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Briefings in Bioinformatics May 2021Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a...
Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a genetic test to select patients for immunotherapy targeting PD-1 and/or CTLA-4 without limitation to cancer type. However, it is unclear whether the MSI-H would broadly alter the tumor microenvironment to confer the therapeutic response of different cancer types to immunotherapy. To fill in this gap, we performed an in silico analysis of tumor immunity among different MSI statuses in five cancer types. We found that consistent with clinical responses to immunotherapy, MSI-H and non-MSI-H samples from colorectal cancer (COAD-READ) exhibited distinct infiltration levels and immune phenotypes. Surprisingly, the immunological difference between MSI-H and non-MSI-H samples was diminished in stomach adenocarcinoma and esophageal carcinoma (STAD-ESCA) and completely disappeared in uterine corpus endometrial carcinoma (UCEC). Regardless of cancer types, the abundance of tumor-infiltrating immune cells, rather than MSI status, strongly associated with the clinical outcome. Since preexisting antitumor immune response in the tumor (hot cancer) is accepted as a prerequisite to the therapeutic response to anti-PD-1/CTLA-4 immunotherapy, our data demonstrate that the impact of MSI varied on immune contexture will lead to the further evaluation of predictive immunotherapy responsiveness based on the universal biomarker of MSI status.
Topics: Biomarkers, Tumor; Humans; Microsatellite Instability; Neoplasms; Prognosis; Single-Cell Analysis; Tumor Microenvironment
PubMed: 32823273
DOI: 10.1093/bib/bbaa180 -
Histopathology Sep 2022Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with...
AIM
Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well established, however, its implications in patients with rectal cancer remain undefined. We therefore aimed to determine the role of MSI with respect to incidence and outcome in patients with rectal cancer.
METHODS AND RESULTS
For this we examined patients from two prospective phase III trials: TME trial and PROCTOR-SCRIPT trial (n = 1250). In addition, we performed a literature review to evaluate the overall prevalence, the effect on survival and the response to neo-adjuvant treatment in patients with MSI rectal cancer compared with microsatellite stable (MSS) rectal cancer. Our TME and PROCTOR-SCRIPT cohort showed no differences in terms of overall survival (OS) (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.69-1.47) and disease-free survival (DFS) (HR 1.00, 95% CI 0.68-1.45) in patients with MSI compared to MSS rectal cancer. The total number of MSI cases in all included studies (including our own) was 1220 (out of 16,526 rectal cancer patients), with an overall prevalence of 6.7% (standard error 1.19%). Both for OS as for DFS there was no impact of MSI status on prognosis (HR 1.00, 95% CI 0.77-1.29 and HR 0.86, 95% CI 0.60-1.22, respectively). The risk ratio (RR) for downstaging and pathological complete response showed also no impact of MSI status (RR 1.15, 95% CI 0.86-1.55 and RR 0.81, 95% CI 0.54-1.22, respectively).
CONCLUSION
Rectal cancer patients with MSI form a distinct and rare subcategory, however, there is no prognostic effect of MSI in rectal cancer patients.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Neoplasm Staging; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rectal Neoplasms
PubMed: 35758193
DOI: 10.1111/his.14710 -
International Journal of Oncology Sep 2021Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations... (Review)
Review
Microsatellite instability‑high/deficient mismatch repair colorectal cancer (MSI‑H/dMMR CRC) is a molecular subtype characterized by high‑frequency mutations within DNA mismatch repair genes. Defects in the DNA mismatch repair machinery lead to subsequent frame‑shift mutations, resulting in the generation of frame‑shift peptides that serve as neoantigens. This has translated into exquisite sensitivity to immune checkpoint inhibitors (ICIs) and a significant clinical benefit from immune therapies in this patient population. The present article provides a comprehensive review of the advances in the field of immune therapies for MSI‑H/dMMR metastatic CRC, with a focus on the major randomized clinical trials that led to Food and Drug Administration approval of specific ICIs for this population, a detailed review of the molecular background responsible for tumor response, as well as the mechanisms of resistance to ICI therapy. Finally, ongoing investigations of other immunotherapeutic strategies to address and overcome the challenges that currently limit response and long‑term response to ICIs were presented.
