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Nature Communications Nov 2023Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is...
Mismatch Repair Deficiency (dMMR)/Microsatellite Instability (MSI) is a key biomarker in colorectal cancer (CRC). Universal screening of CRC patients for MSI status is now recommended, but contributes to increased workload for pathologists and delayed therapeutic decisions. Deep learning has the potential to ease dMMR/MSI testing and accelerate oncologist decision making in clinical practice, yet no comprehensive validation of a clinically approved tool has been conducted. We developed MSIntuit, a clinically approved artificial intelligence (AI) based pre-screening tool for MSI detection from haematoxylin-eosin (H&E) stained slides. After training on samples from The Cancer Genome Atlas (TCGA), a blind validation is performed on an independent dataset of 600 consecutive CRC patients. Inter-scanner reliability is studied by digitising each slide using two different scanners. MSIntuit yields a sensitivity of 0.96-0.98, a specificity of 0.47-0.46, and an excellent inter-scanner agreement (Cohen's κ: 0.82). By reaching high sensitivity comparable to gold standard methods while ruling out almost half of the non-MSI population, we show that MSIntuit can effectively serve as a pre-screening tool to alleviate MSI testing burden in clinical practice.
Topics: Humans; Microsatellite Instability; Artificial Intelligence; Reproducibility of Results; Early Detection of Cancer; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 37932267
DOI: 10.1038/s41467-023-42453-6 -
Journal of Translational Medicine Feb 2024The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the...
BACKGROUND
The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the demand for such tests beyond Lynch syndrome. International guideline recommendations accept immunohistochemistry (IHC) for dMMR or molecular techniques (PCR or NGS) for MSI status determinations considering the two tests are equal, although there are scattered reports contradicting to this presumption.
MATERIALS AND METHODS
Here we have directly compared four protein MMR immunohistochemistry (IHC) to MSI Pentaplex PCR test in a large cancer patient cohort (n = 1306) of our diagnostic center where the two tests have been run parallel in 703 cases.
RESULTS
In this study we have found a high discrepancy rate (19.3%) of the two tests which was independent of the tumor types. The MSI PCR sensitivity for MMR IHC status was found to be very low resulting in a relatively low positive and negative predicting values. As a consequence, the correlation of the two tests was low (kappa < 0.7). During analysis of the possible contributing factors of this poor performance, we have excluded low tumor percentage of the samples, but identified dMMR phenotypes (classic versus non-classic or unusual) as possible contributors.
CONCLUSION
Although our cohort did not include samples with identified technical errors, our data strongly support previous reports that unidentified preanalytical factors might have the major influence on the poor performance of the MSI PCR and MMR IHC. Furthermore, the case is open whether the two test types are equally powerful predictive markers of immunotherapies.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; Brain Neoplasms; DNA Mismatch Repair
PubMed: 38350968
DOI: 10.1186/s12967-024-04960-y -
Gene May 2021Microsatellite instability (MSI) is closely related to the prognosis and therapy response of colon cancer. Colon cancer patients with MSI show resistance to...
Microsatellite instability (MSI) is closely related to the prognosis and therapy response of colon cancer. Colon cancer patients with MSI show resistance to 5-Fluorouracil (5-FU) but sensitivity to immunosuppressive checkpoint inhibitors (ICIs). The relevant mechanism behind the opposite response remains unclear. Multi-omics research data of colon cancer patients were acquired from The Cancer Genome Atlas (TCGA) database, GEO database, and DAFI dataset. Transcriptome data were normalized to gene expression data through the R software package "Limma". Somatic mutations data were analyzed and visualized through the R software package "maftools". CIBERSORT algorithm was used to estimate the relative proportion of 22 infiltrating immune cell types. We demonstrated MSI patients showed both overexpressed immune checkpoints (mRNA level) and activated tumor-infiltrating lymphocytes (TILs), which may explain the satisfying response of ICIs. The additionally, we also demonstrated MSI promoted the mRNA expression of thymidylate synthase (TYMS) through regulating its copy number variation. As a main target of 5-FU, overexpressed TYMS promoted the resistance of 5-FU. Furthermore, we demonstrated MSI patients showed significantly increased somatic mutations compared with microsatellite stability (MSS) patients, except APC, TP53, and KRAS mutations. The substitutions and location of somatic mutations in different genes were at variance between MSS and MSI patients. In conclusion, our research determined mechanisms of MSI associated treatment response, and may provide potential value for improving the survival of colon cancer patients.
