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Microsatellite instability

Microsatellite instability (MSI) is a hypermutable phenotype of the genome characterized by frequent insertions, deletions, and other mutations in repetitive DNA sequences known as microsatellites, which are short tandem repeats of 1–6 nucleotide units scattered throughout the genome.^[1] This instability arises primarily from deficiencies in the DNA mismatch repair (MMR) system, a cellular mechanism that corrects errors occurring during DNA replication, such as base-base mismatches or small insertion-deletion loops in repetitive regions.^[2] As a result, MSI leads to a significantly elevated mutation rate, particularly in tumors, and serves as a key biomarker in oncology for identifying cancers with defective MMR (dMMR).^[3] The MMR system functions through a series of protein complexes, including MutSα (formed by MSH2 and MSH6) and MutLα (formed by MLH1 and PMS2), which recognize replication errors, recruit exonucleases to excise faulty DNA segments, and facilitate accurate resynthesis using the intact strand as a template.^[2] Defects causing MSI can be germline mutations in MMR genes, accounting for hereditary cases like Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), or somatic alterations, including biallelic mutations or epigenetic silencing via promoter hypermethylation (most commonly of MLH1 in sporadic tumors).^[2] In Lynch syndrome, pathogenic variants in MLH1, MSH2, MSH6, or PMS2 genes increase lifetime cancer risk, particularly for colorectal and endometrial cancers, while sporadic MSI often associates with the CpG island methylator phenotype (CIMP) and BRAF mutations in older patients.^[2]^[3] MSI occurs in a subset of solid tumors across various types, with an overall prevalence of approximately 3.8% in large pan-cancer cohorts, though rates vary widely: up to 31.4% in endometrial carcinomas, 19.7% in colon adenocarcinomas, and notable frequencies in gastric, ovarian, and urothelial cancers.^[1] In colorectal cancer (CRC), MSI-high (MSI-H) tumors represent about 12–15% of cases and are divided into Lynch-associated (roughly 3%) and sporadic (roughly 12%) subtypes.^[3]^[2] These tumors typically display mucinous histology, poor differentiation, and prominent tumor-infiltrating lymphocytes, contributing to a favorable prognosis compared to microsatellite-stable (MSS) counterparts, with 5-year survival rates of approximately 80-90% in Lynch syndrome-associated CRC.^[4] Clinically, MSI status is crucial for diagnosis, prognosis, and treatment decisions, as MSI-H/dMMR tumors exhibit high tumor mutational burden (TMB) and neoantigen load, rendering them highly responsive to immune checkpoint inhibitors (ICIs) like pembrolizumab and nivolumab.^[3] Testing methods include polymerase chain reaction (PCR) for microsatellite markers (e.g., Bethesda panel), immunohistochemistry (IHC) for MMR protein expression, and next-generation sequencing (NGS) platforms like FoundationOne CDx, with liquid biopsies emerging for non-invasive detection showing over 98% concordance with tissue-based assays.^[3]^[2] The U.S. Food and Drug Administration (FDA) has approved pembrolizumab for unresectable or metastatic MSI-H/dMMR solid tumors, based on trials like KEYNOTE-177 demonstrating improved progression-free survival in MSI-H metastatic CRC with fewer adverse events than chemotherapy, as well as nivolumab plus ipilimumab as first-line therapy for MSI-H/dMMR unresectable or metastatic colorectal cancer (as of April 2025).^[3]^[5] Ongoing research explores synthetic lethality targets, such as WRN helicase inhibition, specifically for MSI-H cancers.^[3]

Fundamentals

Microsatellites

Microsatellites, also known as short tandem repeats (STRs), are tandemly repeated DNA sequences consisting of motifs 1–6 base pairs in length, typically repeated 10–60 times.^[6] These repetitive elements are ubiquitous across eukaryotic genomes, including the human genome, where they arise from the duplication of short nucleotide sequences during evolution.^[7] Common motifs include dinucleotide repeats such as (CA)_n and mononucleotide repeats like (A)_n, which are among the most prevalent in humans.^[8] In the human genome, microsatellites account for approximately 3% of the total sequence length and are predominantly enriched in non-coding regions, such as introns and intergenic spaces, though they are also found in coding exons and promoter regions.^[7] This distribution reflects their evolutionary persistence despite high mutation rates, with estimates suggesting over 1 million such loci genome-wide.^[9] Their presence in functional genomic elements underscores their biological relevance beyond mere repetitive filler. Under normal conditions, microsatellites contribute to several key functions, including the regulation of gene expression through modulation of transcription factor binding and promoter spacing.^[10] They also influence chromatin structure by affecting nucleosome positioning and DNA bending, which can impact higher-order genome organization.^[11] Furthermore, the inherent variability of microsatellite lengths provides evolutionary adaptability, allowing populations to fine-tune gene activity in response to environmental pressures via repeat number expansions or contractions.^[12] This variability stems from a propensity for instability during DNA replication, primarily due to polymerase slippage, which generates insertions or deletions; the mismatch repair system serves as a primary safeguard against such errors in repetitive sequences.^[6]

Mismatch Repair System

The DNA mismatch repair (MMR) system functions as a post-replicative proofreading mechanism that identifies and corrects base-base mismatches and small insertion-deletion loops (IDLs) arising from DNA polymerase errors during replication, thereby maintaining genomic stability.^[13] This pathway enhances the overall fidelity of DNA replication by correcting the majority of residual errors that escape the intrinsic proofreading activity of DNA polymerases, reducing the mutation rate by 100- to 1000-fold.^[13] Without MMR, sequences like microsatellites become particularly vulnerable to unrepaired IDLs, leading to instability.^[14] Key components of the eukaryotic MMR system include the MutS and MutL homologs, which form heterodimers to execute repair. The MutSα heterodimer, composed of MSH2 and MSH6, primarily recognizes base-base mismatches and small IDLs of 1-2 nucleotides, while MutSβ (MSH2-MSH3) targets larger IDLs up to 15 nucleotides.^[13] The MutLα complex, formed by MLH1 and PMS2, acts as an endonuclease to coordinate downstream repair events, with MLH1 serving as the obligatory partner for other MutL homologs like PMS1, MLH3, and PMS2.^[14] Additional proteins such as MSH3, MSH5, and MLH3 contribute to specialized functions, including the repair of specific mismatch types and roles in meiosis.^[13] The MMR process proceeds in a coordinated, strand-specific manner. First, MutSα or MutSβ binds to the mismatch or IDL, undergoing a conformational change upon ATP binding to recruit MutLα, forming a ternary sliding clamp complex that translocates along the DNA.^[13] Strand discrimination occurs via pre-existing nicks or ends in the nascent strand, often directed by PCNA and RFC at replication foci, or through hemimethylation in prokaryotes (though eukaryotes primarily use nicks).^[14] MutLα then introduces a nick 5' to the mismatch via its latent endonuclease activity, followed by recruitment of EXO1 exonuclease for excision of the error-containing strand segment, which can span hundreds of nucleotides.^[13] Finally, DNA polymerase δ, aided by RPA and RFC, resynthesizes the excised region using the parental strand as template, and DNA ligase I seals the nick to complete repair.^[14] The MMR pathway exhibits remarkable evolutionary conservation across prokaryotes and eukaryotes, with core components like MutS and MutL homologs present from bacteria to humans, underscoring its essential role in preventing mutagenesis.^[15] Defects in MMR genes are prevalent in various cancers, occurring in approximately 5-15% of colorectal cancers and higher rates in endometrial (up to 30%) and gastric tumors, often due to inherited or somatic alterations.^[14]

