Tislelizumab in previously treated,locally advanced unresectable/metastatic microsatellite instability-high/mismatch repair-deficient solid tumors

Objective:The open-label,phase II RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8%)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8%).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7%;95%confidence interval(95%CI),35.1−58.6;one-sided P<0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1%(95%CI,25.1–54.6);gastric/gastroesophageal junction(n=9):55.6%(95%CI,21.2−86.3);others(n=20):60.0%(95%CI,36.1−80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10%;five(6.7%)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade≥3 occurred in 53.8%of patients;7.5%of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status

BACKGROUND Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability(MSI)(MSI-H)metastatic colorectal cancer.However,the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI(MSI-L),and microsatellite stable(MSS)metastatic colorectal cancer remains unclear.AIM To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer,and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months.METHODS We conducted a retrospective cohort study using the National Cancer Database(NCDB)to evaluate the overall survival(OS)of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy.The study population was stratified by MSI status(MSI-H,MSI-L,and MSS).Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS,adjusting for potential confounders.RESULTS A total of 21951 patients with metastatic colorectal cancer were included in the analysis,of which 2358 were MSI-H,and 19593 were MSI-L/MSS.In the MSI-H cohort,immunotherapy treatment(n=142)was associated with a significantly improved median OS compared to chemotherapy(n=860).After adjusting for potential confounders,immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort[adjusted hazard ratio(aHR):0.57,95%confidence interval(95%CI):0.43-0.77,P<0.001].In the MSS cohort,no significant difference in median OS was observed between immunotherapy treatment and chemotherapy(aHR:0.94,95%CI:0.69-1.29,P=0.715).CONCLUSION In this population-based study using the NCDB,immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer,but not in those with MSI-L/MSS metastatic colorectal cancer.Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer.

Simulation of a soft-gamma-ray polarimeter on board a microsatellite

Gamma-ray polarimetry is a new and prospective tool for studying extremely high-energy celestial objects and is of great significance for the field of astrophysics.With the rapid development of microsatellite technology,the advantages of space exploration have become increasingly apparent.Therefore,we simulated a soft-gamma-ray polarimeter for a microsatellite based on the Compton scattering principle.We performed detailed Monte Carlo simulations using monoenergetic gamma-ray linear-polarization sources and Crab-like sources in the energy range of 0.1-10 MeV considering the orbital background.The polarimeter exhibited excellent polarization detection performance.The modulation factor was 0.80±0.01,and the polarization angles were accurate within an error of 0.2°at 200 keV for on-axis incidence.For the Crab-like sources for on-axis incidence,the polarization degrees were consistent with the set values within the error tolerance,the modulation factor was 0.76±0.01,and the minimum detectable polarization reached 2.4%at 3σfor an observation time of10^(6) s.Additionally,the polarimeter exhibited recoil electron tracking,imaging,and powerful background suppression in a large field of view(FoV;∼2πsr).The proposed polarimeter meets the requirements of a space soft-gamma-ray polarization detector and has promising research prospects.

Modular flexible“Tetris”microsatellite platform based on sandwich assembly mode

In this paper,a flexible modular“Tetris”microsatellite platform is studied to implement the rapid integration and assembly of microsatellites.The proposed microsatellite platform is fulfilled based on a sandwich assembly mode which consists of the isomorphic module structure and the standard mechanical-electric-data-thermal interfaces.The advantages of the sandwich assembly mode include flexible reconfiguration and efficient assembly.The prototype of the sandwich assembly mode is built for verifying the performance and the feasibility of the proposed mechanical-electric-data-thermal interfaces.Finally,an assembly case is accomplished to demonstrate the validity and advantages of the proposed“Tetris”microsatellite platform.