Topics: Clinical Trials as Topic; Colorectal Neoplasms; DNA Mismatch Repair; Drug Approval; Drug Resistance, Neoplasm; Humans; Immune Checkpoint Inhibitors; Microsatellite Instability; Neoplasm Metastasis; United States; United States Food and Drug Administration
PubMed: 34396449
DOI: 10.3892/ijo.2021.5254 -
Biomolecules & Biomedicine Mar 2023Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the... (Meta-Analysis)
Meta-Analysis Review
Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the intrinsic resistance to and efficacy of immunotherapy in patients with MSI-H CRC. The PubMed and Web of Science databases were searched using keywords such as "colorectal cancer," "immunotherapy," and "clinical experiment." Random-effects models were used to generate the combined complete response, partial response, stable disease, progressive disease, objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. We then performed a subgroup analysis based on the ORR and incidence of intrinsic resistance. The meta-analysis included seven clinical trials. The incidences of complete response, partial response, stable disease, and progressive disease summarized by the random-effects model were 8%, 37%, 26%, and 25%, respectively. The ORR and DCR were 45% and 71%, respectively. The ORRs of programmed cell death protein 1 inhibitor (anti-PD-1), programmed death ligand 1 inhibitor (anti-PD-L1), and anti-PD-1 combined with cytotoxic T lymphocyte-associated antigen 4 inhibitor (anti-CTLA-4) immunotherapy were 38%, 54%, and 57%, respectively. The ORR of immune checkpoint inhibitors for first- and third-line therapy was 56% and 32%, respectively. Dual-drug immunotherapy significantly reduced the incidence of intrinsic resistance to immunotherapy (12% vs 31%). The incidences of intrinsic resistance to first-line therapy and second-line and later therapy were 29% and 26%, respectively. Approximately 25% of patients with MSI-H CRC had intrinsic resistance to immunotherapy. Anti-PD-1 combined with anti-CTLA-4 significantly increased the ORR, thereby reducing the incidence of intrinsic resistance. Moving immunotherapy into earlier lines of therapy, although not reducing the incidence of intrinsic resistance, can improve the ORR in patients with MSI-H CRC.
Topics: Humans; Microsatellite Instability; Colonic Neoplasms; Immunotherapy
PubMed: 36408953
DOI: 10.17305/bjbms.2022.8286 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... May 2021Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of...
Lymphoma is one of the most common malignant tumor of the hematologic system. The genome instability is not only an important molecular basis for the development of lymphoma, but also has important value in the diagnosis and prognosis of lymphoma. There are 2 types of genome instability: Microsatellite instability (MSI/MIN) at gene level and chromosomal instability at chromosome level. Through the study on genes associated with lymphoma, the unstable genes associated with lymphoma could be found, meanwhile the mechanism of its occurrence and development of lymphoma could be explored, and the important basis of molecular biology could also be provided in the field of current hot lymphoma precision medical research.
Topics: Genomic Instability; Humans; Lymphoma; Microsatellite Instability; Microsatellite Repeats; Neoplasms
PubMed: 34148893
DOI: 10.11817/j.issn.1672-7347.2021.190427 -
Methods in Molecular Biology (Clifton,... 2020A high level of microsatellite instability (MSI-H+) is an emerging predictive and prognostic biomarker for immunotherapy response in cancer. Recently, MSI-H+ has been...
A high level of microsatellite instability (MSI-H+) is an emerging predictive and prognostic biomarker for immunotherapy response in cancer. Recently, MSI-H+ has been detected in a variety of cancer types, in addition to the classical cancers associated with Lynch Syndrome. Clinical testing for MSI-H+ is currently performed primarily through traditional polymerase chain reaction (PCR) or immunohistochemistry (IHC) assays. However, next-generation sequencing (NGS)-based approaches have been developed which have multiple advantages over traditional assays. For instance, NGS has the ability to interrogate thousands of microsatellite loci compared with just 5-7 loci that are detected by PCR. In this chapter, we detail the biochemical and computational steps to detect MSI-H+ from analysis of paired tumor and normal samples through NGS. We begin with DNA extraction, describe sequencing library preparation and quality control (QC), and outline the bioinformatics steps necessary for sequence alignment, preprocessing, and MSI-H+ detection using the software tool MANTIS. This workflow is intended to facilitate more widespread usage and adaptation of NGS-powered MSI detection, which can be eventually standardized for routine clinical testing.
Topics: Biomarkers, Tumor; Gene Library; High-Throughput Nucleotide Sequencing; Humans; Microsatellite Instability; Neoplasms; Prognosis; Sequence Analysis, DNA
PubMed: 31502149
DOI: 10.1007/978-1-4939-9773-2_5 -
International Journal of Colorectal... Aug 2021For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status.
