Microsatellite instability: a review of what the oncologist should know

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Abstract

The patients with high microsatellite instability (MSI-H)/mismatch repair deficient (dMMR) tumors recently have been reported that can benefit from immunotherapy, and MSI can be used as a genetic instability of a tumor detection index. However, many studies have shown that there are many heterogeneous phenomena in patients with MSI tumors in terms of immunotherapy, prognosis and chemotherapy sensitivity. Here we mainly review the research results of MSI detection methods, the mechanisms of MSI occurrence and its relationship with related tumors, aiming to make a brief analysis of the current research status of MSI and provide comparable reference and guidance value for further research in this field.

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Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Zachary Chalmers, Caitlin Connelly, David Fabrizio … (2017)

Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.

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Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

Rebecca Moss, Michael Axelson, Andrew Hill … (2017)

Metastatic DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer has a poor prognosis after treatment with conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators. All of these features are associated with the response to PD-1 blockade in other tumour types. Therefore, we aimed to study nivolumab, a PD-1 immune checkpoint inhibitor, in patients with dMMR/MSI-H metastatic colorectal cancer.

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Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer

Michael Overman, Sara Lonardi, Ka Wong … (2018)

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC.

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Author and article information

Contributors

Hui Luo: luohui@gdmu.edu.cn

Xiao Zhu:

ORCID: http://orcid.org/0000-0002-1737-3386

bioxzhu@yahoo.com , xzhu@gdmu.edu.cn

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 13 January 2020

Publication date PMC-release: 13 January 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 16

Affiliations

[1 ]ISNI 0000 0004 1760 3078, GRID grid.410560.6, Guangdong Key Laboratory for Research and Development of Natural Drugs, , Guangdong Medical University, ; Zhanjiang, 524023 China

[2 ]ISNI 0000 0004 1760 3078, GRID grid.410560.6, The Marine Biomedical Research Institute, Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang, , Guangdong Medical University, ; Zhanjiang, 524023 China

[3 ]ISNI 0000 0004 1760 3078, GRID grid.410560.6, Cancer Center, , The Affiliated Hospital, Guangdong Medical University, ; Zhanjiang, 524023 China

Author information

Xiao Zhu http://orcid.org/0000-0002-1737-3386

Article

Publisher ID: 1091

DOI: 10.1186/s12935-019-1091-8

PMC ID: 6958913

PubMed ID: 31956294

SO-VID: 7e503b5a-c09c-46d0-b95f-8372db805363

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 October 2019

Date accepted : 28 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81541153

Award Recipient : Xiao Zhu

Funded by: Southern Science and Engineering Guangdong Laboratory Zhanjiang

Award ID: ZJW-2019-07

Award Recipient : Hui Luo

Funded by: The Public Service Platform of South China for R&D Biomedicine Resources

Award ID: GDMUK201808

Award Recipient : Xiao Zhu

Funded by: Guangdong Provincial Science and Technology Programs

Award ID: 2016A050503046, 2015A050502048

Award ID: 2016B030309002

Award Recipient : Xiao Zhu

Funded by: Zhanjiang Science and Technology Plan

Award ID: 2017A06012

Award Recipient : Xiao Zhu

Funded by: “Group-type” Special Supporting Project for Educational Talents in Universities

Award ID: 4SG19057G

Award Recipient : Xiao Zhu

Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;

Award ID: 2018A030310155

Award Recipient : Haiqing Luo

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: msi,cancer,msi-h/dmmr,microsatellite dna

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: msi, cancer, msi-h/dmmr, microsatellite dna

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Microsatellite instability: a review of what the oncologist should know

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Karger: Oncology

Most cited references 100

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer

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Cited by 174

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