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Microsatellite instability in cancer: a novel landscape for diagnostic and therapeutic approach

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Abstract

Defective DNA mismatch repair creates a strong mutator phenotype, recognized as microsatellite instability (MSI). Various next-generation sequencing-based methods for evaluating cancer MSI status have been established, and NGS-based studies have thoroughly described MSI-driven tumorigenesis. Accordingly, high-frequency MSI (MSI-H) has been detected in 81 tumor types, including those in which MSI was previously underrated. The findings have increased the use of immunotherapy, which is assumed to be efficient in tumors having a high mutation burden and/or neoantigen load. In MSI tumorigenesis, positively and negatively selected driver gene mutations have been characterized in colorectal cancers. Recent advancements in genome-wide studies of MSI-H cancers have developed novel diagnostic and therapeutic approaches, including CXCR2 inhibitor, a synthetic lethal therapy targeting the Werner gene and inhibition of nonsense-mediated mRNA decay. MSI is a predictive marker for chemotherapy as well as immunotherapy. Thus, analyses of MSI status and MSI-related alterations in cancers are clinically relevant. We present an update on MSI-driven tumorigenesis, focusing on a novel landscape of diagnostic and therapeutic approaches.

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References

  • Aaltonen LA, Peltomaki P, Leach FS et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816

    Article  CAS  PubMed  Google Scholar 

  • Ballal VVJ (2014) Oral medicine: Amlexanox. Br Dent J 217:208

    Article  PubMed  Google Scholar 

  • Behan FM, Iorio F, Picco G et al (2019) Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568:511–516

    Article  CAS  PubMed  Google Scholar 

  • Bhuvanagiri M, Schlitter AM, Hentze MW, Kulozik AE (2010) NMD: RNA biology meets human genetic medicine. Biochem J 430:365–377

    Article  CAS  PubMed  Google Scholar 

  • Bokhari A, Jonchere V, Lagrange A et al (2018) Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability. Oncogenesis 7:70

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chan WK, Bhalla AD, Le Hir H et al (2009) A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat Struct Mol Biol 16:747–753

    Article  CAS  PubMed  Google Scholar 

  • Chan EM, Shibue T, McFarland JM et al (2019) WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature 568:551–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang L, Chang M, Chang HM, Chang F (2018) Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol 26:e15–e21

    CAS  PubMed  Google Scholar 

  • Corso S, Isella C, Bellomo SE et al (2019) A comprehensive PDX gastric cancer collection captures cancer cell-intrinsic transcriptional MSI traits. Cancer Res 79:5884–5896

    Article  CAS  PubMed  Google Scholar 

  • Domingo E, Freeman-Mills L, Rayner E et al (2016) Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol 1:207e16

    Article  Google Scholar 

  • El-Bchiri J, Buhard O, Penard-Lacronique V et al (2005) Differential nonsense mediated decay of mutated mRNAs in mismatch repair deficient colorectal cancers. Hum Mol Genet 14:2435–2442

    Article  CAS  PubMed  Google Scholar 

  • El-Bchiri J, Guilloux A, Dartigues P et al (2008) Nonsense-mediated mRNA decay impacts MSI-driven carcinogenesis and anti-tumor immunity in colorectal cancers. PLoS One 3:e2583

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eso Y, Shimizu T, Takeda H, Takai A, Marusawa H (2020) Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers. J Gastroenterol 55:15–26

    Article  CAS  PubMed  Google Scholar 

  • Foltz SM, Liang WW, Xie M, Ding L (2017) MIRMMR: binary classification of microsatellite instability using methylation and mutations. Bioinformatics 33:3799–3801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujimoto A, Fujita M, Hasegawa T, Wong JH, Maejima K, Oku-Sasaki A, Nakano K, Shiraishi Y, Miyano S, Yamamoto G, Akagi K, Imoto S, Nakagawa H (2020) Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types. Genome Res 30:334–346

    Article  PubMed Central  Google Scholar 

  • Galon J, Angell HK, Bedognetti D, Marincola FM (2013) The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 39:11–26