Discordant patterns of genetic variation between mitochondrial and microsatellite markers in Acanthogobius ommaturus across the coastal areas of China

Acanthogobius ommaturus, which belongs to the family Gobiidae, is a euryhaline and demersal fish that is widely distributed in the coastal areas, harbors, and estuaries of China, D. P. R. Korea and Japan. In this study, the genetic diversity and genetic structure of five geographical populations of A. ommaturus was assessed using the mitochondrial hypervariable region gene and microsatellite markers. The results of the two genetic markers indicated that the A. ommaturus populations had a high level of genetic diversity. The mitochondrial marker detected weak genetic differentiation among populations, and the Neighbor-Joining tree showed that there was no obvious pedigree branches and geographic structure as well. However, population of Zhoushan showed significant genetic differentiation with other populations by microsatellite markers. The population of A.ommaturus has not experienced bottleneck effect recently. We speculated that the Pleistocene climate change and juvenile fish dispersal played an important role in the population differentiation of A. ommaturus.

Molecular phylogenetics and population demographic history of Amphioctopus fangsiao,inferred from mitochondrial and microsatellite DNA markers

Amphioctopus fangsiao(Cephalopoda:Octopodidae)is an important commercial species in the coastal waters of China.In recent years,however,the resource of A.fangsiao have declined because of habitat destruction and overfishing.To analyze the genetic variations of A.fangsiao caused by the fluctuation of resources,the population genetic structure of nine sampling locations collected from the Bohai Sea to the South China Sea were investigated,using mtDNA COI fragments and microsatellite DNA.The results of F-statistics,AMOVA,STRUCTURE and PCA analyses showed three phylogeographic clades(Clades A,B and C),revealing limited genetic exchange between north and south populations.These clades diverged in 2.23(Clades A and B)and 3.67(Clades A,B and C)million years ago,during the dramatic environmental fluctuations,such as sea level and temperature changes,have exerted great influence on the survival distribution pattern of global organisms.Our results for low genetic connectivity among A.fangsiao populations provide insights into the development of management strategies,that is,to manage this species as separate management unit.

Development and Characterization of Microsatellite Markers for Harpadon nehereus Based on High-Throughput Sequencing and Cross-Species Amplification in Three Myctophiformes Fishes

Harpadon nehereus is a widespread economical fish found in the coastal seas of China and has important ecological value in the marine ecosystem.H_(o)wever,its germplasm resources have been seriously degraded due to natural factors and anthropogenic activities.In this study,high-throughput sequencing was applied to search for microsatellite loci in H.nehereus transcriptome to provide references for its resource conservation and utilization.Polymorphic loci were developed by non-denaturing polyacrylamide gel electrophoresis,and their cross-species amplified ability was detected in three related species.A total of 5652 microsatellites were identified from 16974320 unigenes.Among the primer pairs designed for 100 SSRs for PCR amplification,80%were successfully amplified,and 26 loci were polymorphic with a high number of alleles from 3 to 11 each.The expected(H_(e))and observed(H_(o))heterozygosities were 0.355–0.885 and 0.375–0.958,respectively.Most of the loci were highly polymorphic(polymorphism information content:0.316–0.852;mean:0.713),and these markers can be applied in the population genetic diversity research of H.nehereus.H_(o)wever,the transferability of these primers was low,probably because of the close relation of the collected species.In follow-up work,simple sequence repeats will be excavated with genome-based technologies,and related species will be gathered to address the present inadequacies.

Discrepancy among microsatellite instability detection methodologies in non-colorectal cancer:Report of 3 cases

BACKGROUND Microsatellite instability(MSI)is a predictive biomarker for cancer immunotherapy.The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors.It can be assessed using next-generation sequencing(NGS),fluorescent multiplex PCR,and immunohistochemistry(IHC).CASE SUMMARY Here,we report 3 cases with discordant MSI results detected using different methods.A cholangiocellular carcinoma case revealed proficient mismatch repair(MMR)by IHC but high MSI(MSI-H)by liquid NGS.A cervical cancer case revealed deficient MMR by IHC,microsatellite stable by PCR,and MSI-H by NGS.Lastly,an endometrial cancer case revealed proficient MMR by IHC but MSI-H by NGS.CONCLUSION IHC for MMR status is the first choice due to several advantages.However,in cases of indeterminate IHC results,molecular testing by MSI-PCR is preferred.Recently,NGS-based MSI assays are being widely used to detect MSI-H tumors.All three methods have high accuracy;however,the inconsistencies between them may lead to misdiagnosis.

