over 60 years old with LS, and most of them were found in normal adenocarcinoma, villous adenoma, adenoma over 1 cm and highly dysplastic adenoma.

Fig. 1
figure 1

Lynch syndrome screening process. Lynch syndrome screening process. MMR immunohistochemical method is used to detect whether 4 MMR proteins of hMLH1, hPMS2, hMSH2 and hMSH6 are missing, and whether BRAF V600E mutation exists in hMLH1 negative protein and whether EpCAM mutation exists in hMLH1 positive protein, so as to determine whether there is MMR functional defect. MSI detection is to determine the stability of MSI sites by detecting nucleotide marker: two of the unstable loci were MSI-H, the instability of one of the loci was MSI-L, MSS was defined as the instability of zero loci. MMR mismatch repair, MSI-H microsatellite high instability, MSI-L microsatellite low instability, MSS microsatellite stability

Full size image

Colorectal cancer

MSI is closely related to colorectal cancer (CRC), and some studies have found MS loci related to CRC. Saeterdal et al. [36] clarified that between high-level microsatellite instability colorectal cancer patients, compared with MSS tumors, tumors are infiltrated with dense cytotoxic T cells. The study of Nouri Nojadeh et al. [37] confirmed that NR-21, BAT-26 and BAT-25 markers play an important role in judging MSI status in CRC. Promega MSI analytical reagent [38], which has five quasi-singlet markers (NR-21, BAT-25, MONO-27, NR-24 and BAT-26), can accurately identify MSI-H CRC without matching normal DNA at present. BRAF mutation affects the MMR function of early diseases, and has an important effect on CRC. Fujiyoshi et al. [39] found that the prognosis of MSI-H colorectal cancer was good, which was the important reason of BRAF mutation in early diseases, while the prognosis of MSS and MSI-L CRC was poor. However, a study of Goldstein et al. [40] showed that BRAF mutation is associated with MSI-H in metastatic CRC patients with advanced BRAF mutation,but BRAF mutation is a bad factor. According to the article of Carr et al. [41], lifestyle can affect the molecular pathological types of colorectal cancer and statistics show that moderate and high alcohol consumption is associated with an increased risk of MSI-H colon cancer. MSI can be used as a significant molecular marker for prognosis and adjuvant therapy of CRC [42]. MSI has different effects on the lymph nodes and distant metastasis of CRC in different periods, and on the prognosis of patients. Other studies suggested that patients with stage I and stage II MSI colorectal cancer have good prognosis, high 5-year survival rate, low recurrence rate and deterioration rate, but patients with stage III MSI colorectal cancer have the opposite results [43]. Arakawa et al. [44] suggested that most of the tumors in MSI-H colorectal cancer patients occur on the right side.

Gastric cancer

Choi et al. [45] suggest that microsatellite instability is also found in gastric cancer. Using hMLH1 and hMSH2 in IHC and MSI analysis system, patients with MSI related gastric cancer can be detected [46]. Small intestinal adenocarcinoma is the most common type of gastric cancer in Lynch individuals. Imamura et al. [47] found that MSI esophagogastric junction adenocarcinoma (EGJ) which is a special gastric cancer is closely related to genetic instability. And the researchers suggested that tumors in Siewert type I are not related to MSI, while tumors in Siewert type II and III are related to MSI. Smyth et al. [48] illuminated that the survival time of patients with MSI-H gastric cancer who can be operated on is not better than that of patients with MSI-L or MSS. Because the American Society of clinical oncology gastrointestinal cancer symposium found that MSI can be used as a good prognostic indicator for resectable primary gastric cancer, future clinical trials need to consider whether to use immunosuppressive checkpoint inhibitors (ICI) to treat gastric cancer with high microsatellite instability due to MSI as a stratification factor [49]. For the mechanism of ICI treatment, one study found that it may be because of the high expression of CD8 positive T cell molecular marker, PD-L1 gene and IFN γ (interferon-γ) gene in patients with MSI-H. Marrelli et al. [50] stated that the tumor of MSI-H patients with gastric cancer is common in women, and most of them occur in non-cardia area.

Breast cancer

Abida et al. [51] found that the prognosis of MSI-H patients with breast cancer is poor, which is different from the relationship between MSI and prognosis of breast cancer. IHC detection of hMSH2, hMLH1 and MSI related loci D3S1766 and D2S2739 can identify MSI related breast cancer [52]. At present, the clearest influencing factor is BRCA1. A study of Zhu et al. has shown that BRCA1 expression function can affect the silencing mechanism of satellite DNA in chromatin, which will be damaged by BRCA1 mutation, resulting in failure of normal cell replication process. At the same time, the mutation of BRCA1, which can make the repair function of DNA loss, will cause microsatellite instability and abnormal cells [53].

Prostate cancer

An analysis of prostate cancer has shown that MSI-H/dMMR phenotypes can be detected in some prostate cancer patients, including pathogenic embryonic mutants carrying Lynch syndrome-related genes. Using IHC to detect MMR related proteins and MSI analysis and NGS can improve the accuracy of MSI related prostate cancer recognition [6, 54]. Although this phenomenon is not common, it has therapeutic significance. And the study of Abida et al. showed that MSI-H/dMMR patients with bladder cancer have good prognosis for the anti-PD-1/PD-L1 treatment [55].