Topics: Aged; Aged, 80 and over; Colonic Neoplasms; DNA Copy Number Variations; Female; Gene Expression Regulation, Neoplastic; Genomics; Humans; Male; Microsatellite Instability; Mutation; Thymidylate Synthase; Transcriptome
PubMed: 33636290
DOI: 10.1016/j.gene.2021.145534 -
Expert Opinion on Pharmacotherapy Feb 2022Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent...
INTRODUCTION
Unresectable metastatic colorectal cancer (mCRC) has a poor prognosis. Emerging treatment paradigms have improved outcomes in selected unresectable mCRC cases. Recent therapeutic advancements are due in part to a shift in trial designs. By examining CRC as a heterogeneous group of various tumor subtypes, researchers have identified molecular distinctions that have led to promising targets.
AREAS COVERED
Nineteen antineoplastic agents are included in the National Comprehensive Cancer Network guidelines for the palliative management of mCRC. However, not all patients will be candidates for each agent. New therapies for rare mCRC subtypes have emerged. Herein, the authors review these rare mCRC subtypes: microsatellite instability-high/deficient mismatch repair, BRAFV600E-mutant, and human epidermal growth factor receptor 2-positive tumors. Additionally, they provide an overview of unresectable mCRC management and future directions.
EXPERT OPINION
Treatment in the majority of mCRC patients (RAS wild-type or RAS-mutant, microsatellite instability-stable or -low/mismatch repair-proficient, BRAFV600E wild-type, or HER2-negative) needs further advancement and remains an unmet need. The authors believe that the key to identifying more breakthroughs in these mCRC patients is to continue to differentiate their tumors molecularly and clinically.
Topics: Antineoplastic Agents; Colorectal Neoplasms; Humans; Microsatellite Instability; Molecular Targeted Therapy
PubMed: 34534031
DOI: 10.1080/14656566.2021.1982895 -
Clinical Colorectal Cancer Jun 2023Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy,... (Review)
Review
Upper gastrointestinal tract tumors historically have a poor prognosis. The decision to treat esophageal or gastric cancers by surgery, radiotherapy, systemic therapy, or a combination of these treatment modalities should always be discussed multidisciplinary. The introduction of immunotherapy has drastically transformed the treatment landscape of multiple solid malignancies. Emerging data from early and late phase clinical trials suggests that the use of immunotherapies that target immune checkpoint proteins such as PD-1/PD-L1 result in superior overall survival in advanced, metastatic, or recurrent esophageal and gastric cancer, whether or not with specific molecular characteristics such as PD-L1 expression level or microsatellite instability. This review offers an overview of the most recent advances in the field of immunotherapy treatment in esophageal and gastric cancer.
Topics: Humans; Stomach Neoplasms; Esophageal Neoplasms; B7-H1 Antigen; Immunotherapy; Microsatellite Instability
PubMed: 37005190
DOI: 10.1016/j.clcc.2023.03.001 -
The International Journal of... Nov 2023The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency... (Review)
Review
The DNA mismatch repair pathway is involved in the identification, excision, and repair of base-base mismatches and indel loops in the genome. Mismatch repair deficiency occurs in approximately 20% of all cancers and results in a type of DNA damage called microsatellite instability. In 2017, the immune checkpoint inhibitor, Pembrolizumab, an anti-PD-1 therapy, was approved for use in all unresectable or metastatic tumours that were mismatch repair deficient or had high microsatellite instability regardless of tissue origin. This landmark approval was the first time a drug had been approved in a site agnostic way, but accumulating data has revealed that up to 50% of mismatch repair deficient tumours are refractory to treatment and there is a huge amount of variability in the therapeutic benefit amongst responders. Several mechanisms of resistance to immune checkpoint blockade for mismatch repair deficient cancers have been identified but our understanding of what is driving resistance in a proportion of patients remains lacking. In this review article, we discuss the emerging mechanisms of resistance which may enable optimal stratification of patients for treatment with immune checkpoint inhibitors in the future.
Topics: Humans; Immune Checkpoint Inhibitors; DNA Mismatch Repair; Biomarkers, Tumor; Microsatellite Instability; Colorectal Neoplasms
PubMed: 37862741
DOI: 10.1016/j.biocel.2023.106477 -
The American Journal of Nursing Jul 2022Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient...
