Skip to main content

Advertisement

SpringerLink
Log in

Distinctive Tumor Biology of MSI-High Colorectal Cancer

  • Translational Colorectal Oncology (Y Jiang, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

High-frequency microsatellite instability (MSI-H) accounts for roughly 15 % of all cases of colorectal cancer (CRC) and results from pathogenic mutations or epigenetic changes in mismatch repair (MMR) proteins, primarily MLH1, MSH2, MSH6, and PMS2. These alterations can be inherited, as in the case of Lynch syndrome, or can be acquired sporadically, including cases of epigenetic alteration along crucial regulatory sequences. Cancers that develop in the setting of MSI-H possess a unique clinicopathologic phenotype, with a high degree of mutation resulting in potential recognition by the immune system. These features have directed therapeutic investigation in recent years to involve consideration of immune-stimulating agents, which might exploit the inherent immunogenicity of these tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: Cancer J Clin. 2015;65(1):5–29.

    Google Scholar 

  2. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology. 2010;138(6):2029–43. e10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Leslie A et al. The colorectal adenoma–carcinoma sequence. Br J Surg. 2002;89(7):845–60.

    Article  CAS  PubMed  Google Scholar 

  4. Bettington M et al. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology. 2013;62(3):367–86.

    Article  PubMed  Google Scholar 

  5. Grady W. Genomic instability and colon cancer. Cancer Metastasis Rev. 2004;23(1–2):11–27.

    Article  CAS  PubMed  Google Scholar 

  6. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Al-Sohaily S et al. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27(9):1423–31.

    Article  CAS  PubMed  Google Scholar 

  8. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138(6):2073–87. e3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.

    Article  CAS  PubMed  Google Scholar 

  10. Hughes LAE et al. The CpG island methylator phenotype in colorectal cancer: progress and problems. Biochimica et Biophysica Acta (BBA) - Rev Cancer. 2012;1825(1):77–85.

    Article  CAS  Google Scholar 

  11. Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability in colorectal cancer: prognostic, predictive, and therapeutic implications. Clin Cancer Res: Off J Am Assoc Cancer Res. 2012;18(6):1506–12.

    Article  CAS  Google Scholar 

  12. Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Archives Pathol Laboratory Med. 2011;135(10):1269–77.

    Article  CAS  Google Scholar 

  13. Dietmaier W et al. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997;57(21):4749–56.

    CAS  PubMed  Google Scholar 

  14. Tomlinson I et al. Does MSI-low exist? J Pathol. 2002;197(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  15. Halford S et al. Low-level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative trait. Cancer Res. 2002;62(1):53–7.

    CAS  PubMed  Google Scholar 

  16. González-García I et al. Standardized approach for microsatellite instability detection in colorectal carcinomas. J Natl Cancer Inst. 2000;92(7):544–9.

    Article  PubMed  Google Scholar 

  17. Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers. 2004;20(4–5):199–206.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The international collaborative group on hereditary nonpolyposis colorectal cancer. Gastroenterology. 1997;113(4):1146–58.

    Article  CAS  PubMed  Google Scholar 

  19. Bonadona V et al. CAncer risks associated with germline mutations in mlh1, msh2, and msh6 genes in lynch syndrome. JAMA. 2011;305(22):2304–10.

    Article  CAS  PubMed  Google Scholar 

  20. Lynch HT et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76(1):1–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Boland CR et al. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Familial Cancer. 2008;7(1):41–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chang DK et al. Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000;275(24):18424–31.

    Article  CAS  PubMed  Google Scholar 

  23. Kansikas M, Kariola R, Nystrom M. Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. Hum Mutat. 2011;32(1):107–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Peltomäki P. Epigenetic mechanisms in the pathogenesis of Lynch syndrome. Clin Genet. 2014;85(5):403–12.

    Article  PubMed  Google Scholar 

  25. Ollikainen M et al. Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene. 2007;26(31):4541–9.

    Article  CAS  PubMed  Google Scholar 

  26. Ward RL et al. Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry. Genet Med. 2013;15(1):25–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Ligtenberg MJL et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3[prime] exons of TACSTD1. Nat Genet. 2009;41(1):112–7.

