Advertisement

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

  • Hisato Kawakami
  • Aziz Zaanan
  • Frank A. Sinicrope
Lower Gastrointestinal Cancers (AB Benson, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Lower Gastrointestinal Cancers

Opinion statement

TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12–15 % have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor-infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-fluorouracil (FU)-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.

Keywords

Colorectal cancer DNA mismatch repair Microsatellite instability Adjuvant chemotherapy 

Notes

Acknowledgments

FAS is supported by a National Cancer Institute Senior Scientist Award (Grant No. K05CA-142885). HK is supported by a fellowship grant from the Uehara Memorial Foundation.

Compliance with Ethics Guidelines

Conflict of Interest

Hisato Kawakami, Aziz Zaanan, and Frank A. Sinicrope declare that they have no conflict of interest.

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.

References and Recommended Reading

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

  1. 1.••
    Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–7. This paper provides valuable data on the molecular heterogeniety of CRC.Google Scholar
  2. 2.
    Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–87.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Buhard O, Cattaneo F, Wong YF, et al. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol. 2006;24:241–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–57.PubMedGoogle Scholar
  7. 7.
    Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998;95:6870–5.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011;155:69–79.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Boland CR. Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer. 2005;4:211–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Peltomaki P. Lynch syndrome genes. Fam Cancer. 2005;4:227–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Watson P, Vasen HF, Mecklin JP, et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123:444–9.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10.PubMedCrossRefGoogle Scholar
  13. 13.
    Domingo E, Niessen RC, Oliveira C, et al. BRAF-V600E is not involved in the colorectal tumorigenesis of HNPCC in patients with functional MLH1 and MSH2 genes. Oncogene. 2005;24:3995–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Vasen HF, Mecklin JP, Khan PM, et al. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991;34:424–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Toyota M, Issa JP. CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol. 1999;9:349–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Hughes LA, Khalid-de Bakker CA, Smits KM, et al. The CpG island methylator phenotype in colorectal cancer: progress and problems. Biochim Biophys Acta. 1825;2012:77–85.Google Scholar
  19. 19.
    Wang L, Cunningham JM, Winters JL, et al. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003;63:5209–12.PubMedGoogle Scholar
  20. 20.
    Tol J, Nagtegaal ID, Punt CJ. BRAF mutation in metastatic colorectal cancer. N Engl J Med. 2009;361:98–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Limsui D, Vierkant RA, Tillmans LS, et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J Natl Cancer Inst. 2010;102:1012–22.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.•
    Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60–00 trial. J Clin Oncol. 2010;28:466–74. This study showed that BRAF mutation was not prognostic for recurrence-free survival but was for overall survival, particularly in patients with MSI-L and MSI-S tumors.PubMedCrossRefGoogle Scholar
  23. 23.
    Sinicrope FA, Rego RL, Halling KC, et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology. 2006;131:729–37.PubMedCrossRefGoogle Scholar
  24. 24.
    Gafa R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer. 2000;89:2025–37.PubMedCrossRefGoogle Scholar
  25. 25.
    Halling KC, French AJ, McDonnell SK, et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst. 1999;91:1295–303.PubMedCrossRefGoogle Scholar
  26. 26.
    Lanza G, Gafa R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24:2359–67.PubMedCrossRefGoogle Scholar
  27. 27.
    Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917–23.PubMedGoogle Scholar
  28. 28.
    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.PubMedCrossRefGoogle Scholar
  29. 29.•
    Sinicrope FA, Shi Q, Smyrk TC, et al. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015;148:88–99. Stage-independent variability in clinical outcome and response to therapy is likely due to molecular heterogeneity. Using a combination of KRAS, BRAF and MMR status, useful subtyping of colon cancers for prognosis can be achieved as was shown in a large adjuvant chemotherapy trial.PubMedCrossRefGoogle Scholar
  30. 30.••
    Phipps AI, Limburg PJ, Baron JA, et al. Association between molecular subtypes of colorectal cancer and patient survival. Gastroenterology. 2015;148:77–87 e2. The findings suggest that the biologic distinctions between the subtypes based on combinations of tumor markers translate to important differences in survival.PubMedCrossRefGoogle Scholar
  31. 31.
    Roth AD, Delorenzi M, Tejpar S, et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst. 2012;104:1635–46.PubMedCrossRefGoogle Scholar
  32. 32.
    Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 2010;7:153–62.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Li LS, Morales JC, Veigl M, et al. DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets. Br J Pharmacol. 2009;158:679–92.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Davis TW, Wilson-Van Patten C, Meyers M, et al. Defective expression of the DNA mismatch repair protein, MLH1, alters G2-M cell cycle checkpoint arrest following ionizing radiation. Cancer Res. 1998;58:767–78.PubMedGoogle Scholar
  35. 35.
    Meyers M, Wagner MW, Hwang HS, et al. Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res. 2001;61:5193–201.PubMedGoogle Scholar
  36. 36.
    Koi M, Umar A, Chauhan DP, 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;54:4308–12.PubMedGoogle Scholar
  37. 37.