Mechanisms

Deficient Mismatch Repair

Deficient mismatch repair (dMMR) refers to the impaired function of the DNA mismatch repair (MMR) system, which fails to correct base-base mismatches and small insertion/deletion loops (IDLs) that arise during DNA replication, resulting in a hypermutator phenotype characterized by an elevated overall mutation rate.^[16]^[17] This deficiency primarily affects the core MMR proteins, such as MLH1, MSH2, MSH6, and PMS2, leading to the accumulation of unrepaired errors across the genome.^[18] The direct consequence of dMMR is microsatellite instability (MSI), where uncorrected IDLs in repetitive microsatellite sequences cause contractions or expansions in their lengths, manifesting as altered repeat unit numbers.^[16]^[17] These slippage events during replication are particularly prone to occur in microsatellites due to their repetitive nature, and without MMR intervention, they persist as permanent mutations, driving genomic instability.^[18] A hallmark mutational signature of dMMR is the increased frequency of frameshift mutations within coding microsatellites, which disrupt the reading frame of genes and often result in premature stop codons, producing truncated or nonfunctional proteins.^[16]^[17] These frameshift events contribute to a high tumor mutational burden, with dMMR tumors exhibiting substantially more somatic mutations—on average over 1,700 compared to fewer than 100 in proficient MMR tumors.^[18] Such frameshift mutations generate novel frameshift peptides that serve as neoantigens, highly immunogenic due to their uniqueness to the tumor, thereby enhancing the tumor's visibility to the immune system and promoting anti-tumor immune responses.^[16]^[17] This immunogenicity arises from the presentation of these aberrant peptides on major histocompatibility complex molecules, distinguishing dMMR tumors from those with proficient repair.^[18] Unlike chromosomal instability (CIN), which involves large-scale structural alterations such as aneuploidy and chromosomal rearrangements, dMMR-mediated MSI specifically targets small-scale mutations in repetitive sequences, representing a distinct pathway of genomic instability.^[16]^[17]

Somatic and Germline Causes

Microsatellite instability (MSI) arises from deficient mismatch repair (dMMR), which can result from either germline or somatic alterations. Germline causes are primarily associated with Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal dominant condition caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, or by deletions in the adjacent EPCAM gene that lead to epigenetic silencing of MSH2.^[19]^[20] These inherited mutations impair the DNA mismatch repair system's ability to correct replication errors, predisposing carriers to early-onset cancers, particularly colorectal and endometrial.^[19] In contrast, somatic causes predominate in sporadic cases and often involve biallelic hypermethylation of the MLH1 promoter, which silences MLH1 expression and accounts for the majority of dMMR in non-hereditary colorectal cancers.^[21] This epigenetic modification is frequently accompanied by the BRAF V600E mutation, which is detected in up to 68% of colorectal tumors with MLH1 promoter hypermethylation and serves as a marker to distinguish sporadic dMMR from Lynch syndrome-associated cases, as BRAF mutations are rare in the latter.^[22]^[23] Approximately 15% of colorectal cancers exhibit high MSI (MSI-H), with about 3% attributable to germline mutations in Lynch syndrome and the remaining 12% linked to sporadic somatic events such as MLH1 hypermethylation.^[24] Beyond these, POLE mutations in the exonuclease domain represent an alternative mechanism causing an ultramutator phenotype with MSI-like features, independent of dMMR, and are observed in a subset of endometrial and colorectal tumors.^[25] Environmental factors, including dietary influences or lifestyle elements, may contribute to MLH1 promoter methylation by altering epigenetic patterns, though their precise role remains under investigation.^[26]^[27] Tumor testing for MSI or immunohistochemistry for mismatch repair proteins is a critical initial step in identifying potential Lynch syndrome cases among MSI-H tumors, enabling subsequent germline genetic testing to confirm inherited etiology and guide family screening.^[28] This approach helps differentiate germline from somatic causes, as approximately 90% of Lynch-associated colorectal tumors show MSI-H, facilitating targeted surveillance and risk assessment.^[29]

