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Frontiers in Immunology 2022Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that... (Review)
Review
Colorectal cancers (CRCs) with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) show molecular and clinicopathological characteristics that differ from those of proficient mismatch repair/microsatellite stable CRCs. Despite the importance of MSI-H/dMMR status in clinical decision making, the testing rates for MSI and MMR in clinical practice remain low, even in high-risk populations. Additionally, the real-world prevalence of MSI-H/dMMR CRC may be lower than that reported in the literature. Insufficient MSI and MMR testing fails to identify patients with MSI-H/dMMR CRC, who could benefit from immunotherapy. In this article, we describe the current knowledge of the clinicopathological features, molecular landscape, and radiomic characteristics of MSI-H/dMMR CRCs. A better understanding of the importance of MMR/MSI status in the clinical characteristics and prognosis of CRC may help increase the rates of MMR/MSI testing and guide the development of more effective therapies based on the unique features of these tumors.
Topics: Humans; Microsatellite Instability; DNA Mismatch Repair; Colonic Neoplasms; Colorectal Neoplasms; Prognosis
PubMed: 36618386
DOI: 10.3389/fimmu.2022.1019582 -
Nature Communications Apr 2023Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot...
Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot reliably inform patient prognosis or genomic variations crucial for treatment selections. To address these challenges, we develop the Multi-omics Multi-cohort Assessment (MOMA) platform, an explainable machine learning approach, to systematically identify and interpret the relationship between patients' histologic patterns, multi-omics, and clinical profiles in three large patient cohorts (n = 1888). MOMA successfully predicts the overall survival, disease-free survival (log-rank test P-value<0.05), and copy number alterations of CRC patients. In addition, our approaches identify interpretable pathology patterns predictive of gene expression profiles, microsatellite instability status, and clinically actionable genetic alterations. We show that MOMA models are generalizable to multiple patient populations with different demographic compositions and pathology images collected from distinctive digitization methods. Our machine learning approaches provide clinically actionable predictions that could inform treatments for colorectal cancer patients.
Topics: Humans; Multiomics; Colorectal Neoplasms; Mutation; Microsatellite Instability; Disease-Free Survival
PubMed: 37055393
DOI: 10.1038/s41467-023-37179-4 -
Surgical Pathology Clinics Dec 2022Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For... (Review)
Review
Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For localized PCa, gene expression assays can support clinical decisions regarding active surveillance and adjuvant treatment. In metastatic PCa, homologous recombination deficiency, microsatellite instability-high (MSI-H), and CDK12 deficiency constitute main actionable alterations. Alterations in DNA repair genes confer variable sensitivities to poly(ADP-ribose)polymerase inhibitors, and the use of genomic instability assays as predictive biomarker is still incipient. MSI can be assessed by immunohistochemistry To date there is a lack of consensus as to testing standards.
Topics: Male; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Microsatellite Instability; Prostatic Neoplasms; Genetic Testing; Molecular Biology
PubMed: 36344179
DOI: 10.1016/j.path.2022.08.002 -
Frontiers in Immunology 2022Patients with locally advanced colorectal cancer (LACRC) have a high risk of recurrence and metastasis, although neoadjuvant therapy may provide some benefit. However,... (Review)
Review
Patients with locally advanced colorectal cancer (LACRC) have a high risk of recurrence and metastasis, although neoadjuvant therapy may provide some benefit. However, patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) LACRC receive little benefit from neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT). The 2015 KEYNOTE-016 trial identified MSI-H/dMMR as a biomarker indicative of immunotherapy efficacy, and pointed to the potential use of immune checkpoint inhibitors (ICIs). In 2017, the FDA approved two ICIs (pembrolizumab and nivolumab) for treatment of MSI-H/dMMR metastatic CRC (mCRC). In 2018, the CheckMate-142 trial demonstrated successful treatment of mCRC based on "double immunity" provided by nivolumab with ipilimumab, a regimen that may become a standard first-line treatment for MSI-H mCRC. In 2018, the FDA approved nivolumab alone or with ipilimumab for patients who progressed to MSI-H/dMMR mCRC after standard chemotherapy. The FDA then approved pembrolizumab alone as a first-line treatment for patients with MSI-H/dMMR CRC that was unresectable or metastatic. There is now interest in using these drugs in neoadjuvant immunotherapy (nIT) for patients with MSI-H/dMMR non-mCRC. In 2020, the NICHE trial marked the start of using nIT for CRC. This novel treatment of MSI-H/dMMR LACRC may change the approaches used for neoadjuvant therapy of other cancers. Our review of immunotherapy for CRC covers diagnosis and treatment, clinical prognostic characteristics, the mechanism of nIT, analysis of completed prospective and retrospective studies, and ongoing clinical trials, and the clinical practice of using nIT for MSI-H/dMMR LACRC. Our team also proposes a new organ-preservation strategy for patients with MSI-H/dMMR low LARC.
Topics: Colonic Neoplasms; Colorectal Neoplasms; Humans; Immunotherapy; Ipilimumab; Microsatellite Instability; Neoadjuvant Therapy; Nivolumab; Prospective Studies; Retrospective Studies
PubMed: 35371084
DOI: 10.3389/fimmu.2022.795972 -
Frontiers in Immunology 2020Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of... (Review)
Review
Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
Topics: Antigens, Neoplasm; Cancer Vaccines; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Immunotherapy, Adoptive; Microsatellite Instability; Prognosis; Tumor Escape
PubMed: 32210966
DOI: 10.3389/fimmu.2020.00369 -
Frontiers in Immunology 2023Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer.