Application of sintilimab combined with anlotinib hydrochloride in the clinical treatment of microsatellite stable colorectal cancer

BACKGROUND Microsatellite stable(MSS)colorectal cancer(CRC)is a common type of tumor with limited treatment options.Sintilimab and anlotinib hydrochloride are two extensively studied anticancer drugs.AIM To probe the clinical value of combining sintilimab with anlotinib hydrochloride in MSS CRC treatment.METHODS During the period spanning from April 2019 to April 2022,Zhejiang Provincial People’s Hospital accommodated a cohort of 92 patients diagnosed with MSS CRC who were classified into two distinct groups in our study,the observation group and the control group.The control group was administered anlotinib hy-drochloride as their designated therapy,whereas the observation group received the additional treatment of sintilimab in conjunction with the therapy assigned to the control group.The administration of treatment occurred in cycles consisting of a duration of 3 wk,and the evaluation of effectiveness took place subsequent to the completion of two consecutive cycles of treatment within both groups.A comparative analysis between the two groups was conducted to assess the short-term efficacy and ascertain the incidence of adverse events transpiring throughout the duration of the treatment period.Changes in the levels of carcinoembryonic Life Questionnaire-Core 30 were compared between the two groups prior to and subsequent to therapy.Finally,a 1-year follow-up was conducted for both groups of patients,and the survival status was recorded and analyzed.RESULTS The short-term effectiveness displayed by the observation group surpassed that exhibited by the control group,with a statistically significant discrepancy(76.09%vs 50.00%),reaching a significance level denoted as P<0.05.Following the administration of treatment,the observation group manifested a considerable reduction in numerous serum indicators,which were found to be lower than the corresponding pretreatment levels within the same group as well as the post-treatment levels observed in the control group(P<0.05).Post-treatment,the T lymphocyte subset levels within the observation group demonstrated a remarkable amelioration,surpassing the corresponding pre-treatment levels observed within the same group as well as the post-treatment levels observed in the control group(P<0.05).Subsequent to the therapeutic intervention,the observation group showcased a notable amelioration in the scores associated with multiple dimensions of life quality.These scores outperformed the pretreatment scores within the same group as well as the post-treatment scores observed in the control group(P<0.05).The safety levels of drug use in the two group were comparable(19.57%vs 13.04%),and no distinct difference was observed upon comparison(P>0.05).After the completion of treatment,both groups of patients underwent a 1-year follow-up outside the hospital.Throughout this period,1 patient within the observation group and 2 patients within the control group became untraceable and were lost to follow-up.During the follow-up period of the observation group,12 patients died,resulting in a survival rate of 73.33%(33/45),while in the control group,21 patients died,resulting in a survival rate of 52.27%(23/44).The implementation of Kaplan-Meier survival analysis revealed a conspicuous contrast in survival rates exhibited by the two groups(log-rank=4.710,P=0.030).CONCLUSION The combination of sintilimab and anlotinib hydrochloride demonstrated favorable efficacy in the treatment of MSS CRC patients,leading to improvements in patient immunity and prognosis.Additionally,it exerted inhibitory effects on the expression of carcinoembryonic antigen,CA199,and CA125.

Bat 26 Microsatellite Instability in Oral Cavity Cancers in Senegal

Oral cavity cancers are part of head and neck cancers. They have become frequent in the world in general and Senegal in particular. This study evaluates microsatellite instability tumors in oral cavity cancers in Senegal. Forty cancerous tissues, 20 healthy tissues, and 12 blood tissues were included in this study. These tissues were collected from each patient during the biopsy after obtaining consent. DNA extraction, Polymerase Chain Reaction (PCR) and sequencing were carried out to obtain sequences. Mutation surveyor, Bioedit and Dnasp software were used to perform our analyses. High instability was found in 57.5% of patients with cancer. Moreover, 90% of the patients had the same motif on healthy and cancerous tissue. Furthermore, 26.12%, 20.72%, and 11.71% polymorphic sites were found in cancerous, healthy and blood tissue respectively. Thus, a similarity between cancerous and healthy tissues seems to exist. This implies that instability of the Bat 26 microsatellite could occur early in the occurrence of oral cavity cancers.