Detection and Classification

Testing Methods

Microsatellite instability (MSI) testing primarily relies on polymerase chain reaction (PCR)-based assays that amplify specific microsatellite loci in tumor DNA compared to matched normal tissue. The standard approach uses the Bethesda panel, which includes five mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, and MONO-27. These markers are selected for their near-monomorphic nature in the general population, minimizing the need for normal tissue controls. Instability is determined by observing shifts in allele lengths via capillary electrophoresis; a tumor is considered unstable at a locus if there is a change of two or more base pairs.^[30]^[31]^[32] A tumor is classified as MSI-high (MSI-H) if two or more of these markers show instability, while fewer than two indicates microsatellite stable (MSS) status. This method is highly sensitive and specific, with commercial kits like Promega's MSI Analysis System facilitating standardized implementation on formalin-fixed paraffin-embedded (FFPE) tissue. PCR-based testing remains the gold standard for MSI detection due to its reproducibility and direct assessment of microsatellite alterations.^[33]^[31]^[34] Immunohistochemistry (IHC) serves as a complementary or alternative method by evaluating the expression of mismatch repair (MMR) proteins in tumor cells. It involves staining FFPE sections with antibodies against the four key MMR proteins: MLH1, MSH2, MSH6, and PMS2. Loss of nuclear staining in tumor tissue compared to intact staining in adjacent normal tissue indicates deficient MMR (dMMR), which correlates strongly (>98%) with MSI-H status. IHC is particularly useful for identifying which specific protein is deficient, guiding further genetic testing, and is less technically demanding than PCR, allowing rapid turnaround in pathology labs.^[35]^[36]^[37] Next-generation sequencing (NGS) has emerged as a versatile platform for MSI detection, often integrated into broader genomic profiling. Targeted NGS panels interrogate hundreds to thousands of microsatellite loci across the genome, using algorithms like MSIsensor to score instability based on read count ratios and allelic imbalances between tumor and normal samples. Whole-exome sequencing can also detect MSI by analyzing microsatellite-rich regions. NGS offers high concordance (>95%) with PCR-based methods and provides additional tumor mutation burden data, though it requires higher DNA input and computational resources. Tools like MSIsensor are validated for both whole-exome and targeted panels, enabling pan-cancer MSI assessment.^[38]^[39]^[40] Emerging non-invasive methods include liquid biopsy using circulating tumor DNA (ctDNA) from plasma. This approach employs NGS or droplet digital PCR to detect MSI in cell-free DNA, with algorithms adapted from tissue-based tools like MSIsensor-ct achieving up to 100% concordance with tissue testing at low ctDNA fractions (≥0.05%). It enables serial monitoring without tissue sampling, though challenges like low tumor shedding in early-stage disease limit sensitivity. AI-assisted histopathology analyzes hematoxylin and eosin (H&E)-stained slides using deep learning models, such as MSIntuit, to predict MSI status with 98% sensitivity and 99% negative predictive value in colorectal cancer cohorts. These models, trained on large image datasets, can pre-screen cases to reduce confirmatory testing needs.^[41]^[42]^[43] Standardization of MSI testing is guided by the National Comprehensive Cancer Network (NCCN) guidelines, which recommend universal screening for all newly diagnosed colorectal and endometrial cancers using either IHC or PCR-based methods to identify dMMR/MSI-H tumors. This approach ensures equitable access to Lynch syndrome evaluation and immunotherapy eligibility assessment across patient populations.^[44]^[45]

MSI Status Categories

Microsatellite instability (MSI) status is categorized based on the extent of instability observed in a panel of microsatellite markers, typically the five-marker Bethesda panel, which distinguishes between microsatellite instability-high (MSI-H), microsatellite instability-low (MSI-L), and microsatellite stable (MSS) phenotypes. These categories reflect underlying defects in the DNA mismatch repair (MMR) system and guide clinical classification of tumors.^[33] MSI-H is defined as instability in 40% or more of the markers in the panel, corresponding to at least two unstable markers out of five, and is strongly associated with deficient MMR (dMMR). This status indicates a hypermutated genome with elevated tumor mutation burden (TMB), often exceeding 10 mutations per megabase, due to unchecked replication errors.^[33]^[46] In contrast, MSS denotes no detectable instability across the panel markers and correlates with proficient MMR (pMMR), reflecting intact DNA repair mechanisms and typically low TMB.^[33]^[47] MSI-L is characterized by instability in fewer than 40% of markers, usually a single unstable marker, and is considered rare with uncertain clinical significance, as its prognostic and therapeutic implications remain debated.^[33]^[48] At the molecular level, MSI-H tumors demonstrate hypermutation, resulting in a substantially increased TMB that enhances neoantigen presentation. In sporadic MSI-H cases, this phenotype frequently co-occurs with the CpG island methylator phenotype-high (CIMP-high), involving widespread promoter hypermethylation, particularly of the MLH1 gene, which silences MMR function.^[46]^[49] The prevalence of MSI-H varies by cancer type, occurring in approximately 15% of colorectal cancers, 20-30% of endometrial cancers, and varying from approximately 10% in gastric cancers to less than 5% in prostate cancers.^[50]^[51]^[52]^[53]

Clinical Relevance

Role in Cancer

Microsatellite instability-high (MSI-H) status promotes tumorigenesis by accelerating the accumulation of mutations, particularly through frameshift alterations in coding microsatellites of key genes involved in cell growth regulation. These mutations frequently inactivate tumor suppressor genes such as BAX, which encodes a pro-apoptotic protein, and TGFBR2, which mediates transforming growth factor-β signaling to inhibit proliferation, leading to uncontrolled cell growth and survival advantages in affected cells.^[54]^[55] Such frameshifts are hallmarks of deficient mismatch repair (dMMR) and contribute to a hypermutated phenotype that drives oncogenesis across MSI-H tumors.^[56] MSI-H is most prevalent in colorectal cancer, affecting approximately 15% of cases, endometrial cancer at around 25%, and gastric cancer in 10-20% of instances, with lower but notable frequencies in ovarian, urothelial, and sebaceous tumors.^[57]^[58] In colorectal cancer, MSI-H tumors often arise through distinct pathways: sporadic cases, comprising the majority (about 85% of MSI-H colorectal cancers), result from somatic hypermethylation of the MLH1 promoter, which is associated with the serrated neoplasia pathway characterized by BRAF mutations and CpG island methylator phenotype (CIMP-high).^[59] In contrast, hereditary MSI-H colorectal cancers are linked to germline mutations in mismatch repair genes, as seen in Lynch syndrome, accounting for the remaining 15% of cases.^[23] MSI-H tumors exhibit distinctive histopathological features, including mucinous histology, prominent tumor-infiltrating lymphocytes, and Crohn's-like lymphocytic reactions at the invasive front, alongside poor differentiation and a predilection for right-sided location in colorectal cases.^[60]^[61] These characteristics reflect the underlying genomic instability and immune recognition triggered by the high mutational burden. Beyond colorectal and endometrial cancers, MSI-H occurs in subsets of non-colorectal malignancies, such as gliomas where detection is challenging due to low prevalence, and breast cancers, particularly those with medullary features that show dMMR and elevated neoantigen loads.^[62]^[63]