    Article  CAS  PubMed  Google Scholar 

  28. Nagasaka T et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch syndrome colorectal cancers. Cancer Res. 2010;70(8):3098–108.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Weisenberger DJ et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38(7):787–93.

    Article  CAS  PubMed  Google Scholar 

  30. Parsons MT et al. Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification. J Med Genet. 2012;49(3):151–7.

    Article  CAS  PubMed  Google Scholar 

  31. Rodriguez-Soler M et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013;144(5):926–32. e1; quiz e13-4.

    Article  CAS  PubMed  Google Scholar 

  32. Mensenkamp AR et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in lynch syndrome-like tumors. Gastroenterology. 2014;146(3):643–646.e8. The authors show that two specific somatic mutations account for over half of the cases of MSI in patients without underlying germline mutations or promoter hyper-methylation.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang B et al. Antimetastatic role of Smad4 signaling in colorectal cancer. Gastroenterology. 2010;138(3):969–80. e1-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Parsons R et al. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995;55(23):5548–50.

    CAS  PubMed  Google Scholar 

  35. Jung B et al. Loss of activin receptor type 2 protein expression in microsatellite unstable colon cancers. Gastroenterology. 2004;126(3):654–9.

    Article  CAS  PubMed  Google Scholar 

  36. Rampino N et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997;275(5302):967–9.

    Article  CAS  PubMed  Google Scholar 

  37. Baba Y. PTGER2 overexpression in colorectal cancer is associated with microsatellite instability, independent of CpG island methylator phenotype. Cancer Epidemiol, Biomarkers Prev: Publ Am Assoc Cancer Res, Am Soc Prev Oncol. 2010;19(3):822–31.

    Article  CAS  Google Scholar 

  38. Calin GA et al. Genetic progression in microsatellite instability high (MSI-H) colon cancers correlates with clinico-pathological parameters: a study of the TGRbetaRII, BAX, hMSH3, hMSH6, IGFIIR and BLM genes. Int J Cancer J Int du Cancer. 2000;89(3):230–5.

    Article  CAS  Google Scholar 

  39. Nosho K et al. PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia. 2008;10(6):534–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Nosho K et al. Cyclin D1 is frequently overexpressed in microsatellite unstable colorectal cancer, independent of CpG island methylator phenotype. Histopathology. 2008;53(5):588–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Souza RF et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet. 1996;14(3):255–7.

    Article  CAS  PubMed  Google Scholar 

  42. Smyrk TC et al. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer. 2001;91(12):2417–22.

    Article  CAS  PubMed  Google Scholar 

  43. Prall F et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol. 2004;35(7):808–16.

    Article  CAS  PubMed  Google Scholar 

  44. Schwitalle Y et al. Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology. 2008;134(4):988–97.

    Article  CAS  PubMed  Google Scholar 

  45. Sherwood AM et al. Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunol, Immunotherapy: CII. 2013;62(9):1453–61. This article suggests presence of an adaptive immune response within CRC cells that varies in strength and breadth among patients.

    Article  CAS  Google Scholar 

  46. Buckowitz A et al. Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases. Br J Cancer. 2005;92(9):1746–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Alexander J et al. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol. 2001;158(2):527–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Kloor M et al. Clinical significance of microsatellite instability in colorectal cancer. Langenbeck’s archives of surgery / Deutsche Gesellschaft fur Chirurgie. 2014;399(1):23–31.

    Article  PubMed  Google Scholar 

  49. Jenkins MA et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007;133(1):48–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Thibodeau SN et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58(8):1713–8.

    CAS  PubMed  Google Scholar 

  51. Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23(3):609–18.

    Article  CAS  PubMed  Google Scholar 

  52. Sinicrope FA et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology. 2006;131(3):729–37.

    Article  CAS  PubMed  Google Scholar 

  53. Watanabe T et al. Chromosomal instability (CIN) phenotype, CIN high or CIN low, predicts survival for colorectal cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(18):2256–64.

