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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 -
International Journal of Molecular... Sep 2023Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing...
Approximately 20-30% of endometrial carcinomas (EC) are characterized by mismatch repair (MMR) deficiency (dMMR) or microsatellite instability (MSI), and their testing has become part of the routine diagnosis. The aim of this study was to establish and compare the MMR status using various approaches. Immunohistochemistry (IHC), PCR-based MSI, and the detection of defects in the four key MMR genes (MLH1, PMS2, MSH2, and MSH6) via methylation-specific multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) were performed. MSH3 expression was also evaluated. A set of 126 early-stage EC samples were analyzed, 53.2% of which were dMMR and 46.8% of which were proficient MMR (pMMR) as determined using IHC, whereas 69.3% were classified as microsatellite stable, while 8.8% and 21.9% were classified MSI-low (MSI-L) and MSI-high (MSI-H), respectively. In total, 44.3% of the samples showed genetic or epigenetic alterations in one or more genes; MLH1 promoter methylation was the most common event. Although acceptable concordance was observed, there were overall discrepancies between the three testing approaches, mainly associated with the dMMR group. IHC had a better correlation with MMR genomic status than the MSI status determined using PCR. Further studies are needed to establish solid conclusions regarding the best MMR assessment technique for EC.
Topics: Female; Humans; DNA Mismatch Repair; Endometrial Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; Microsatellite Instability
PubMed: 37833916
DOI: 10.3390/ijms241914468 -
Genomics, Proteomics & Bioinformatics Feb 2020Microsatellite instability (MSI) is a key biomarker for cancer therapy and prognosis. Traditional experimental assays are laborious and time-consuming, and...
Microsatellite instability (MSI) is a key biomarker for cancer therapy and prognosis. Traditional experimental assays are laborious and time-consuming, and next-generation sequencing-based computational methods do not work on leukemia samples, paraffin-embedded samples, or patient-derived xenografts/organoids, due to the requirement of matched normal samples. Herein, we developed MSIsensor-pro, an open-source single sample MSI scoring method for research and clinical applications. MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative site selection method to enable MSI detection without matched normal samples. We demonstrate that MSIsensor-pro is an ultrafast, accurate, and robust MSI calling method. Using samples with various sequencing depths and tumor purities, MSIsensor-pro significantly outperformed the current leading methods in both accuracy and computational cost. MSIsensor-pro is available at https://github.com/xjtu-omics/msisensor-pro and free for non-commercial use, while a commercial license is provided upon request.
Topics: Humans; Microsatellite Instability; Microsatellite Repeats; Neoplasms; Software
PubMed: 32171661
DOI: 10.1016/j.gpb.2020.02.001 -
American Society of Clinical Oncology... Apr 2022With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair... (Review)
Review
With the development of immune checkpoint inhibitors, immunotherapy researchers have facilitated substantial progress for patients with mismatch repair deficient/microsatellite instability-high colorectal cancer, which has led to practice changes at a head-spinning pace. However, this benefit has not been translated into microsatellite stable colorectal cancer, which carries the hallmarks of chromosomal instability. So far, clinical trials have not shown any substantial clinical benefits of immune checkpoint inhibitor therapy for patients with microsatellite stable colorectal cancer, which has been disappointing. Recently, combinations of immune checkpoint inhibitors with tyrosine kinase inhibitors and targeted therapies have been investigated for potential synergistic effects that may increase antitumor activity in the tumor microenvironment and achieve more substantial clinical and radiologic responses. In this article, we discuss the current state of the science for the use of immune checkpoint inhibitors in microsatellite stable colorectal cancers, and we review the molecular underpinnings of inherited physiologic barriers for the delivery of effective immunotherapy. We also elaborate on existing therapeutic opportunities to convert microsatellite stable colorectal cancer into an "immune hot" cancer, which may define the future treatment paradigm of colorectal cancer for which there is a great unmet need.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Microsatellite Instability; Microsatellite Repeats; Tumor Microenvironment
PubMed: 35658496
DOI: 10.1200/EDBK_349811 -
Frontiers in Immunology 2023For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic... (Review)
Review
For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic CRC failed to meet surgical indications or achieve pathological complete response after surgery. Perioperative therapy has been proven to effectively lower tumor staging and reduce recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have shown unprecedented prolongation of survival time and satisfactory safety in patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), while the therapeutic effect obtained by patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) was considered minimal. However, recent studies found that certain CRC patients with dMMR/MSI-H presented intrinsic or acquired immune resistance, and pMMR/MSS CRC patients can also achieve better efficacy. Therefore, more predictors are required for screening patients with potential clinical benefits. Since the discovery of synergistic effects between immunotherapy, chemotherapy, and radiotherapy, different immunotherapy-based therapies have been applied to the perioperative therapy of CRC in an increasing number of research. This review comprehensively summarized the past and current progress of different combinations of immunotherapy in perioperative clinical trials for CRC, focusing on the efficacy and safety, and points out the direction for future development.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Brain Neoplasms; Colorectal Neoplasms; Microsatellite Instability
PubMed: 38022667
DOI: 10.3389/fimmu.2023.1269341 -
International Journal of Clinical... Jun 2024Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory...
BACKGROUND
Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features.
METHODS
The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis.