Prognostic Implications

Microsatellite instability-high (MSI-H) status is associated with a favorable prognosis in early-stage colorectal cancer, particularly in stages II and III, where patients exhibit significantly better overall survival compared to those with microsatellite stable (MSS) tumors. Studies have reported 5-year relapse-free survival rates of approximately 67% for MSI-H versus 55% for MSS in stage II disease, representing an absolute improvement of around 12 percentage points, with hazard ratios indicating a 30-40% reduced risk of death independent of other prognostic factors.^[64] This survival advantage is attributed to the high immunogenicity of MSI-H tumors, driven by elevated mutational burden and dense lymphocytic infiltration, which enhances anti-tumor immune responses in localized disease. The prognostic benefit of MSI-H is stage-dependent, providing a clear advantage in non-metastatic settings due to these immunogenic features, but showing neutral or potentially worse outcomes in metastatic colorectal cancer, where the rarity of MSI-H (about 4% of cases) and altered tumor microenvironment diminish the protective effect. As a predictive biomarker, MSI-H indicates poor response to 5-fluorouracil-based adjuvant chemotherapy in stages II and III, with no survival benefit observed in treated patients (hazard ratio for death: 1.07), contrasting with the marked improvement seen in MSS tumors.^[65] Conversely, MSI-H predicts high sensitivity to immunotherapy, as demonstrated in the KEYNOTE-177 trial, where first-line pembrolizumab yielded significantly longer progression-free survival than chemotherapy in MSI-H metastatic colorectal cancer (median 16.5 months versus 8.2 months).^[66] In the context of Lynch syndrome, the hereditary form of MSI-H colorectal cancer, patients experience earlier onset (typically before age 50) and a higher risk of multiple primary tumors, yet they demonstrate superior overall survival rates, with 5-year survival exceeding 90% for colorectal cancers compared to sporadic cases.^[4] This improved prognosis in Lynch syndrome mirrors that of sporadic MSI-H tumors and underscores the role of mismatch repair deficiency in conferring resilience across both etiologies.

Therapeutic Applications

Immunotherapy

Microsatellite instability-high (MSI-H) tumors exhibit a high tumor mutational burden (TMB), often exceeding 10 mutations per megabase, which results from deficient mismatch repair and leads to frameshift mutations that generate immunogenic neoantigens.^[67] These neoantigens are presented on the tumor cell surface, eliciting a robust CD8+ T-cell response that enhances the efficacy of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis.^[68] The correlation between high TMB in MSI-H tumors and improved outcomes with ICIs underscores their role as a predictive biomarker for immunotherapy responsiveness.^[67] Pembrolizumab, a PD-1 inhibitor, received accelerated FDA approval in May 2017 for adult and pediatric patients with unresectable or metastatic MSI-H solid tumors that have progressed following prior treatment, marking the first tissue-agnostic approval based on MSI status.^[69] In the phase 3 KEYNOTE-177 trial, pembrolizumab demonstrated superior progression-free survival compared to chemotherapy as first-line therapy for MSI-H/dMMR metastatic colorectal cancer, with a median progression-free survival of 16.5 months versus 8.2 months, leading to its approval for this indication in June 2020; the 5-year follow-up analysis confirmed an overall survival benefit, with a median OS of 77.5 months and 5-year OS rate of 54.8% for pembrolizumab compared to chemotherapy.^[66]^[70] Nivolumab, another PD-1 inhibitor, was approved by the FDA in July 2017 for MSI-H/dMMR metastatic colorectal cancer based on the phase 2 CheckMate-142 trial, which showed an objective response rate of 31% and durable responses in heavily pretreated patients. The combination of nivolumab and ipilimumab (a CTLA-4 inhibitor) further improved outcomes in the same trial, achieving an objective response rate of 55% and a 3-year overall survival rate of 69% in MSI-H/dMMR metastatic colorectal cancer. In April 2025, the FDA approved the combination of nivolumab and ipilimumab as first-line therapy for unresectable or metastatic MSI-H/dMMR colorectal cancer in adult and pediatric patients aged 12 years and older.^[71] Across advanced MSI-H cancers, ICIs yield objective response rates of 40-50%, with many responses being durable and lasting beyond 2 years, in contrast to rates below 10% observed in microsatellite stable (MSS) tumors.^[72] This differential efficacy highlights the immunogenic nature of MSI-H tumors, where ICIs effectively unleash T-cell-mediated tumor clearance.^[73] The therapeutic benefits of ICIs extend pan-cancer beyond colorectal origins, demonstrating notable efficacy in endometrial and gastric cancers with MSI-H status; for instance, pembrolizumab monotherapy achieved response rates of approximately 48% in advanced MSI-H endometrial cancer.^[74] In MSI-H gastric cancer, nivolumab has shown promising activity, with response rates around 44% in pretreated patients.^[75] Additionally, activation of the cGAS-STING pathway in MSI-H tumors, triggered by cytosolic DNA from replication errors, amplifies type I interferon signaling and enhances ICI-induced antitumor immunity by promoting dendritic cell maturation and T-cell priming.^[76]

Synthetic Lethality Targets

Synthetic lethality refers to the phenomenon where the simultaneous disruption of two non-lethal pathways leads to cell death, offering a strategy to selectively target microsatellite instability-high (MSI-H) cancer cells that rely on alternative DNA repair mechanisms due to deficient mismatch repair (dMMR). In MSI-H tumors, the accumulation of insertion/deletion loops (IDLs) during DNA replication generates replication stress, making these cells dependent on specific helicases and repair factors for survival, while microsatellite stable (MSS) cells with proficient MMR are less affected.^[77] The Werner syndrome RecQ helicase (WRN) has emerged as a key synthetic lethal target in MSI-H cancers, where it is essential for resolving replication stress caused by IDLs at microsatellite repeats. WRN inhibition selectively induces DNA damage and apoptosis in dMMR cells by preventing the unwinding of these structures, sparing proficient MMR cells that do not accumulate such errors. A notable example is the small-molecule inhibitor HRO761, which potently blocks WRN helicase activity and demonstrates selective cytotoxicity in MSI-H models.^[77]^[77] Preclinical studies have shown that WRN depletion or inhibition significantly impairs MSI-H tumor growth; for instance, CRISPR-mediated WRN knockout reduced the viability of MSI-H colorectal and endometrial cancer cell lines by over 90%, while having minimal impact on MSS counterparts, and markedly suppressed xenograft tumor formation in vivo.^[78] Clinically, WRN inhibitors like HRO761 are advancing in trials for MSI-H solid tumors. In an interim analysis of the phase I/Ib study (NCT05838768, initiated in 2023) presented at ESMO 2025, HRO761 monotherapy in the dose-escalation phase showed an overall response rate of 8.6% (10.5% in colorectal cancer), disease control rate of 68.6%, and median progression-free survival of 5.6 months in 35 patients with advanced dMMR/MSI-H cancers, with a favorable safety profile (59.6% any-grade treatment-related adverse events, no grade 4/5 events).^[79]^[80] The study continues to evaluate safety, tolerability, and preliminary efficacy as monotherapy or in combination with agents like irinotecan in patients with advanced dMMR/MSI-H cancers. Additionally, NTRK fusion kinases are enriched in MLH1 promoter-hypermethylated colorectal cancers lacking BRAF or RAS mutations, representing actionable targets in this MSI-H subset, with responses observed to inhibitors such as larotrectinib in early reports.^[77]^[81] Beyond WRN, other synthetic lethal vulnerabilities in MSI-H tumors include PARP inhibitors, which exploit BRCA-like homologous recombination deficiencies in some dMMR contexts, leading to replication fork collapse and cell death. Similarly, inhibitors of ATR or CHK1 kinases target replication fork protection in MSI-H cells burdened by chronic DNA damage, inducing selective lethality through unchecked fork stalling and collapse.^[82]^[83]^[84]