    Article  Google Scholar 

  54. Gavin PG et al. Mutation profiling and microsatellite instability in stage II and III colon cancer: an assessment of their prognostic and oxaliplatin predictive value. Clin Cancer Res: Off J Am Assoc Cancer Res. 2012;18(23):6531–41.

    Article  CAS  Google Scholar 

  55. Koi M et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N’-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 1994;54(16):4308–12.

    CAS  PubMed  Google Scholar 

  56. Carethers JM et al. Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N’-nitro-N-nitrosoguanidine. J Clin Invest. 1996;98(1):199–206.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Hawn MT et al. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 1995;55(17):3721–5.

    CAS  PubMed  Google Scholar 

  58. Carethers JM et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999;117(1):123–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Fink D et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996;56(21):4881–6.

    CAS  PubMed  Google Scholar 

  60. Aebi S et al. Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res: Off J Am Assoc Cancer Res. 1997;3(10):1763–7.

    CAS  Google Scholar 

  61. Hemminki A et al. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology. 2000;119(4):921–8.

    Article  CAS  PubMed  Google Scholar 

  62. Elsaleh H et al. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet. 2000;355(9217):1745–50.

    Article  CAS  PubMed  Google Scholar 

  63. Ribic CM et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. de Vos tot Nederveen Cappel WH et al. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int J Cancer J Int du Cancer. 2004;109(3):468–71.

    Article  CAS  Google Scholar 

  65. Storojeva I et al. Prognostic and predictive relevance of microsatellite instability in colorectal cancer. Oncol Rep. 2005;14(1):241–9.

    CAS  PubMed  Google Scholar 

  66. Benatti P et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res: Off J Am Assoc Cancer Res. 2005;11(23):8332–40.

    Article  CAS  Google Scholar 

  67. Lanza G et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24(15):2359–67.

    Article  CAS  Google Scholar 

  68. Jover R et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut. 2006;55(6):848–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Kim GP et al. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a national cancer institute-national surgical adjuvant breast and bowel project collaborative study. J Clin Oncol: Off J Am Soc Clin Oncol. 2007;25(7):767–72.

    Article  CAS  Google Scholar 

  70. Des Guetz G et al. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45(10):1890–6.

    Article  CAS  PubMed  Google Scholar 

  71. Sargent DJ et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(20):3219–26.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Bertagnolli MM et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: cancer and leukemia group B protocol 89803. J Clin Oncol: Off J Am Soc Clin Oncol. 2009;27(11):1814–21.

    Article  CAS  Google Scholar 

  73. Klingbiel D et al. Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol. 2015;26(1):126–32.

    Article  CAS  PubMed  Google Scholar 

  74. des Guetz G et al. Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer. Anticancer Res. 2007;27(4C):2715–9.

    PubMed  Google Scholar 

  75. Kim ST et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol. 2010;66(4):659–67.

    Article  CAS  PubMed  Google Scholar 

  76. Sinicrope FA et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31(29):3664–72. The study demonstrates differences in prognosis for stage III MMR-deficient CRC based on tumor site and degree of lymph node involvement.

    Article  CAS  Google Scholar 

  77. Le DT et al. PD-1 blockade in tumors with mismatch-repair deficiency. New England Journal of Medicine, 2015. The article provides evidence for efficacy of immune checkpoint blockade in the treatment of metastastic, MMR-deficient CRC.

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Neil Majithia declares that he has no conflict of interest.

Benjamin R. Kipp has received support through a grant from Abbott Molecular, Inc.

Axel Grothey has received support through research grants to the Mayo Foundation from Genentech, Bayer, Eisai, BBI, and Eli Lilly.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Neil Majithia

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Benjamin R. Kipp

  3. Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Axel Grothey

Authors
  1. Neil Majithia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin R. Kipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Axel Grothey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Axel Grothey.

Additional information

This article is part of the Topical Collection on Translational Colorectal Oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Majithia, N., Kipp, B.R. & Grothey, A. Distinctive Tumor Biology of MSI-High Colorectal Cancer. Curr Colorectal Cancer Rep 11, 281–287 (2015). https://doi.org/10.1007/s11888-015-0283-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11888-015-0283-4

Keywords

Search

Navigation