Isolation and characterization of polymorphic microsatellite loci in large yellow croaker, Larimichthys crocea

An （AC）n-microsatellite-enriched library for Larimichthys crocea was constructed in this study. Primers for fifty simple sequence repeat （SSR） loci were synthesized and genotyped on 30 L. crocea individuals from Guanjingyang wild population （WP） in Fujian Province and 38 individuals from Ningbo cultured population （CP） in Zhejiang Province. Only 21 loci were successfully amplified and polymorphic in two populations. In WP, the observed heterozygosity （Ho） ranged from 0.233 to 0.900 and the expected heterozygosity （HE） ranged from 0.326 to 0.893, with an average of 7.8 alleles/locus, the polymorphism information content （PIC） ranged from 0.283 to 0.866 （mean 0.731）. In CP, the Ho ranged from 0.189 to 0.892 and the HE ranged from 0.333 to 0.800, with an average of 4.4 alleles/locus. The probability test showed significant departures from HWE in 9 and 2 of the 21 loci in WP and in CP, respectively. Deficiency of heterozygotes at four loci showed the presence of null alleles （P 〈0.01）. The PIC of 20 microsatellite loci in WP were greater than 0.50. Overall, these novel markers are potentially useful for the study of population genetics, construction of genetic linkage and quantitative trait loci maps in large yellow croaker.

Telomere erosion is independent of microsatellite instability but related to loss of heterozygosity in gastric cancer

AIM To correlate the length of the telomere to microsatellite instability (MSI) and loss of heterozygosity (LOH) of APC, MCC and DCC genes in gastric carcinomas.METHODS Telomeric restriction fragment (TRF) length of gastric cancer was measured with Southern blot. LOH of APC, MCC and DCC genes, microsatellite instability (MSI) and frameshift mutation of hMSH6, TGF-βR Ⅱ and BAX genes were analyzed by PCR-based methods.RESULTS Sixty-eight cases of sporadic gastric carcinoma were studied for MSI using five microsatellite markers. MSI in at least one locus was detected in 17 (25%) of 68 tumors analyzed. Frameshift mutations of hMSH6, TGF-βR Ⅱ and BAX were detected in 2,6 and 3 of gastric carcinomas respectively showing high MSI (≥ 2 loci, n = 8), but none was found in those showing Iow MSI (only one locus, n = 9) or MSS (tumor lacking MSI or stable, n = 51). Thirty-five cases, including all high MSI and Iow MSl, were studied for TRF. The mean TRF length was not correlated with clinicopathological parameters.No association was observed between TRF length and MSI or frameshift mutation. On the contrary, LOH at the DCC locus was related to telomere shortening (P＜ 0.01). This tendency was also observed in APC and MCC genes,although there was no statistical significance.CONCLUSION The development of gastric cancer can arise through two different genetic pathways. In high MSI gastric cancers, defective mismatch repair allows mutations to accumulate and generate the high MSI phenotype. In gastric cancers showing either Iow MSI or MSS, multiple deletions may represent the LOH pathway.Telomere erosion is independent of high MSI phenotype but related to the LOH pathway in gastric cancer.

Characterization of six tumorsuppressor genes and microsatellite instability in hepatocellular carcinomain southern African blacks