Cholangiocarcinoma

Goeppert et al. [56] have found that MSI-H can be detected in a small number of cholangiocarcinoma patients who are not related to liver trematode. Patients with MSI related cholangiocarcinoma can be detected by analyzing MSI related loci BAT25, BAT26, and CAT25 [56]. And they found that most of the patients with MSI-H were young patients with atypical tissue morphology. And they also suggested that MSI-H/dMMR patients with cholangiocarcinoma have good prognosis for the anti-PD-1/PD-L1 treatment.

Leukemia

Walker et al. [57] discovered that MSI can’t be detected in patients with acute myeloid leukemia. However, Patel et al. [58] clarified that MSI was detected in patients with chronic myeloid leukemia, while there was no MSI in normal people, so it was speculated that there was a certain relationship between chronic myeloid leukemia and microsatellite instability. They found that analysis of MSI related loci D17S261 and D3S643 is helpful to identify MSI related chronic leukemia. And his study suggested that MSI-H/dMMR patients with chronic myeloid leukemia have good prognosis for the anti-PD-1/PD-L1 treatment.

Bladder cancer

IHC detection of hMLH1, hMSH2 and hMSH6 and MSI analysis can detect MSI associated bladder cancer [59]. A study of Skeldon et al. [60] has indicated that patients with MSI-H Lynch syndrome have a rising risk of bladder cancer because of hMSH2 mutations. However, one study of Giedl et al. [59] demonstrated that a lot of young patients have a low risk of bladder cancer when they get MSI-H Lynch syndrome. Though researcher had found only a few number of bladder cancer patients were diagnosed with MSI-H, these patients can benefit from anti-PD-1/PD-L1 treatment. Zekri et al. [61] suggested that the MSI related loci D16S476, D9S171 of MSI-H patients with bladder cancer are consistent with those in urine, and the MSI of urine sediment can be considered as a clinical assistant diagnosis. Wadhwa et al. [62] stated that MSI related loci D9S63, D9S156, and D9S283 can be used to screen patients with high micro bladder cancer.

Ovarian cancer

A research of by Howitt et al. [63] made known that an increased number of CD8+, PD-1+, and TILS in MSI patients. Compared with MSS, the patients with Clear-cell ovarian carcinoma (CCOCs) are likely to benefit from immunotherapy. MSI analysis and MMR related protein detection of hMSH2 and hMSH6 can be used to identify MSI ovarian cancer [64].

Endometrial carcinoma

MSI analysis and IHC MMR related protein detection can be used to identify MSI endometrial carcinoma. Compared with MSS, UCEC patients with MSI have higher immune components, CD3+ and CD8+ TIL. A study of Howitt et al. [65] has demonstrated that the immune blocking effect of the tumor itself is great relative to generate immunosuppressive microenvironment. Llosa et al. found that this immune function is caused by the upregulation of several checkpoint ligands, among which PD-1/PD-L1 is an important ligand [66]. The prognosis of early Endometrial Carcinoma (EC) is not correlated with MSI [67], but the results of EC in the middle and late stage were opposite. Bilbao et al. showed that the intermediate and advanced endometrial cancer of MSI was associated with poor prognosis index [34, 68].

Pancreatic ductal adenocarcinoma

Wilentz et al. showed that MSI-H can be detected in a small number of Pancreatic ductal adenocarcinoma (PDAC) patients [69]. MSI can be detected in Medullary carcinomas of the pancreas and Acinar cell carcinomas of the pancreas. And hMLH1 and hMSH2 inactivation have been detected in many pancreatic cancer patients [70]. Yamamoto et al. found that PDAC patients with dMMR/MSI have a significantly good prognosis [71].

Thyroid cancers

Using NGS and IHC, MSI analysis can detect patients with MSI related thyroid cancer. Genutis et al. reported that MSI-H can be detected in patients with thyroid cancer, especially in patients with follicular thyroid cancer (FTC) [72]. It is also considered to be associated with delayed MMR inactivation in advanced thyroid cancer. And MSI-H patients with FTC have a prolonged survival time.

Adrenocortical carcinoma

Some studies have found that adrenocortical cancer (ACC) is related to MSI. McCabe et al. showed that the occurrence of MSI in adrenocortical carcinoma is related to the deletion mutations of MSH2 [73]. A study of Bonneville et al. suggested that MSI-H/dMMR patients with adrenocortical cancer have high variation load [74]. There is no relevant literature about the effect of MSI on the prognosis of cortical carcinoma.