METHODS
A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration.
RESULTS
From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit.
CONCLUSIONS
MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immunotherapy; Microsatellite Instability; Microsatellite Repeats; Prognosis
PubMed: 33604737
DOI: 10.1007/s00384-021-03874-1 -
Frontiers in Immunology 2022Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and...
BACKGROUND
Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and immunotherapy resistance. However, the detailed underlying mechanism requires further investigation. Consequently, identifying molecular biomarkers with prognostic significance and revealing the role of MSI in COAD is important for addressing key obstacles in the available treatments.
METHODS
CIBERSORT and ESTIMATE analyses were performed to evaluate immune infiltration in COAD samples, followed by correlation analysis for MSI and immune infiltration. Then, differentially expressed genes (DEGs) in MSI and microsatellite stability (MSS) samples were identified and subjected to weighted gene co-expression network analysis (WGCNA). A prognostic model was established with univariate cox regression and LASSO analyses, then evaluated with Kaplan-Meier analysis. The correlation between the prognostic model and immune checkpoint inhibitor (ICI) response was also analyzed.
RESULTS
In total, 701 significant DEGs related to MSI status were identified, and WGCNA revealed two modules associated with the immune score. Then, a seven-gene prognostic model was constructed using LASSO and univariate cox regression analyses to predict survival and ICI response. The high-risk score patients in TCGA and GEO cohorts presented a poor prognosis, as well as a high immune checkpoint expression, so they are more likely to benefit from ICI treatment.
CONCLUSION
The seven-gene prognostic model constructed could predict the survival of COAD and ICI response and serve as a reference for immunotherapy decisions.
Topics: Humans; Prognosis; Microsatellite Instability; Colonic Neoplasms; Adenocarcinoma; Immune Checkpoint Inhibitors; Biomarkers, Tumor
PubMed: 36275690
DOI: 10.3389/fimmu.2022.988303 -
Medicine Aug 2022Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated variant of gastric adenocarcinoma, which has been proposed as a novel disease entity. As a...
RATIONALE
Gastric adenocarcinoma of the fundic gland is a rare, well-differentiated variant of gastric adenocarcinoma, which has been proposed as a novel disease entity. As a result of mismatch repair deficiency, microsatellite instability has been frequently observed in various human cancers and widely performed in the area of cancer pathogenesis. Herein, we report a case of gastric adenocarcinoma of fundic gland presented with microsatellite instability phenotype.
PATIENT CONCERNS
A 46-year-old man was referred to our hospital for abdominal distension and pain.
DIAGNOSIS
The patient contained 3 tumor lesions with different degrees of histologic differentiation and microsatellite instability. The lesions were located in the upper third of the stomach. The tumor size was 55 mm. Macroscopically, tumor showed an ulcerative type. In terms of depth of invasion, tumor lesion invaded into subserosa with lymphatic invasion. In addition, this patient did not present GNAS mutation but harbored AXIN2 mutation. By immunohistochemistry, the expression level of β-catenin protein in the nucleus of the carcinoma cells was obviously higher than that in normal nucleus. Compared with microsatellite instability-low lesion, PD-1, PD-L1, and CD8 were positive in the microsatellite instability-high lesions.
INTERVENTIONS
The patient underwent surgical resection and postoperative chemotherapy.
OUTCOMES
The patient experienced distant metastasis and died from severe complications after 6 months of treatment.
LESSONS
These results suggested that the mutation of Wnt component genes associated with Wnt/β-catenin signaling pathway activation may play a role in promoting the occurrence of gastric adenocarcinoma of fundic gland. This is the first report of a gastric adenocarcinoma of fundic gland with microsatellite instability. These findings modify our understanding of the pathophysiology of gastric adenocarcinoma of fundic gland.
Topics: Adenocarcinoma; Brain Neoplasms; Colorectal Neoplasms; Humans; Male; Microsatellite Instability; Middle Aged; Neoplastic Syndromes, Hereditary; Stomach Neoplasms; Wnt Signaling Pathway
PubMed: 36042639
DOI: 10.1097/MD.0000000000030311 -
Journal of Clinical Oncology : Official... Feb 2019
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Humans; Microsatellite Instability
PubMed: 30550362
DOI: 10.1200/JCO.18.01664