Recent Advances

Key Discoveries Since 2010

During the period from 2010 to 2015, microsatellite instability-high (MSI-H) status emerged as a pan-cancer biomarker, highlighting its role across multiple tumor types beyond colorectal and endometrial cancers, with prevalence noted in up to 15% of gastric, 20-30% of endometrial, and smaller subsets of other solid tumors.^[85] The Cancer Genome Atlas (TCGA) analyses, particularly the 2012 comprehensive molecular characterization of colon and rectal cancer, revealed that MSI-H tumors exhibit significantly elevated tumor mutation burden (TMB), often exceeding 100 mutations per megabase, linking this phenotype to hypermutated genomes driven by mismatch repair deficiency. In 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab for the treatment of unresectable or metastatic MSI-H solid tumors, marking the first tissue-agnostic cancer therapy based on a biomarker rather than tumor histology.^[69] This approval was supported by pooled data from five clinical trials demonstrating an objective response rate of 40% in MSI-H tumors, underscoring the predictive value of MSI-H for immune checkpoint inhibitor efficacy across diverse cancer types.^[86] By 2020, the phase 3 KEYNOTE-177 trial established pembrolizumab as a first-line therapy for MSI-H metastatic colorectal cancer, showing a median progression-free survival of 16.5 months compared to 8.2 months with chemotherapy, with sustained benefits in overall survival trends observed in long-term follow-up.^[66] Concurrently, research identified synthetic lethality between Werner syndrome helicase (WRN) and MSI-H tumors, as WRN dependency in mismatch repair-deficient cells leads to replication stress and cell death upon inhibition, with preclinical models confirming selective killing of MSI-H cancer cells. From 2021 to 2023, frameshift peptide vaccines targeting neoantigens from MSI-induced frameshift mutations entered clinical trials, such as the phase I/IIa study (NCT01461148) vaccinating advanced MSI-H colorectal cancer patients with peptides like AIM2(-1), which induced robust T-cell responses in all participants (100%) and was well-tolerated, paving the way for preventive applications in Lynch syndrome carriers.^[87]^[88] Additionally, MSI-H was increasingly recognized in rare cancers, including prostate cancer, where it occurs in 2-5% of cases and correlates with high TMB and improved responses to immunotherapy, as evidenced by case series showing partial responses in advanced disease.^[89]^[90] In 2024, next-generation sequencing studies revealed fusion kinase drivers, such as NTRK and RET fusions, in up to 12-19% of sporadic MSI-H colorectal cancers with MLH1 promoter hypermethylation, offering potential targets for tyrosine kinase inhibitors in these hypermutated subsets.^[3] The Lynch syndrome spectrum was further expanded to include emerging germline variants in accessory mismatch repair genes like MSH3, with functional assays confirming their contribution to MSI phenotypes in non-classic cases, broadening screening recommendations.^[91] In 2025, long-term follow-up data from the KEYNOTE-177 trial confirmed a 5-year overall survival rate of 54.8% with pembrolizumab in MSI-H metastatic colorectal cancer, while the 10-year analysis of KEYNOTE-016 demonstrated durable remissions in deficient mismatch repair (dMMR)/MSI-H solid tumors. Additionally, results from a phase 2 trial of nivolumab plus ipilimumab in advanced dMMR/MSI-H non-colorectal cancers showed significant antitumor activity, with an objective response rate of approximately 50%, supporting its role as a treatment option beyond anti-PD-1 monotherapy.^[92]^[93]^[94]