Preventive measures for MSI-H/dMMR related diseases

As research into MSI-H/dMM related diseases developing, scientists are attempting to search for ways to prevent them. According to the NCCN guidelines, MSI or MMR testing should be considered for all types of colorectal cancer. And early detection of MSI or MMR and prophylactic polypectomy can reduce CRC mortality [75]. Ruschoff et al. [76] suggested that aspirin/sulinda may play a preventive role in reducing the risk of Lynch syndrome-related cancer by reducing microsatellite instability in colorectal cancer cells, especially in patients with hMSH2 and hMLH1 gene changes. Data research showed that HLA-A0201-restricted cytotoxic T cell epitope (FSP11) is expected to become an integral part of MSI-H tumor vaccine in the future, because MSI-H -related transfer peptide (FSP) can induce anti MSI-H tumor response [77].

The treatment of MSI-H/dMMR related diseases

For patients with MSI-H/dMMR related diseases, scientists are seeking some precise treatments. As early as in the 2011 NCCN guidelines, MSI detection was required before the use of 5-FU as a chemotherapeutic agent in patients with CRC. Warusavitarne et al. [78] reported that 5-FU is not used as adjuvant chemotherapy for patients with MSI-H and dMMR characteristics for the reason that patients with MSI-H/dMMR have poor results after 5-FU adjuvant chemotherapy. Sargent et al. [79] showed that the effect of adjuvant chemotherapy with fluorouracil monotherapy for stage II CRC patients with MSI-H is not good, so it is not necessary to use fluorouracil monotherapy as adjuvant therapy for stage II CRC patients with MSI-H. However, the study of Benson et al. [80] stated that the MMR status of patients with stage III to IV CRC does not affect the outcome of 5-FU treatment. No matter whether the MMR function is abnormal, 5-FU has a curative effect for the MMR status of patients with stage III to IV CRC [81].

Some studies have shown that due to dMMR cancer cells can produce heterologous antigens that are easily recognized by T cells,the effectiveness of PD-1 inhibitors on solid tumors expressing MSI-H is higher than that of solid tumors expressing MSI-L and MSS [82]. Keytruda is therefore approved by FDA for solid tumors with MSI-H/dMMR characteristics based on the biomarkers contained in the tumors [83]. MSI-H can be used as one of the predictors of the efficacy of immunotherapy at present. Phase III clinical trial IMblaze370 made clear that the PD-L1 inhibitor Atezolizumab alone or combined with the mek1/2 inhibitor Cobimetinib did not work well, because the PD-1/PD-L1 inhibitor requires a sufficient amount of new antigen to be recognized by T cells for its effect. We can also find this in Mark Yarchoan’s article that the high benefit rate of dMMR patients on PD-1/PD-L1 inhibitors may be related to the gradual accumulation of mutations [84]. The drug treatment of colorectal cancer is developing constantly (Table 3). FDA approved Nivolumab for patients over 12 years of age with advanced metastatic colon cancer who developed MSI-H or dMMR after previous treatment with fluoropyrimidine, oxaliplatin or irinotecan [85, 86]. Overman et al. [87] suggested that Nivolumab is effective not only for patients with dMMR/MSI-H metastatic colorectal cancer, but also for those with poor prognosis of BRAF mutation in CRC. It can be inferred that Nivolumab is also effective for dMMR/MSI-H metastatic colorectal cancer caused by BRAF mutation. The FDA approved the combination therapy of Nivolumab and Ipilimumab as the first immunosuppressive combination therapy for metastatic CRC with worsened MSI-H/dMMR after treatment with oxaliplatin, irinotecan and fluoropyrimidine [88]. The results of CheckMate-142 trial showed that low dose ipilimumab combined with nivolumab can reduce the toxic and side effects of patients, and can play a better therapeutic effect on patients with partial metastatic CRC, so it can be used as a new first-line treatment [89, 90]. A study by O’Neil et al. [91] showed that Pembrolizumab is safe and less adverse events for patients with advanced PD-L1 positive CRC. It can be used as a drug of choice for patients with advanced anti-PD-L1 positive CRC. One study of Innocenti et al. [92] found that chemotherapy plus Cetuximab was significantly less effective than chemotherapy plus bevacizumab in the treatment of MSI-H patients. They hypothesized that, there are different reasons for the efficacy of bevacizumab and cetuximab. The reduced efficacy of the EGFR inhibitor (cetuximab) is due to the adverse effect of the over methylation of the MSI-H tumor on the EGFR inhibitor, resulting in the low expression of the EGFR ligand. Because the vascular normalization induced by bevacizumab can enhance the infiltration and activation of Th1 lymphocytes, thereby achieving immune stimulation and enhancing the anti-tumor effect of cellular immunity, bevacizumab is more effective than cetuximab in the treatment of MSI-H tumor patients.