    Arnold CN, Goel A, Boland CR. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int J Cancer. 2003;106:66–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Fischer F, Baerenfaller K, Jiricny J. 5-Fluorouracil is efficiently removed from DNA by the base excision and mismatch repair systems. Gastroenterology. 2007;133:1858–68.PubMedCrossRefGoogle Scholar
  39. 39.••
    Sargent DJ, Marsoni S, Monges G, 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;28:3219–26. The study examined the prognostic and predictive impact of DNA mismatch repair status for 5-fluorouracil-based adjvuant chemotherapy.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29:1261–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Group QC. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370:2020–9.CrossRefGoogle Scholar
  43. 43.
    Sinicrope FA, Foster NR, Thibodeau SN, et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011;103:863–75.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.•
    Sargent DJ, Shi Q, Yothers G, et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): A pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol 2014;32:5 s, 2014 (suppl; abstr 3507). Study data confirm the lack of benefit of adjuvant 5-FU in stage II colon cancers with deficient mismatch repair.Google Scholar
  45. 45.
    Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343–51.PubMedCrossRefGoogle Scholar
  46. 46.
    Kuebler JP, Wieand HS, O'Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198–204.PubMedCrossRefGoogle Scholar
  47. 47.
    Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29:1465–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Fink D, Nebel S, Aebi S, et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 1996;56:4881–6.PubMedGoogle Scholar
  49. 49.
    Zaanan A, Flejou JF, Emile JF, et al. Defective mismatch repair status as a prognostic biomarker of disease-free survival in stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy. Clin Cancer Res. 2011;17:7470–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Zaanan A, Cuilliere-Dartigues P, Guilloux A, et al. Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin. Ann Oncol. 2010;21:772–80.PubMedCrossRefGoogle Scholar
  51. 51.
    Des Guetz G, Lecaille C, Mariani P, et al. Prognostic impact of microsatellite instability in colorectal cancer patients treated with adjuvant FOLFOX. Anticancer Res. 2010;30:4297–301.PubMedGoogle Scholar
  52. 52.
    Kim ST, Lee J, Park SH, et al. Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol. 2010;66:659–67.PubMedCrossRefGoogle Scholar
  53. 53.••
    Gavin PG, Colangelo LH, Fumagalli D, 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 Ass Cancer Res. 2012;18:6531–41. Important manuscript that examined biomarkers with clinical outcome in a large cohort of stage II and III colon cancer patients from a phase III clinical trials. Study found that BRAF mutations were associated with poor survival post-recurrence.CrossRefGoogle Scholar
  54. 54.
    Gavin PG, Paik S, Yothers G, et al. Colon cancer mutation: prognosis/prediction–response. Clin Cancer Res. 2013;19:1301.PubMedCrossRefGoogle Scholar
  55. 55.
    Flejou JF, Andre T, Chibaudel B, et al. Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study. J Clin Oncol. 2013;31.Google Scholar
  56. 56.
    Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012;307:1383–93.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.•
    Sinicrope FA, Mahoney MR, Smyrk TC, 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. 2013;31:3664–72. This paper revealed that the prognostic impact of dMMR on DFS was dependent on the primary tumor site in patients with stage III CRC treated with FOLFOX ± cetuximab as adjuvant chemotherapy.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Gonsalves WI, Mahoney MR, Sargent DJ, et al. Patient and tumor characteristics and BRAF and KRAS mutations in colon cancer, NCCTG/Alliance N0147. J Natl Cancer Inst. 2014;106.Google Scholar
  59. 59.
    Sha D, Lee AM, Shi Q, et al. Association study of the let-7 miRNA-complementary site variant in the 3' untranslated region of the KRAS gene in stage III colon cancer (NCCTG N0147 Clinical Trial). Clin Cancer Res. 2014;20:3319–27.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Sinicrope FA, Yoon HH, Mahoney MR, et al. Overall survival result and outcomes by KRAS, BRAF, and DNA mismatch repair in relation to primary tumor site in colon cancers from a randomized trial of adjuvant chemotherapy: NCCTG (Alliance) N0147. J Clin Oncol. 2014;32(5 s). suppl; abstr 3525.Google Scholar
  61. 61.
    Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol. 2007;25:3456–61.PubMedCrossRefGoogle Scholar
  62. 62.
    Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009;20:674–80.PubMedCrossRefGoogle Scholar
  63. 63.
    Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27:3117–25.PubMedCrossRefGoogle Scholar
  64. 64.
    Bertagnolli MM, Niedzwiecki D, Compton CC, 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. 2009;27:1814–21.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.•
    Klingbiel D, Saridaki Z, Roth AD, et al. Prognosis of stage II and III colon carcinoma treated with adjuvant 5-FU or FOLFIRI in relation to microsatellite status, results of the PETACC-3 trial. Ann Oncol 2015;26:126–32. Adjuvant study found that MSI-H was significantly associated with RFS in stage II and III colon cancer patients treated with 5-FU/LV alone or combined with irinotecan. However, the relationship with OS was only significant for stage II patients.Google Scholar
  66. 66.
    Allegra CJ, Yothers G, O'Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11–6.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.•
    Pogue-Geile K, Yothers G, Taniyama Y, et al. Defective mismatch repair and benefit from bevacizumab for colon cancer: findings from NSABP C-08. J Natl Cancer Inst. 2013;105:989–92. Adjuvant chemotherapy study in stage III colon cancer patients suggested the potential survival benefit of the addition of bevacizumab to FOLFOX compared to FOLFOX alone among patients with dMMR tumors.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Hisato Kawakami
    • 1
  • Aziz Zaanan
    • 1
  • Frank A. Sinicrope
    • 1
  1. 1.Mayo Clinic and Mayo Cancer CenterRochesterUSA

Personalised recommendations