Diagnostic Innovations

Since 2015, next-generation sequencing (NGS) has revolutionized microsatellite instability (MSI) detection through algorithms like MSIsensor and mSINGS, enabling precise scoring from tumor-normal paired sequencing data without relying solely on traditional PCR panels. MSIsensor, introduced in 2014 and refined in subsequent applications, analyzes read-count distributions at thousands of microsatellite loci to quantify instability, achieving high sensitivity (up to 95%) and specificity (98%) in colorectal cancer cohorts by comparing allele frequencies between tumor and normal samples. Complementing this, mSINGS (2016) offers a tumor-only approach, leveraging genomic scarring patterns from short NGS reads to classify MSI status with comparable accuracy (AUC >0.90), reducing the need for matched normals and facilitating integration into routine clinical workflows for pan-cancer screening. These tools have expanded MSI assessment to whole-exome and targeted panels, improving throughput and reducing costs by over 50% compared to orthogonal methods in large-scale studies. Liquid biopsies using circulating tumor DNA (ctDNA) have emerged as a non-invasive innovation for MSI detection, particularly for monitoring treatment response and early relapse in advanced cancers. The Guardant360 CDx assay, approved in 2022 by Japan's Ministry of Health, Labour and Welfare as a companion diagnostic for MSI-high (MSI-H) solid tumors, employs hybrid-capture NGS to detect MSI signatures in ctDNA with 87% sensitivity and 99% specificity across multiple cancer types, enabling dynamic assessment without tissue biopsies. This approach supports real-time therapeutic decisions, such as eligibility for immunotherapy, and has shown promise in detecting MSI in low-shedding tumors like pancreatic cancer, where tissue-based testing is challenging. Artificial intelligence (AI) and digital pathology have advanced MSI prediction from routine hematoxylin and eosin (H&E)-stained slides, bypassing molecular testing in resource-limited settings. Machine learning models, such as convolutional neural networks trained on whole-slide images, predict MSI-H status in colorectal cancer with high accuracy; for instance, a 2023 self-attention-enabled model achieved an AUC of 0.93 by identifying tumor microenvironment features like immune infiltration patterns associated with MSI. These AI tools demonstrate generalizability across datasets, with external validation yielding AUCs up to 0.95 in independent cohorts, potentially accelerating universal screening by integrating with existing pathology pipelines and reducing diagnostic turnaround to hours. Multiplex immunohistochemistry (IHC) combined with spatial transcriptomics provides detailed mapping of mismatch repair (MMR) protein loss alongside immune infiltrates, enhancing MSI interpretation in heterogeneous tumors. A 2023 high-plex spatial transcriptomics study of endometrial cancers revealed distinct immune landscapes in MMR-deficient (dMMR) tumors, showing clustered CD8+ T-cell infiltration proximal to MMR-low regions, which correlates with MSI-H and improved immunotherapy outcomes (sensitivity 92%). This integration allows simultaneous assessment of MMR status and spatial immune dynamics, informing personalized treatment beyond binary MSI classification. The 2022 National Comprehensive Cancer Network (NCCN) guidelines expanded universal MSI screening recommendations to include all newly diagnosed colorectal, endometrial, and select gastroesophageal cancers, irrespective of age or family history, to identify Lynch syndrome and MSI-H for immunotherapy eligibility. These updates emphasize cost-effectiveness, with models showing incremental cost-effectiveness ratios below $50,000 per quality-adjusted life-year gained in high-incidence settings, and adaptations for low-resource environments via IHC-first strategies that lower per-test costs to under $200 while maintaining 90% detection rates.