Table 3 Summary of drug therapy for colorectal cancer patients with MSI characteristics
Full size table

There are new developments in the treatment of other MSI-H tumors. Recent research of Kim et al. [93] proposed that PD-1 inhibitors can be used to treat patients with metastatic gastric cancer with positive MSI-H. As for whether adjuvant chemotherapy drugs or not, it has been found that chemotherapy has no significant effect on the prognosis of gastric cancer patients with MSI-H, and the expression of PD-L1 is related to the better survival of patients, but its potential benefits of PD-L1 may be weakened due to chemotherapy, so it is suggested that patients with MSI-H should avoid adjuvant chemotherapy [94]. A data analysis of Pietrantonio et al. in the same year also showed that chemotherapy was not good for the prognosis of MSI patients with gastric cancer, and pointed out that for all patients with local advanced gastric cancer who considered to receive adjuvant chemotherapy, we should detect their MSI, and for MSI patients, we should consider to avoid chemotherapy and only take surgical treatment [20]. Olaparib which can inhibit the repair of DNA damage in cancer cells is related to reduce MSI as well as promote apoptosis, and strengthen other drugs’ effect such as platinum in combination, and then achieve the effect of treatment of breast cancer [95]. Although immunosuppressive agents can be applied to patients with MSI-H tumors, some studies have found that the number of patients with MSI-H tumors who benefit from immunosuppressive agents is less. Recently, however, it has been proposed that ICI combined with radiotherapy can reduce the incidence of adverse events in patients with advanced biliary tumors. ICI combined with radiotherapy is recommended as a treatment plan for patients with advanced biliary tumors [96]. Researchers conducted MSI sensor score analysis on 1033 patients with prostate cancer and found that a total of 32 patients had MSI-H tumor [55]. Among them, more than half of the patients had stable condition or remission after receiving anti-PD-1/PD-L1 treatment. In 2016, Fader published a clinical study on Pembrolizumab for PD-1 blockade in patients with dMMR EC, providing a new therapeutic direction for patients with dMMR EC. ASCO 2017 reported that anti-PD-1/PD-L1 drugs have great potential in EC treatment. The mechanism of chemotherapeutic drug resistance to tumor has been further discovered. Fader et al. [97] found that the drug resistance is mainly related to dMMR. The DNA self-repair function of tumor cells can resist the damage of chemotherapeutic drugs such as temozolomide and cisplatin to the DNA function of tumor cells, so as to achieve the effect of drug resistance. A study of Habra et al. have shown that ACC is not effective in immunotherapy of dendritic cells without immune response [98].

Relationships between MSI and TMB

MSI is due to MMR deletion or gene replication process deletion or error, leading to changes in the length of MS. TMB refers to tumor mutational burden, representing the number of mutations per million bases. Both MSI and TMB represent the production of new antibodies. Studies have stated clearly that there are many patients with MSI-H who have high TMB levels [99]. And Bonneville et al. found that MSI-H adrenocortical carcinoma and cervical squamous cell carcinoma have obvious high mutation [74]. Tumors with high mutation rates may respond well to checkpoint inhibitors (CPI), so we can consider using CPI to treat MSI-H patients with TMB [100].

Conclusions and perspectives

A large number of studies have shown that MSI is closely related to tumor. The development of fluorescence multiplex PCR and CE and IHC promote the development of MSI detection, but there are also factors affecting the accuracy, considering whether it is related to the MMR protein that cannot be detected at present [16]. For example, if the dMMR caused by MSH6 mutation cannot meet the criteria of MSI-H diagnosis, scientists need to increase MS loci other than BAT-25 and BAT-26 and three multi nuclear repeat loca D2S123, D5S346 and D17S250 to improve the accuracy of MSI. The latest smMIPs [17] and deep learning from histology in tumor are very promising for clinical application of MSI detection. However, smMIPs can only be used for the detection of chromatic cancer, prostate cancer, and objective cancer and deep learning from history in tumor [20] still needs a large number of clinical experiments to improve the accuracy. Therefore, NGS can be considered [6], despite IHC and PCR are still widely used.

Early diagnosis of MSI is of great significance to the prognosis and treatment of MSI. At present, it is found that there is a certain correlation between MSI related tumor and clinical phenotype, which can be detected early by MSI in high-risk MSI patients. For example, the tumor of MSI-H patients with gastric cancer generally occurs in non-cardia area [50]. Because of tumor heterogeneity, the prognosis of different MSI is different. For example, the prognosis of most MSI-H cancer patients is good, while the prognosis of breast cancer [51] and endometrial cancer [67] patients with MSI-H is bad. Besides, early diagnosis can help to take preventive measures for its diseases, such as Lynch syndrome, and early use of aspirin in patients with hMSH2 and hMLH1 gene changes is of great significance to reduce the risk of cancer related to Lynch syndrome [76]. At the same time, early development of vaccines that can induce anti-tumor response is also of great significance for the prevention of MSI-H tumors. For example, the latest discovery of FSP11, which can be an important component of vaccines [77].

Although some studies have found the specific MS site of MSI tumor, but because MSI is a multi-channel process, it is still complex to study the disease caused by MSI and the treatment mechanism of MSI tumor. It has been found that MSI leads to drug resistance of tumor [97]. More clinical studies on the relationship between MSI related sites and tumor drug resistance are needed to improve the therapeutic effect of chemotherapy. For MSI-H patients with TMB, CPI inhibitors can be considered for treatment of MSI-H tumors [100]. With immunotherapy widely used in tumor treatment, a large number of data show that MSI-H can be used in immunosuppressive therapy, MSI can be used as an effective positive immunotherapy predictor. But the benefit of tumor is different in different periods. For example, nivolumab is suitable for patients with advanced metastatic colorectal cancer [85]. If the newly found synthetic lethal target silencing WRN [29] can be used in clinical treatment, more MSI patients will benefit in the future.