AIM To analyse cumulative loss of heterozygosity (LOH) of chromosomal regions and tumor suppressor genes in hepatocellular carcinomas (HCCs) from 20 southern African blacks. METHODS p53, RB1, BRCA1, BRCA2, WT1 and E cadherin genes were analysed for LOH, and p53 gene was also analysed for the codon 249 mutation, in tumor and adjacent non tumorous liver tissues using molecular techniques and 10 polymorphic microsatellite markers. RESULTS p53 codon 249 mutation was found in 25% of the subjects, as was expected, because many patients were from Mozambique, a country with high aflatoxin B 1 exposure. LOH was found at the RB1, BRCA2 and WT1 loci in 20%(4/*!20) of the HCCs, supporting a possible role of these genes in HCC. No LOH was evident in any of the remaining genes. Reports of mutations of p53 and RB1 genes in combination, described in other populations, were not confirmed in this study. Change in microsatellite repeat number was noted at 9/*!10 microsatellite loci in different HCCs, and changes at two or more loci were detected in 15%(3/*!20) of subjects. CONCLUSION We propose that microsatellite/genomic instability may play a role in the pathogenesis of a subset of HCCs in black Africans.

Microsatellite instability,MMR gene expression and proliferation kinetics in colorectal cancer with famillial predisposition

INTRODUCTIONGenetic instability is a conunon property of manyhuman cancers,including those of HNPCC.A novel form of genetic instability involving somaticalterations,such as deletions and insertions insimple repeated sequences,has been found.Microsatellitcs are relatively short runs of tandemlyrepeated sequences scattered throughout

Era of universal testing of microsatellite instability in colorectal cancer

Colorectal cancer (CRC) incidence and mortality are constantly decreasing, but CRC still remains the third most prevalent cancer and the third most common cause of cancer death in both males and females in the United States. Recent rapid declines in CRC incidence rates have largely been attributed to increases in screening that can detect and remove precancerous polyps, and the decrease in death rates for CRC largely reflects improvements in early detection, treatment and the understanding of molecular/genetic basis of CRC. One of the important molecular/genetic findings is the presence of microsatellite instability (MSI) in CRCs. Many studies have shown the importance of MSI testing in diagnosing Lynch syndrome and predicting prognosis and response to chemotherapeutic agents in CRCs. Increased emphasis has been placed on the importance of MSI testing for all newly diagnosed individuals with CRCs. Both immunohistochemical staining (IHC) and polymerase chain reaction (PCR)-based MSI testing show high sensitivity and specificity in detecting MSI. The current clinical guidelines and histopathology features are indicative of, but not reliable in diagnosing Lynch syndrome and CRCs with MSI. Currently, there are evidences that universal testing for MSI starting with either IHC or PCR-based MSI testing is cost effective, sensitive, specific and is getting widely accepted.

Potential roles of tumor suppressor genes and microsatellite instability in hepatocellular carcinogenesis in southern African blacks

MAJOR POINTS OF THE COMMENTED ARTICLECumulative loss of heterozygosity(LOH)ofchromosomal regions and tumor suppressor geneshas been reported in hepatocellular carcinomas(HCCs) from China,Japan,and Korea.In thisissue of the World Journal of Gastroenterology,Martins et al report an analysis of LOH andmicrosatellite instability in HCCs from a group of

Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer

Colorectal cancers(CRCs)with a high level of microsatellite instability(MSI-H)are clinicopathologically distinct tumors characterized by predominance in females,proximal colonic localization,poor differentiation,mucinous histology,tumor-infiltrating lymphocytes,a Crohn’s-like lymphoid reaction and a favorable prognosis.In terms of their molecular features,MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations,including DNA mismatch repair deficiency,target microsatellite mutations,BRAF mutations,a CpG island methylator phenotype-high(CIMP-H)status,and a low level of genomic hypomethylation.The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences;for example,in Eastern Asian countries,relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries.Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy,there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs.Here,we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs,as well as several putative prognostic or predictive molecular markers,including HSP110 expression,beta2-microglobulin mutations,myosin 1a expression,CDX2/CK20 expression,SMAD4expression,CIMP status and LINE-1 methylation levels.

Advances in immuno-oncology biomarkers for gastroesophageal cancer:programmed death ligand 1,microsatellite instability,and beyond

Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.

Causes and consequences of microsatellite instability in gastric carcinogenesis

Loss of DNA mismatch repair(MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability(MSI). In gastric cancer(g C), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in g C as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for g C and their applicability in the MSI subset are also discussed.