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Apr 12, 2023 · Short tandem repeats (STRs; also known as microsatellites) are 1–6 base pair (bp) tandem repeats, accounting for approximately 3% of the ...<|control11|><|separator|>
[6]
Microsatellite DNA - an overview | ScienceDirect Topics
The most common dinucleotide sequence in eukaryotes is the (CA)n repeat, and there are 50,000 to 100,000 (CA)n repeats in the entire human genome. The genes ...
[7]
Patterns of microsatellite distribution across eukaryotic genomes
Feb 22, 2019 · SSRs contribute to 3% of the human genome [2], and display a non-random distribution in many genomes [1, 3]. They have high mutation rates due ...
[8]
Functional Mechanisms of Microsatellite DNA in Eukaryotic Genomes
I review evidence demonstrating roles for microsatellites in modulation of transcription factor binding, spacing between promoter elements, enhancers, cytosine ...
[9]
[PDF] Microsatellites and their genomic distribution, evolution, function and ...
SSRs contribute to DNA structure, chromatin organi- zation, regulation of DNA recombination, transcription and translation, gene expression and cell cycle dyna-.
[10]
Distribution, function and evolution characterization of microsatellite ...
Jan 6, 2016 · Moreover, microsatellites in the UTRs may have the “tuning ability” on functional genes, conferring the genes adaptive roles in evolution.
[11]
DNA mismatch repair: Molecular mechanism, cancer, and ageing
Any mechanism for mismatch recognition by MutS proteins must take into account the inverse correlation between the efficiency of repair for any given mismatch ...
[12]
Mismatch Repair Pathway, Genome Stability and Cancer - Frontiers
This review aims to describe the mismatch DNA repair (MMR) system whose deficiency is responsible for MSI and discuss the cellular roles of MMR genes.
[13]
DNA MISMATCH REPAIR* | Annual Reviews
Jul 7, 2005 · DNA mismatch repair (MMR) is an evolutionarily conserved process that corrects mismatches generated during DNA replication and escape proofreading.<|separator|>
[14]
Deficient mismatch repair: Read all about it (Review) - PMC - NIH
Defects in the DNA mismatch repair (MMR) proteins, result in a phenotype called microsatellite instability (MSI), occurring in up to 15% of sporadic colorectal ...
[15]
Deficient Mismatch Repair and Microsatellite Instability in Solid ...
The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors ...
[16]
Mismatch repair deficiency/microsatellite instability-high as a ...
May 31, 2019 · This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death- ...
[17]
Lynch Syndrome - GeneReviews® - NCBI Bookshelf - NIH
Feb 5, 2004 · A multigene panel that includes MLH1, MSH2, MSH6, PMS2, and EPCAM is recommended. Other colorectal cancer-predisposing genes (e.g., MUTYH ...
[18]
Germline deletions in the EPCAM gene as a cause of Lynch syndrome
Aug 12, 2013 · Carriers of mutations in MLH1, MSH2 or MSH6 have a 30-80% cumulative risk of developing colorectal cancer and women have additional 27-71% ...
[19]
Colorectal tumour BRAF V600E and MLH1 promoter methylation ...
Tumour BRAF V600E mutation and MLH1 promoter methylation are reported to be associated with MSI-H, sporadic colorectal cancer.
[20]
BRAF V600E Mutation Analysis Simplifies the Testing Algorithm for ...
Other studies have reported that the BRAF V600E mutation can be detected in 40% to 87% of all sporadic MSI colon tumors26,43 and 68% of CRCs with MLH1 promoter ...
[21]
Microsatellite instability, MLH1 promoter methylation, and BRAF ...
Jan 6, 2009 · CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.Combined Bisulfite... · Mlh1 Promoter Methylation · Braf Mutation Analysis
[22]
High microsatellite instability (MSI-H) colorectal carcinoma - NIH
Feb 13, 2016 · MSI refers to the hypermutable state of cells caused by impaired DNA mismatch repair (MMR). It consists of insertion and deletion mutations in ...
[23]
POLE mutations as an alternative pathway for microsatellite ...
Sep 15, 2014 · POLE mutations as an alternative pathway for microsatellite instability in endometrial cancer: Implications for Lynch syndrome testing.
[24]
Microsatellite Instability, MLH1 Promoter Methylation, and BRAF ...
This observation suggests that combinations of genetic and environmental factors play important roles in the development of CRC. ... Dietary factors and ...
[25]
Impact of BRAF, MLH1 on the incidence of microsatellite instability ...
Aug 21, 2008 · We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched ...
[26]
Diagnosis of Lynch Syndrome and Strategies to Distinguish ... - NIH
Microsatellite instability (MSI) is a hallmark of Lynch syndrome (LS)-related tumors but is not specific, as most of MSI/mismatch repair-deficient (dMMR) tumors ...
[27]
Tumor screening for Lynch Syndrome
MSI: Approximately 90% of colon tumors from individuals with Lynch Syndrome demonstrate microsatellite instability (MSI), whereas only approximately 15% of ...
[28]
Comparison of the Microsatellite Instability Analysis System ... - NIH
The MSI Analysis System consists of five nearly monomorphic mononucleotide markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) for MSI determination and two ...
[29]
Simplified microsatellite instability detection protocol provides ... - NIH
At present, the most frequently used PCR-based commercial MSI testing kit is a five mononucleotide marker kit developed by Promega, Madison, WI. Five ...
[30]
Microsatellite instability testing in colorectal cancer using the ... - NIH
Apr 27, 2018 · The additional markers serve as back-up if one of the Bethesda panel markers cannot be properly determined due to technical reasons such as PCR ...Fig. 1 · Fig. 3 · Table 2
[31]
Revised Bethesda Guidelines for Hereditary Nonpolyposis ...
Third, there are two classes of MSI: 1) MSI-H, in which 40% or more of the microsatellite markers demonstrate instability and 2) MSI-L, in which less than 40% ...
[32]
Microsatellite Status Detection of Colorectal Cancer - PubMed Central
PCR is more accurate in MSI detection, it is considered to be the Golden criteria of diagnosis of microsatellite status detection. Therefore, we judge the ...
[33]
Immunohistochemistry versus Microsatellite Instability Testing ... - NIH
To improve the accuracy of MSI testing using the Bethesda panel of MSI markers, a panel of five mononucleotide markers was developed and incorporated into a ...Literature Review · Advantages Of Msi · Limitations Of Msi<|separator|>
[34]
Immunohistochemical null-phenotype for mismatch repair proteins in ...
The MMR proteins are routinely assessed by pathologists through the use of immunohistochemistry (IHC) as an initial test for detecting MMR deficiency.
[35]
Testing for deficient mismatch repair and microsatellite instability
Oct 24, 2023 · DNA mismatch repair deficiency (dMMR) determined by immunohistochemistry (MMR-IHC) is closely correlated (> 98%) with the microsatellite ...
[36]
Detection of microsatellite instability biomarkers via next-generation ...
Next-generation sequencing and new analytical software have permitted expanded testing for MSI-H+ detection. NGS-based methods demonstrate superior ...
[37]
A Novel Algorithm for Detecting Microsatellite Instability Based ... - NIH
Accurate MSI judgments were achieved using NGS data, which could provide comparable MSI detection with the gold standard, PCR-based methods.
[38]
Performance assessment of computational tools to detect ... - NIH
Aug 12, 2024 · The latest version of MSIsensor comes with both WXS and whole genome sequencing (WGS) recommended settings despite having never been tested on ...
[39]
Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current ...
Mar 18, 2021 · This review aimed to discuss the current body of evidence supporting the potential of liquid biopsy as a tool for MSI testing in CRC.
[40]
Detection of microsatellite instability-high (MSI-H) by liquid biopsy ...
This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ...
[41]
Validation of MSIntuit as an AI-based pre-screening tool for MSI ...
Nov 6, 2023 · In a 2019 study, we showed that deep learning could accurately detect MSI from H&E slides in CRC. Since then, several studies have presented ...
[42]
Certain pMMR colorectal cancer patients should undergo additional ...
Jul 1, 2025 · The 2023 NCCN guidelines recommend universal screening for all CRC patients, including MMR status evaluation by IHC, MSI testing via MSI-PCR, ...
[43]
Universal screening of colorectal tumors for lynch syndrome - NIH
Sep 5, 2024 · Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify ...
[44]
Microsatellite-Stable Tumors with High Mutational Burden Benefit ...