In general, the detection method of MSI, the mechanism of MSI and its relationship with related tumors have made progress. However, it is still necessary to detect MSI in rare tumors, and improve the number of MSI related tumors and the classification of tumors. It is believed that with the more accurate detection technology of MSI and the clearer relationship between the mechanism of MSI and MSI-related tumors, MSI will open up a new field for the diagnosis, prevention and treatment of diseases.

Availability of data and materials

Not applicable.

Abbreviations

CE:

capillary electrophoresis

CRC:

colorectal cancer

CTLA4:

cytotoxic T-lymphocyte-associated protein 4

dMMR:

mismatch repair deficient

IHC:

immunohistochemistry

MMR:

mismatch repair

MS:

microsatellite

MSI-H:

microsatellite high instability

NGS:

next-generation sequencing

PCR:

polymerase Chain Reaction

PD-L1:

programmed cell death-Ligand 1

smMIPs:

single-molecule molecular inversion probes

VEGF:

vascular endothelial growth factor

References

  1. Garrido-Ramos MA. Satellite DNA: an evolving topic. Genes. 2017;8(9):230.

    Article  PubMed Central  CAS  Google Scholar 

  2. Lower SS, McGurk MP, Clark AG, et al. Satellite DNA evolution: old ideas, new approaches. Curr Opin Genet Dev. 2018;49:70–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bonneville R, Krook MA, Chen HZ, et al. Detection of microsatellite instability biomarkers via next-generation sequencing. Methods Mol Biol. 2020;2055:119–32.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nikanjam M, Arguello D, Gatalica Z, et al. Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden, and PD-L1 expression in cancer patients. Int J Cancer. 2019. https://0-doi-org.brum.beds.ac.uk/10.1002/ijc.32661.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cohen R, Hain E, Buhard O, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol. 2018. https://0-doi-org.brum.beds.ac.uk/10.1001/jamaoncol.2018.4942.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hempelmann JA, Lockwood CM, Konnick EQ, et al. Microsatellite instability in prostate cancer by PCR or next-generation sequencing. J Immunother Cancer. 2018;6(1):29.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cheng DT, Prasad M, Chekaluk Y, et al. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med Genomics. 2017;10(1):33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. First Comprehensive Companion Diagnostic OK’d. Cancer Discov 2018, 8(3):OF4.

  9. Suraweera N, Duval A, Reperant M, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002;123(6):1804–11.

    Article  CAS  PubMed  Google Scholar 

  10. Berg KD, Glaser CL, Thompson RE, et al. Detection of microsatellite instability by fluorescence multiplex polymerase chain reaction. J Mol Diagn. 2000;2(1):20–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Arulananda S, Thapa B, Walkiewicz M, et al. Mismatch repair protein defects and microsatellite instability in malignant pleural mesothelioma. J Thorac Oncol. 2018;13(10):1588–94.

    Article  PubMed  Google Scholar 

  12. Cheah PL, Li J, Looi LM, et al. Screening for microsatellite instability in colorectal carcinoma: practical utility of immunohistochemistry and PCR with fragment analysis in a diagnostic histopathology setting. Malays J Pathol. 2019;41(2):91–100.

    CAS  PubMed  Google Scholar 

  13. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58(22):5248–57.

    CAS  PubMed  Google Scholar 

  14. Bacher JW, Flanagan LA, Smalley RL, et al. Development of a fluorescent multiplex assay for detection of MSI-High tumors. Dis Markers. 2004;20(4–5):237–50.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhu X, Chen MS, Tian LW, et al. Single nucleotide polymorphism of rs430397 in the fifth intron of GRP78 gene and clinical relevance of primary hepatocellular carcinoma in Han Chinese: risk and prognosis. Int J Cancer. 2009;125(6):1352–7.

    Article  CAS  PubMed  Google Scholar 

  16. Berardinelli GN, Scapulatempo-Neto C, Duraes R, et al. Advantage of HSP110 (T17) marker inclusion for microsatellite instability (MSI) detection in colorectal cancer patients. Oncotarget. 2018;9(47):28691–701.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Waalkes A, Smith N, Penewit K, et al. Accurate pan-cancer molecular diagnosis of microsatellite instability by single-molecule molecular inversion probe capture and high-throughput sequencing. Clin Chem. 2018;64(6):950–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu J, Li D, Luo H, et al. Circular RNAs: the star molecules in cancer. Mol Aspects Med. 2019;70:141–52.

    Article  CAS  PubMed  Google Scholar 

  19. Kautto EA, Bonneville R, Miya J, et al. Performance evaluation for rapid detection of pan-cancer microsatellite instability with MANTIS. Oncotarget. 2017;8(5):7452–63.

    Article  PubMed  Google Scholar 

  20. Pietrantonio F, Miceli R, Raimondi A, et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in Gastric cancer. J Clin Oncol. 2019;37:3392–400.