    Article  CAS  PubMed  Google Scholar 

  • Ganesh K, Stadler ZK, Cercek A et al (2019) Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol 16:361–375

    Article  PubMed  PubMed Central  Google Scholar 

  • Gargiulo P, Della Pepa C, Berardi S et al (2016) Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated endometrial cancers: new candidates for checkpoint blockade immunotherapy? Cancer Treat Rev 48:61–68

    Article  CAS  PubMed  Google Scholar 

  • Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S (2016) The evolving role of microsatellite instability in colorectal cancer: a review. Cancer Treat Rev 51:19–26

    Article  CAS  PubMed  Google Scholar 

  • Georgiadis A, Durham JN, Keefer LA et al (2019) Noninvasive detection of microsatellite instability and high tumor mutation burden in cancer patients treated with PD-1 blockade. Clin Cancer Res 25:7024–7034

    Article  PubMed  PubMed Central  Google Scholar 

  • Hänggi K, Ruffell B (2019) Oncogenic KRAS drives immune suppression in colorectal cancer. Cancer Cell 35:535–537

    Article  PubMed  CAS  Google Scholar 

  • Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirata T, Yamamoto H, Taniguchi H et al (2007) Characterization of the immune escape phenotype of human gastric cancers with and without high-frequency microsatellite instability. J Pathol 211:516–523

    Article  CAS  PubMed  Google Scholar 

  • Hirotsu Y, Nagakubo Y, Amemiya K et al (2020) Microsatellite instability status is determined by targeted sequencing with MSIcall in 25 cancer types. Clin Chim Acta 502:207–213

    Article  CAS  PubMed  Google Scholar 

  • Imai K, Yamamoto H (2008) Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 29:673–680

    Article  CAS  PubMed  Google Scholar 

  • Innocenti F, Ou FS, Qu X et al (2019) Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol 37:1217–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561

    Article  CAS  PubMed  Google Scholar 

  • Jonchere V, Marisa L, Greene M et al (2018) Identification of positively and negatively selected driver gene mutations associated with colorectal cancer with microsatellite instability. Cell Mol Gastroenterol Hepatol 6:277–300

    Article  PubMed  PubMed Central  Google Scholar 

  • Kategaya L, Perumal SK, Hager JH, Belmont LD (2019) Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience 13:488–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kather JN, Pearson AT, Halama N et al (2019) Deep learning can predict microsatellite instability directly from histology in gastrointestinal cancer. Nat Med 25:1054–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katoh H, Wang D, Daikoku T et al (2013) CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24:631–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawasaki T, Ohnishi M, Suemoto Y et al (2008) WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer. Mod Pathol 21:150–158

    Article  CAS  PubMed  Google Scholar 

  • Lazzari L, Corti G, Picco G et al (2019) Patient-derived xenografts and matched cell lines identify pharmacogenomic vulnerabilities in colorectal cancer. Clin Cancer Res 25:6243–6259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le DT, Durham JN, Smith KN et al (2017) Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le DT, Kim TW, Van Cutsem E et al (2020) Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-jigh/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 38:11–19

    Article  CAS  PubMed  Google Scholar 

  • Liao W, Overman MJ, Boutin AT et al (2019) KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 35:559–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lieb S, Blaha-Ostermann S, Kamper E et al (2019) Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. Elife. 8:e43333

    Article  PubMed  PubMed Central  Google Scholar 

  • Llosa NJ, Cruise M, Tam A et al (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43–51

    Article  CAS  PubMed  Google Scholar 

  • Llosa NJ, Luber B, Siegel N et al (2019) Immunopathologic stratification of colorectal cancer for checkpoint blockade immunotherapy. Cancer Immunol Res 7:1574–1579

    Article  PubMed  PubMed Central  Google Scholar 

  • Mandal R, Samstein RM, Lee KW et al (2019) Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 364:485–491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marabelle A, Le DT, Ascierto PA et al (2020) Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 38:1–10

    Article  CAS  PubMed  Google Scholar 

  • McGranahan N, Furness AJS, Rosenthal R et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mittica G, Ghisoni E, Giannone G et al (2017) Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget 8:90532–90544