The majority (82.1%) of MSI-H tumors were TMB-high; however, only 18.3% of TMB-high tumors were MSI-H. ... TMB and MSI status were analyzed on 148,803 tumor ...
[45]
Microsatellite Stability (MSS) - Know Your Biomarker
The microsatellite stability (or microsatellite stable) biomarker gives information about how your cells handle errors that happen during cell processes.
[46]
EMQN best practice guidelines for analysis and reporting of ... - Nature
Aug 20, 2025 · Here, we will use MSI-H and MSS. “Microsatellite instability-low” (MSI-L) is used to describe a moderate increase in microsatellite ...
[47]
Hypermethylator Phenotype in Sporadic Colon Cancer: Study on a ...
Oct 15, 2008 · In the MSI group, significant associations were seen between CIMP-High and proximal location (P = 0.015), BRAF mutation (P < 0.001), and ...Missing: hypermutation | Show results with:hypermutation
[48]
Microsatellite instability high biomarker (MSI-H) and colorectal cancer
Approximately fifteen percent of colorectal tumors are MSI-H positive. In three to five percent of colorectal patients MSI-H is caused by Lynch syndrome.
[49]
Epidemiology of Microsatellite Instability High (MSI‐H) and Deficient ...
Mar 9, 2020 · MSI-H prevalence among Stage 1/2 cancers was estimated at 15% (8%–23%); Stages 3 and 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), ...Abstract · Methods · Results · Discussion
[50]
Analysis of the Prevalence of Microsatellite Instability in Prostate ...
Dec 27, 2018 · The prevalence of MSI-H/dMMR prostate cancer is unclear, with frequencies ranging from 1.2% to 12.0% in prior reports.
[51]
Significance of mutations in TGFBR2 and BAX in neoplastic ...
Frameshift mutations in the two genes were recurrent in high-frequency MSI (MSI-H) tumors, but these tended to be more common in poorly differentiated tumors. A ...
[52]
Significance of mutations in TGFBR2 and BAX in neoplastic ...
We analyzed MSI and TGFBR2 and BAX frameshift mutations to further clarify the relationships between inactivation of the two genes and genomic instability in ...
[53]
Carcinogenesis and microsatellite instability: the interrelationship ...
MSI accounts for the mutational activation and inactivation of cancer-related genes, those with positive and negative roles in cell growth or survival, which ...Abstract · Introduction · Conclusion
[54]
The evolving role of microsatellite instability in colorectal cancer
Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs).
[55]
The distinct clinical trajectory, metastatic sites, and immunobiology ...
Nov 30, 2022 · Microsatellite-instability-high (MSI-H) cancers are a unique class of tumors that may arise from somatic inactivating mutations or epigenetic ...
[56]
Microsatellite Instability and Colorectal Cancer - Allen Press
Oct 1, 2011 · Microsatellite instability (MSI) is a hallmark feature of Lynch syndrome cancers and occurs in about 15% of sporadic colorectal cancers as well.Genetic Basis For Ls · Genetic Basis For Sporadic... · Algorithmic Testing For LsMissing: prevalence | Show results with:prevalence
[57]
Mucinous carcinoma of the colon: correlation of loss of mismatch ...
MSI-H mucinous carcinomas are right-sided, low-stage tumors with Crohn's-like reaction and tumor-infiltrating lymphocytes.
[58]
Clinicopathological characteristics of high microsatellite instability ...
Dec 23, 2022 · Other histological and morphological features of dMMR/MSI-H CRCs include high numbers of tumor-infiltrating lymphocytes, Crohn's-like ...
[59]
Improved NGS-based detection of microsatellite instability using ...
In addition to glioma, MSI detection is also challenging in other tumors such as cholangiocarcinoma, urothelial or adrenal carcinoma and sebaceous adenoma or ...
[60]
Microsatellite instability in noncolorectal and nonendometrial ...
Jul 6, 2023 · Almost all breast carcinomas had medullary features, and most of them were MSI-H/dMMR. Breast carcinoma with medullary features were shown to be ...
[61]
Tumor Mutational Burden (TMB) as a Predictive Biomarker in Solid ...
Tumors with MSI-H/dMMR typically display high TMB (25–27), and MSI-H/dMMR is an established predictive biomarker for the efficacy of ICIs. Expression of ...
[62]
Tumor Neoantigen Burden as a Biomarker for Immunotherapy ... - NIH
Notably, TMB has become a biomarker for immunotherapy, assuming that higher TMB will increase the probability of tumor neoantigens and specific T-cell responses ...
[63]
FDA grants accelerated approval to pembrolizumab for first tissue ...
May 30, 2017 · On May 23, 2017, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA, Merck & Co.)
[64]
Pembrolizumab in Microsatellite-Instability–High Advanced ...
Dec 2, 2020 · Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H–dMMR metastatic colorectal ...
[65]
Outcomes Following Immune Checkpoint Inhibitor Treatment of ...
May 14, 2020 · Clinical trials have demonstrated that MSI-H status is associated with long-term benefit in patients treated with immune checkpoint inhibitors ( ...
[66]
Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D ...
Oct 14, 2019 · Studies have shown a sustained clinical response to immune checkpoint inhibitors with dramatic clinical improvement in patients with MSI-H/MMR-D CRC.
[67]
Microsatellite instability-high status as a pan-cancer biomarker ... - NIH
Feb 25, 2025 · This meta-analysis provides robust evidence supporting the efficacy of immune checkpoint inhibitors in MSI-H patients across colorectal, ...
[68]
Microsatellite instability and immunotherapy in gastric cancer
MSI-H status has been put forward as a positive indicator of ICIs efficacy in advanced cancer patients. Evidence for the application of immunotherapy in MSI-H ...
[69]
Activation of cGAS-STING Pathway Is Associated with MSI-H Stage ...
Dec 30, 2022 · These data suggest that the cGAS-STING pathway is an important pathway for enhancing the response to ICIs in patients with MSI-H tumours [27].
[70]
Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI ...
Apr 24, 2024 · The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by ...
[71]
Werner syndrome helicase is a selective vulnerability of ... - eLife
Mar 25, 2019 · We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell ...Missing: fold | Show results with:fold
[72]
https://jamanetwork.com/journals/jamaoncology/fullarticle/2765752
[73]
Colorectal Carcinomas Containing Hypermethylated MLH1 ...
Mar 15, 2019 · Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions.
[74]
Abstract 685: PARP inhibitor MK-4827 is synthetic lethal for tumors ...
Apr 15, 2010 · Pre-clinical and clinical evidence demonstrated that PARP inhibitors are synthetic lethal ... Microsatellite Instability (MSI) phenotype in ...
[75]
ATR inhibition induces synthetic lethality in mismatch repair ... - NIH
In this study, Wang et al. show that the inhibition of ATR kinase affords selective lethality to mismatch repair-deficient (MMR-d) cancer cells.
[76]
A synthetic lethal screen identifies ATR-inhibition as a novel ...
Feb 9, 2016 · Effects on proliferation of ATR- and CHK1-inhibitors were assessed at 120 h after treatment in control-, mock- or siPOLD1-treated RKO, SW480 and ...A Synthetic Lethal Screen... · Results · Atr-Genotype Independent...
[77]
Microsatellite Instability as a Biomarker for PD-1 Blockade
Feb 14, 2016 · This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors.
[78]
FDA Approval Summary: Pembrolizumab for the Treatment of ...
Jul 1, 2019 · The FDA approved pembrolizumab on May 23, 2017, for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability- ...
[79]
Study Details | Vaccination Against MSI Colorectal Cancer
Patients with advanced microsatellite unstable (MSI-H) colorectal cancer will be vaccinated with three so called frame shift peptides (FSPs), AIM2(-1), ...
[80]
A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch ...
FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel ...
[81]
Clinicopathological and molecular analysis of microsatellite ...
Oct 12, 2023 · Gastrointestinal Cancers: Colorectal Cancer · Gastrointestinal Cancers: Gastric and Esophageal Cancers · Gastrointestinal Cancers: Hepato ...<|control11|><|separator|>
[82]
Prevalence of microsatellite instability and monitoring response to ...
Microsatellite instability (MSI) is a tissue-agnostic biomarker predictive of response to immune-checkpoint inhibition (pembrolizumab) that can be assessed by ...
[83]
Identification of people with Lynch syndrome from those presenting ...
Feb 15, 2024 · Germline pathogenic variants affecting any of the four MMR genes MLH1, MSH2, MSH6 or PMS2 underlie Lynch syndrome (LS), conferring a strong ...Results · Variation In Mmr Testing · Outcome Of Germline Testing