    Article  PubMed  Google Scholar 

  21. Hughes CR, Queller DC. Detection of highly polymorphic microsatellite loci in a species with little allozyme polymorphism. Mol Ecol. 1993;2(3):131–7.

    Article  CAS  PubMed  Google Scholar 

  22. Lai Y, Sun F. The relationship between microsatellite slippage mutation rate and the number of repeat units. Mol Biol Evol. 2003;20(12):2123–31.

    Article  CAS  PubMed  Google Scholar 

  23. Tang X, Huang Y, Lei J, et al. The single-cell sequencing: new developments and medical applications. Cell Biosci. 2019;9:53.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cortes-Ciriano I, Lee S, Park WY, et al. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;8:15180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tanne A, Muniz LR, Puzio-Kuter A, et al. Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells. Proc Natl Acad Sci USA. 2015;112(49):15154–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhu X, Luo H, Xu Y. Transcriptome analysis reveals an important candidate gene involved in both nodal metastasis and prognosis in lung adenocarcinoma. Cell Biosci. 2019;9:92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Patil DT, Bronner MP, Portier BP, et al. A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA. Diagn Mol Pathol. 2012;21(3):127–33.

    Article  CAS  PubMed  Google Scholar 

  28. Hause RJ, Pritchard CC, Shendure J, et al. Corrigendum: classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2018;24(4):525.

    Article  CAS  PubMed  Google Scholar 

  29. Chan EM, Shibue T, McFarland JM, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature. 2019;568(7753):551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of lynch syndrome pan-cancer. J Clin Oncol. 2018;37(4):286.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bouzourene H, Hutter P, Losi L, et al. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9(2):167–72.

    Article  CAS  PubMed  Google Scholar 

  32. Guarinos C, Castillejo A, Barbera VM, et al. EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients. J Mol Diagn. 2010;12(6):765–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58(8):1713–8.

    CAS  PubMed  Google Scholar 

  34. Cosgrove CM, Tritchler DL, Cohn DE, et al. An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer. Gynecol Oncol. 2018;148(1):174–80.

    Article  CAS  PubMed  Google Scholar 

  35. Dabir PD, Bruggeling CE, van der Post RS, et al. Microsatellite instability screening in colorectal adenomas to detect Lynch syndrome patients?. Eur J Hum Genet: A systematic review and meta-analysis; 2019.

    Google Scholar 

  36. Saeterdal I, Bjorheim J, Lislerud K, et al. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci USA. 2001;98(23):13255–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nouri Nojadeh J, Hashemzadeh S, Samadi Kafil H, et al. Evaluation of microsatellite instability in tumor and tumor marginal samples of sporadic colorectal cancer using mononucleotide markers. EXCLI J. 2018;17:945–51.

    PubMed  PubMed Central  Google Scholar 

  38. Morandi L, de Biase D, Visani M, et al. T([20]) repeat in the 3′-untranslated region of the MT1X gene: a marker with high sensitivity and specificity to detect microsatellite instability in colorectal cancer. Int J Colorectal Dis. 2012;27(5):647–56.

    Article  PubMed  Google Scholar 

  39. Fujiyoshi K, Yamamoto G, Takahashi A, et al. High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases. Oncol Rep. 2017;37(2):785–92.

    Article  CAS  PubMed  Google Scholar 

  40. Goldstein J, Tran B, Ensor J, et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol. 2014;25(5):1032–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Carr PR, Alwers E, Bienert S, et al. Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses. Ann Oncol. 2018;29(4):825–34.

    Article  CAS  PubMed  Google Scholar 

  42. Hasan S, Renz P, Wegner RE, et al. Microsatellite instability (MSI) as an independent predictor of pathologic complete response (PCR) in locally advanced rectal cancer: a National Cancer Database (NCDB) Analysis. Ann Surg. 2018. https://0-doi-org.brum.beds.ac.uk/10.1097/SLA.0000000000003051.

    Article  PubMed  Google Scholar 

  43. Srdjan M, Jadranka A, Ivan D, et al. Microsatellite instability & survival in patients with stage II/III colorectal carcinoma. Indian J Med Res. 2016;143(Supplement):S104–11.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Arakawa K, Hata K, Kawai K, et al. Predictors for high microsatellite instability in patients with colorectal cancer fulfilling the revised bethesda guidelines. Anticancer Res. 2018;38(8):4871–6.

    Article  PubMed  Google Scholar 

  45. Choi YY, Noh SH, Cheong JH. Molecular dimensions of gastric cancer: translational and clinical perspectives. J Pathol Transl Med. 2016;50(1):1–9.

    Article  PubMed  Google Scholar 

  46. Bae YS, Kim H, Noh SH, et al. Usefulness of Immunohistochemistry for microsatellite instability screening in gastric cancer. Gut Liver. 2015;9(5):629–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Imamura Y, Watanabe M, Toihata T, et al. Recent incidence trend of surgically resected esophagogastric junction adenocarcinoma and microsatellite instability status in Japanese Patients. Digestion. 2019;99(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  48. Smyth EC, Wotherspoon A, Peckitt C, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3(9):1197–203.