Pembrolizumab (Keytruda) is now approved as a single agent to treat advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient in those whose disease has progressed following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation.
Topics: Antibodies, Monoclonal, Humanized; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability
PubMed: 35736598
DOI: 10.1097/01.NAJ.0000842244.43543.52 -
Journal of the National Cancer Institute May 2023We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors,...
BACKGROUND
We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features.
METHODS
Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests.
RESULTS
Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P < .001). Among 231 gPVs, 74 (32%) exhibited biallelic inactivation within tumors. For high-penetrance gPVs, 63% (47 of 75) of ECs had biallelic alterations, primarily affecting mismatch repair (MMR) and homologous recombination related genes, including BRCA1,BRCA2, RAD51D, and PALB2. Biallelic inactivation varied across molecular subtypes with highest rates in microsatellite instability-high (MSI-H) or copy-number (CN)-high subtypes (3 of 12 [25%] POLE, 30 of 77 [39%] MSI-H, 27 of 60 [45%] CN-high, 9 of 57 [16%] CN-low; P < .001).
CONCLUSIONS
Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.
Topics: Female; Humans; Mutation; Germ-Line Mutation; Endometrial Neoplasms; Microsatellite Instability; Genetic Predisposition to Disease
PubMed: 36744932
DOI: 10.1093/jnci/djad016 -
Annals of Surgical Oncology Dec 2023Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite... (Review)
Review
Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite instability (MSI) has become a major molecular typing approach for gastric cancer. MSI is well recognized for its important role during the immunotherapy of advanced GC. However, its value remains unclear in resectable gastric cancer. The reported incidence of microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) in resectable gastric cancer varies widely, with no consensus reached on the value of postoperative adjuvant therapy in patients with MSI-H/dMMR resectable GC. It has been established that MSI-H/dMMR tumor cells can elicit an endogenous immune antitumor response and ubiquitously express immune checkpoint ligands such as PD-1 or PD-L1. On the basis of these considerations, MSI-H/dMMR resectable GCs are responsive to adjuvant immunotherapy, although limited research has hitherto been conducted. In this review, we comprehensively describe the differences in geographic distribution and pathological stages in patients with MSI-H/dMMR with resectable gastric cancer and explore the value of adjuvant chemotherapy and immunotherapy on MSI-H/dMMR to provide a foothold for the individualized treatment of this patient population.
Topics: Humans; Stomach Neoplasms; DNA Mismatch Repair; Microsatellite Instability; Immunotherapy; Adjuvants, Immunologic; Colorectal Neoplasms
PubMed: 37667098
DOI: 10.1245/s10434-023-14103-0 -
Frontiers in Immunology 2023Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation.... (Review)
Review
Up to 30% of colorectal, endometrial and gastric cancers have a deficiency in mismatch repair (MMR) protein expression due to either germline or epigenetic inactivation. Patients with Lynch Syndrome who inherit an inactive MMR allele have an up to 80% risk for developing a mismatch repair deficient (MMRd) cancer. Due to an inability to repair DNA, MMRd tumors present with genomic instability in microsatellite regions (MS). Tumors with high MS instability (MSI-H) are characterized by an increased frequency of insertion/deletions (indels) that can encode novel neoantigens if they occur in coding regions. The high tumor antigen burden for MMRd cancers is accompanied by an inflamed tumor microenvironment (TME) that contributes to the clinical effectiveness of anti-PD-1 therapy in this patient population. However, between 40 and 70% of MMRd cancer patients do not respond to treatment with PD-1 blockade, suggesting that tumor-intrinsic and -extrinsic resistance mechanisms may affect the success of checkpoint blockade. Immune evasion mechanisms that occur during early tumorigenesis and persist through cancer development may provide a window into resistance pathways that limit the effectiveness of anti-PD-1 therapy. Here, we review the mechanisms of immune escape in MMRd tumors during development and checkpoint blockade treatment, including T cell dysregulation and myeloid cell-mediated immunosuppression in the TME. Finally, we discuss the development of new therapeutic approaches to tackle resistance in MMRd tumors, including cancer vaccines, therapies targeting immunosuppressive myeloid programs, and immune checkpoint combination strategies.
Topics: Humans; DNA Mismatch Repair; Microsatellite Instability; Stomach Neoplasms; Treatment Outcome; Immunotherapy; Tumor Microenvironment
PubMed: 37492581
DOI: 10.3389/fimmu.2023.1210164