    Article  PubMed  PubMed Central  Google Scholar 

  • Mlecnik B, Bindea G, Angell HK et al (2016) Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability. Immunity 44:698–711

    Article  CAS  PubMed  Google Scholar 

  • Nebot-Bral L, Brandao D, Verlingue L et al (2017) Hypermutated tumours in the era of immunotherapy: the paradigm of personalised medicine. Eur J Cancer 84:290–303

    Article  CAS  PubMed  Google Scholar 

  • O’Neil BH, Wallmark JM, Lorente D et al (2017) Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PLoS One 12:e0189848

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Overman MJ, McDermott R, Leach JL et al (2017) Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 18:1182–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Overman MJ, Lonardi S, Wong KYM et al (2018) Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 36:773–779

    Article  CAS  PubMed  Google Scholar 

  • Ozcan M, Janikovits J, von Knebel Doeberitz M, Kloor M (2018) Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology 7:e1445453

    Article  PubMed  PubMed Central  Google Scholar 

  • Panda A, Mehnert JM, Hirshfield KM et al (2018) Immune activation and benefit from Avelumab in EBV-positive gastric cancer. J Natl Cancer Inst 110:316–320

    Article  CAS  PubMed  Google Scholar 

  • Popp MW, Maquat LE (2018) Nonsense-mediated mRNA decay and cancer. Curr Opin Genet Dev 48:44–50

    Article  CAS  PubMed  Google Scholar 

  • Razavi P, Li BT, Brown DN et al (2019) High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Nat Med 25:1928–1937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruiz-Bañobre J, Goel A (2019) DNA mismatch repair deficiency and immune checkpoint inhibitors in gastrointestinal cancers. Gastroenterology 156:890–903

    Article  PubMed  CAS  Google Scholar 

  • Russo M, Crisafulli G, Sogari A et al (2019) Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366:1473–1480

    Article  CAS  PubMed  Google Scholar 

  • Schrock AB, Ouyang C, Sandhu J et al (2019) Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 30:1096–1103

    Article  CAS  PubMed  Google Scholar 

  • Steele CW, Karim SA, Leach JDG et al (2016) CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancre- atic ductal adenocarcinoma. Cancer Cell 29:832–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thibodeau S, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819

    Article  CAS  PubMed  Google Scholar 

  • Usuki F, Yamashita A, Higuchi I et al (2004) Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich’s disease. Ann Neurol 55:740–744

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Liang C (2018) MSIpred: a python package for tumor microsatellite instability classification from tumor mutation annotation data using a support vector machine. Sci Rep 8:17546

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yamamoto H, Imai K (2015) Microsatellite instability: an update. Arch Toxicol 89:899–921

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto H, Imai K (2019) An updated review of microsatellite instability in the era of next-generation sequencing and precision medicine. Semin Oncol 46:261–270

    Article  PubMed  Google Scholar 

  • Yamamoto H, Adachi Y, Taniguchi H et al (2012) The interrelationship between microsatellite instability and microRNA in gastrointestinal cancer. World J Gastroenterol 18:2745–2755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto H, Watanabe Y, Maehata T et al (2014) An updated review of gastric cancer in the next-generation sequencing era: insights from bench to bedside and vice versa. World J Gastroenterol 20:3927–3937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Japan

    Hiroyuki Yamamoto, Yoshiyuki Watanabe, Tadateru Maehata & Fumio Itoh

  2. Department of Internal Medicine, Kawasaki Rinko General Hospital, Kawasaki, Japan

    Yoshiyuki Watanabe

  3. The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Kohzoh Imai

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  1. Hiroyuki Yamamoto
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  2. Yoshiyuki Watanabe
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  3. Tadateru Maehata
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  4. Kohzoh Imai
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  5. Fumio Itoh
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Correspondence to Hiroyuki Yamamoto.

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Yamamoto, H., Watanabe, Y., Maehata, T. et al. Microsatellite instability in cancer: a novel landscape for diagnostic and therapeutic approach. Arch Toxicol 94, 3349–3357 (2020). https://doi.org/10.1007/s00204-020-02833-z

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