    Article  PubMed  Google Scholar 

  49. Pietrantonio F, Raimondi A, Choi YY, et al. MSI-GC-01: individual patient data (IPD) meta-analysis of microsatellite instability (MSI) and gastric cancer (GC) from four randomized clinical trials (RCTs). J Clin Oncol. 2019;37(4_suppl):66.

    Article  Google Scholar 

  50. Marrelli D, Polom K, Pascale V, et al. Strong prognostic value of microsatellite instability in intestinal type non-cardia gastric cancer. Ann Surg Oncol. 2016;23(3):943–50.

    Article  PubMed  Google Scholar 

  51. Ozer E, Yuksel E, Kizildag S, et al. Microsatellite instability in early-onset breast cancer. Pathol Res Pract. 2002;198(8):525–30.

    Article  CAS  PubMed  Google Scholar 

  52. Fu Q, Yao GY, Tang XL, et al. Microsatellite instability and allele-specific chromosome 3p deletion in breast cancer and precancerous lesions. Zhonghua Zhong Liu Za Zhi. 2007;29(1):34–40.

    CAS  PubMed  Google Scholar 

  53. Zhu Q, Pao GM, Huynh AM, et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature. 2011;477(7363):179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fraune C, Simon R, Hoflmayer D, et al. High homogeneity of mismatch repair deficiency in advanced prostate cancer. Virchows Arch. 2019. https://0-doi-org.brum.beds.ac.uk/10.1007/s00428-019-02701-x.

    Article  PubMed  Google Scholar 

  55. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2018;5:471–8.

    Article  PubMed Central  Google Scholar 

  56. Goeppert B, Roessler S, Renner M, et al. Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma. Br J Cancer. 2019;120(1):109–14.

    Article  CAS  PubMed  Google Scholar 

  57. Walker CJ, Eisfeld AK, Genutis LK, et al. No evidence for microsatellite instability in acute myeloid leukemia. Leukemia. 2017;31(6):1474–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Patel TN, Chakraborty M, Bhattacharya P. Microsatellite instability in chronic myeloid leukemia using D17S261 and D3S643 markers: a pilot study in Gujarat population. Indian J Cancer. 2017;54(2):426–9.

    Article  CAS  PubMed  Google Scholar 

  59. Giedl J, Schneckenpointner R, Filbeck T, et al. Low frequency of HNPCC-associated microsatellite instability and aberrant MMR protein expression in early-onset bladder cancer. Am J Clin Pathol. 2014;142(5):634–9.

    Article  CAS  PubMed  Google Scholar 

  60. Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol. 2013;63(2):379–85.

    Article  CAS  PubMed  Google Scholar 

  61. Zekri AN, Khaled HM, Mohammed MB, et al. Microsatellite instability profiling in Egyptian bladder cancer patients: a pilot study. Curr Probl Cancer. 2019;43(6):100472.

    Article  PubMed  Google Scholar 

  62. Wadhwa N, Mathew BB, Tandon S, et al. Assessment of microsatellite instability for screening bladder cancer in high-risk population. J Cancer Res Ther. 2018;14(5):916–20.

    Article  CAS  PubMed  Google Scholar 

  63. Howitt BE, Strickland KC, Sholl LM, et al. Clear cell ovarian cancers with microsatellite instability: a unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology. 2017;6(2):e1277308.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Takeda T, Banno K, Yanokura M, et al. Synchronous endometrial and ovarian cancer in Lynch syndrome with a MSH2 germline mutation: a case report. Mol Clin Oncol. 2018;9(5):479–84.

    PubMed  PubMed Central  Google Scholar 

  65. Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1(9):1319–23.

    Article  PubMed  Google Scholar 

  66. Llosa NJ, Luber B, Tam AJ, et al. Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors. Clin Cancer Res. 2019;25(17):5250–9.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Hussein YR, Soslow RA. Molecular insights into the classification of high-grade endometrial carcinoma. Pathology. 2018;50(2):151–61.

    Article  CAS  PubMed  Google Scholar 

  68. Bilbao C, Lara PC, Ramirez R, et al. Microsatellite instability predicts clinical outcome in radiation-treated endometrioid endometrial cancer. Int J Radiat Oncol Biol Phys. 2010;76(1):9–13.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol. 2000;156(5):1641–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Humphris JL, Patch AM, Nones K, et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017;152(1):68–74.

    Article  CAS  PubMed  Google Scholar 

  71. Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 2001;61(7):3139–44.

    CAS  PubMed  Google Scholar 

  72. Genutis LK, Tomsic J, Bundschuh RA, et al. Microsatellite instability occurs in a subset of follicular thyroid cancers. Thyroid. 2019;29(4):523–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. McCabe MJ, Pinese M, Chan CL, et al. Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases. Cold Spring Harb Mol Case Stud. 2019;5(2):a003764.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017. https://0-doi-org.brum.beds.ac.uk/10.1200/PO.17.00073.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Benson AB 3rd, Venook AP, Cederquist L, et al. Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15(3):370–98.