METHODS
We searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results.
RESULTS
We included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, <0.01, chi = 65.3, <0.01, = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, <0.01, chi = 42.55, <0.01, = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, <0.01, chi = 1.86, =0.6, = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, <0.01, chi = 3.04, =0.55, = 0%) with the fixed-effects model and little heterogeneity.
CONCLUSION
Neoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.
Topics: Humans; Colorectal Neoplasms; Neoadjuvant Therapy; Colonic Neoplasms; Immunotherapy; Rectal Neoplasms; Microsatellite Instability
PubMed: 36776899
DOI: 10.3389/fimmu.2023.1044353 -
Journal of the National Cancer Institute Aug 2023Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden....
Intratumoral microbes may have multifunctional roles in carcinogenesis. Microsatellite instability (MSI) is associated with higher tumor immunity and mutational burden. Using whole transcriptome and whole genome sequencing microbial abundance data, we investigated associations of intratumoral microbes with MSI, survival, and MSI-relevant tumor molecular characteristics across multiple cancer types including colorectal cancer (CRC), stomach adenocarcinoma, and endometrial carcinoma. Among 451 CRC patients, our key finding was strong associations of multiple CRC-associated genera, including Dialister and Casatella, with MSI. Dialister and Casatella abundance was associated with improved overall survival (hazard ratiomortality = 0.56, 95% confidence interval = 0.34 to 0.92, and hazard ratiomortality = 0.44, 95% confidence interval = 0.27 to 0.72), respectively, comparing higher relative to lower quantiles. Multiple intratumor microbes were associated with immune genes and tumor mutational burden. Diversity of oral cavity-originating microbes was also associated with MSI among CRC and stomach adenocarcinoma patients. Overall, our findings suggest the intratumor microbiota may differ by MSI status and play a role in influencing the tumor microenvironment.
Topics: Humans; Microsatellite Instability; Colorectal Neoplasms; Stomach Neoplasms; Adenocarcinoma; Tumor Microenvironment
PubMed: 37192013
DOI: 10.1093/jnci/djad083 -
Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer.Nature Cancer Oct 2021Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB)...
Immune evasion is a hallmark of cancer, and therapies that restore immune surveillance have proven highly effective in cancers with high tumor mutation burden (TMB) (e.g., those with microsatellite instability (MSI)). Whether low TMB cancers, which are largely refractory to immunotherapy, harbor potentially immunogenic neoantigens remains unclear. Here, we show that tumors from all patients with microsatellite stable (MSS) colorectal cancer (CRC) express clonal predicted neoantigens despite low TMB. Unexpectedly, these neoantigens are broadly expressed at lower levels compared to those in MSI CRC. Using a versatile platform for modulating neoantigen expression in CRC organoids and transplantation into the distal colon of mice, we show that low expression precludes productive cross priming and drives immediate T cell dysfunction. Strikingly, experimental or therapeutic rescue of priming rendered T cells capable of controlling tumors with low neoantigen expression. These findings underscore a critical role of neoantigen expression level in immune evasion and therapy response.
Topics: Animals; Antigens, Neoplasm; Colorectal Neoplasms; Humans; Immunotherapy; Mice; Microsatellite Instability; T-Lymphocytes
PubMed: 34738089
DOI: 10.1038/s43018-021-00247-z -
Biochemistry Jul 2023Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in...
Werner syndrome protein (WRN) is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers characterized by genomic microsatellite instability resulting from defects in DNA mismatch repair pathways. WRN's helicase activity is essential for the viability of these high microsatellite instability (MSI-H) cancers and thus presents a therapeutic opportunity. To this end, we developed a multiplexed high-throughput screening assay that monitors exonuclease, ATPase, and helicase activities of full-length WRN. This screening campaign led to the discovery of 2-sulfonyl/sulfonamide pyrimidine derivatives as novel covalent inhibitors of WRN helicase activity. The compounds are specific for WRN versus other human RecQ family members and show competitive behavior with ATP. Examination of these novel chemical probes established the sulfonamide NH group as a key driver of compound potency. One of the leading compounds, H3B-960, showed consistent activities in a range of assays (IC = 22 nM, = 40 nM, = 32 nM), and the most potent compound identified, H3B-968, has inhibitory activity IC ∼ 10 nM. These kinetic properties trend toward other known covalent druglike molecules. Our work provides a new avenue for screening WRN for inhibitors that may be adaptable to different therapeutic modalities such as targeted protein degradation, as well as a proof of concept for the inhibition of WRN helicase activity by covalent molecules.
Topics: Humans; Werner Syndrome; Exodeoxyribonucleases; RecQ Helicases; High-Throughput Screening Assays; Microsatellite Instability; Werner Syndrome Helicase; Neoplasms
PubMed: 37403936
DOI: 10.1021/acs.biochem.2c00599 -
Archives of Pathology & Laboratory... Oct 2022The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or...
Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer.
CONTEXT.—
The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.
OBJECTIVE.—
To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.
DESIGN.—
The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope.
RESULTS.—
Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract.
CONCLUSIONS.—
An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.
Topics: Female; Humans; Colorectal Neoplasms; DNA Mismatch Repair; Immune Checkpoint Inhibitors; Microsatellite Instability; Pathologists; Pathology, Molecular; Systematic Reviews as Topic
PubMed: 35920830
DOI: 10.5858/arpa.2021-0632-CP