RESULTS
Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively).
CONCLUSION
PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.
Topics: Humans; Microsatellite Instability; Neoplasms, Unknown Primary; B7-H1 Antigen; Male; Female; Middle Aged; Aged; Adult; Aged, 80 and over; Biomarkers, Tumor; Prognosis; Tumor Microenvironment; Immunohistochemistry
PubMed: 38528294
DOI: 10.1007/s10147-024-02494-3 -
Cancer Medicine Oct 2023Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response....
BACKGROUND
Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications.
METHODS
Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI).
RESULTS
Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36.
CONCLUSIONS
TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.
Topics: Humans; Immune Checkpoint Inhibitors; Proto-Oncogene Proteins p21(ras); Prognosis; Cholangiocarcinoma; Mutation; Biomarkers, Tumor; Microsatellite Instability; Bile Ducts, Intrahepatic; Bile Duct Neoplasms
PubMed: 37814942
DOI: 10.1002/cam4.6441 -
Oncoimmunology Apr 2021Colorectal cancers (CRCs) with microsatellite instability (MSI) are due to a defect in the DNA mismatch repair (MMR) system resulting in an accumulation of frame-shift...
Colorectal cancers (CRCs) with microsatellite instability (MSI) are due to a defect in the DNA mismatch repair (MMR) system resulting in an accumulation of frame-shift mutations. They are characterized by a tumor microenvironment richer in cytotoxic CD8 T-cells (CTLs) and a better prognosis compared to microsatellite stable (MSS) CRCs. The mechanisms by which defective MMR system may influence tumor-infiltrating immune cells and their impact on patient survival were still unclear. Thus, we performed a comprehensive analysis of MSI colorectal tumors. We found that the numbers of frame-shift mutations potentially resulting in neo-epitopes were positively correlated to the density of tumor infiltrating CD8 T-cells but were lower than expected at random. We also evidenced that MSI patients could naturally harbor CTLs targeting frame-shift mutation-derived antigens. This favors the hypothesis of an active immunosurveillance in MSI colorectal tumors leading to the genetic evidence of an immunoediting. To evaluate the link between MSI tumor immune contexture and prognosis, we took advantage of a standardized assay that we developed to quantify tumor-infiltrating T-cells, the Immunoscore. Multivariate analyses revealed an advantage of Immunoscore over MSI in predicting recurrence and survival. Our data suggests that the prognostic value of MSI could be attributed to major underlying differences of infiltrating immune cells. Immunotherapeutic treatments, that are more efficient in patients with a preexisting anti-tumor immunity, were approved in MSI patients following successful clinical trials. We suggest that the Immunoscore could be used not only for colorectal tumor prognosis but also for predicting responses to immunotherapies.
Topics: Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Instability; Neoplasm Recurrence, Local; Prognosis; Tumor Microenvironment
PubMed: 33868790
DOI: 10.1080/2162402X.2021.1905935 -
Aging Jan 2024Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported... (Review)
Review
Microsatellite instability-high (MSI-H) has gained considerable interests since it was approved as a tumor-agnostic biomarker in immunotherapy. However, the reported characteristics of MSI-H gastric cancer (GC) are inconsistent due to the biological complexity. Here, we aim to clarify the prevalence, risk factors, clinicopathological/molecular features and outcomes of MSI-H GC though a comprehensive review on 43246 patients from 134 cohorts. Overall, the proportion of MSI-H GC was 14.5% (95% CI, 13.3%-15.8%). Patients with MSI-H GC were less likely to have Epstein-Barr virus infection. High incidences of MSI-H GC were associated with female, older age, lower gastric body, Lauren intestinal histology, WHO tubular and mucinous subtypes, and early disease stage. Additionally, patients with MSI-H GC harbored more mutation, PD-L1 positivity, CD8 overexpression, and higher TMB, but less HER2 positivity and mutation. When treated with conventional strategy, the 5-year survival rates in MSI-H patients (70.3%) and MSI-L/MSS patients (43.7%) were significantly different (<0.001). Patients with MSI-H GC derived larger benefit from immunotherapy in term of overall survival (<0.001) and objective response (=0.02). Since the prevalence of MSI-H GC is relatively high and associated with distinct clinicopathological and molecular characteristics, MSI testing should be conducted during standard diagnostical activity. Moreover, giving MSI-H tumors are often diagnosed at early stage and have favorable outcomes, less aggressive treatment strategies may be considered in clinical practice. In summary, this panoramic review may assist in design and/or interpretation of clinical trials, provide references in drug development, and constitute complementary information in drafting the clinical practice guideline.
Topics: Humans; Female; Stomach Neoplasms; Microsatellite Instability; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Biomarkers, Tumor; Risk Factors; Prognosis
PubMed: 38224334
DOI: 10.18632/aging.205431 -
Genes Jan 2023Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by...
Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including , , , , , , and . The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3'-intronic regions, i.e., in the (ATM serine/threonine kinase), (MRE11 homolog) or the (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the and genes, which as act as players in the MNR (/ (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences.
Topics: Humans; Microsatellite Instability; RNA Precursors; Mutation; DNA Repair; Colorectal Neoplasms, Hereditary Nonpolyposis
PubMed: 36833239
DOI: 10.3390/genes14020311