    Article  CAS  PubMed  Google Scholar 

  76. Ruschoff J, Wallinger S, Dietmaier W, et al. Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci USA. 1998;95(19):11301–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Linnebacher M, Wienck A, Boeck I, et al. Identification of an MSI-H tumor-specific cytotoxic T cell epitope generated by the (-1) frame of U79260(FTO). J Biomed Biotechnol. 2010;2010:841451.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Warusavitarne J, Ramanathan P, Kaufman A, et al. 5-fluorouracil (5FU) treatment does not influence invasion and metastasis in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis. 2006;21(7):625–31.

    Article  PubMed  Google Scholar 

  79. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(20):3219–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Benson AB 3rd, Choti MA, Cohen AM, et al. NCCN practice guidelines for colorectal cancer. Oncology (Williston Park). 2000;14(11A):203–12.

    Google Scholar 

  81. Kwon Y, Park M, Jang M, et al. Prognosis of stage III colorectal carcinomas with FOLFOX adjuvant chemotherapy can be predicted by molecular subtype. Oncotarget. 2017;8(24):39367–81.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Diaz LA, Le DT. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;373(20):1979.

    Article  PubMed  Google Scholar 

  83. Yu Y. Molecular classification and precision therapy of cancer: immune checkpoint inhibitors. Front Med. 2018;12(2):229–35.

    Article  PubMed  Google Scholar 

  84. Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20(6):849–61.

    Article  CAS  PubMed  Google Scholar 

  85. Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. Cancer Discov. 2018;8(3):263.

    Google Scholar 

  86. Tang J, Xu Z, Huang L, et al. Transcriptional regulation in model organisms: recent progress and clinical implications. Open Biol. 2019;9(11):190183.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wilt C, Le DT. Integrating immunotherapy into colorectal cancer care. Oncology (Williston Park). 2018;32(10):494–8.

    Google Scholar 

  89. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9.

    Article  CAS  PubMed  Google Scholar 

  90. Tang Z, Li D, Hou S, et al. The cancer exosomes: clinical implications, applications and challenges. Int J Cancer. 2019. https://0-doi-org.brum.beds.ac.uk/10.1002/ijc.32762.

    Article  PubMed  PubMed Central  Google Scholar 

  91. O’Neil BH, Wallmark JM, Lorente D, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS ONE. 2017;12(12):e0189848.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Innocenti F, Ou F-S, Qu X, et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol. 2019;37(14):1217–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–58.

    Article  CAS  PubMed  Google Scholar 

  94. Choi YY, Kim H, Shin SJ, et al. Microsatellite instability and programmed cell death-ligand 1 Expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC Randomized Controlled Study. Ann Surg. 2019;270(2):309–16.

    Article  PubMed  Google Scholar 

  95. Novohradsky V, Zajac J, Vrana O, et al. Simultaneous delivery of olaparib and carboplatin in PEGylated liposomes imparts this drug combination hypersensitivity and selectivity for breast tumor cells. Oncotarget. 2018;9(47):28456–73.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Sun D, Ma J, Wang J, et al. Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer. Cancer Immunol Immunother. 2019;68(9):1527–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fader AN, Diaz LA, Armstrong DK, et al. Preliminary results of a phase II study: PD-1 blockade in mismatch repair–deficient, recurrent or persistent endometrial cancer. Gynecol Oncol. 2016;141:206–7.

    Article  Google Scholar 

  98. Habra MA, Stephen B, Campbell M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer. 2019;7(1):253.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Campbell BB, Light N, Fabrizio D, et al. Comprehensive analysis of hypermutation in human cancer. Cell. 2017;171(5):1042–1056.e1010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported partly by National Natural Science Foundation of China (81541153); Guangdong Provincial Science and Technology Department (2016A050503046, 2015A050502048 and 2016B030309002); The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources (GDMUK201808); Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang (ZJW-2019-07); Zhanjiang Science and Technology Plan (2017A06012); Guangdong Province Natural Science Foundation (2018A030310155); and “Group-type” Special Supporting Project for Educational Talents in Universities (4SG19057G). The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Author information

Author notes

  1. Kai Li and Haiqing Luo contributed equally to this work

Authors and Affiliations

  1. Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, 524023, China

    Kai Li, Lianfang Huang & Xiao Zhu

  2. The Marine Biomedical Research Institute, Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang, Guangdong Medical University, Zhanjiang, 524023, China

    Kai Li, Lianfang Huang, Hui Luo & Xiao Zhu

  3. Cancer Center, The Affiliated Hospital, Guangdong Medical University, Zhanjiang, 524023, China

    Kai Li & Haiqing Luo

Authors
  1. Kai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haiqing Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lianfang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XZ and HL designed the study. KL and HaL discussed and wrote the manuscript. KL, HaL, LH and XZ revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hui Luo or Xiao Zhu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, K., Luo, H., Huang, L. et al. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 20, 16 (2020). https://0-doi-org.brum.beds.ac.uk/10.1186/s12935-019-1091-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12935-019-1091-8

Keywords

Cancer Cell International

ISSN: 1475-2867

Contact us