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Chemotherapy of MMR-deficient colorectal cancer

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Abstract

Colorectal cancer (CRC) continues to rank as the third most common cancer in Western society and the second leading cause of cancer death in North America. There are at least three distinct, and relatively discreet, molecular pathways associated with this disease: chromosomal instability (CIN), microsatellite instability (MSI) and the cytosine polyguanine island methylator phenotype. Defects in the DNA mismatch repair system (MMR) account for the MSI phenotype and genotype of about 15 % of CRC. Although high frequency MSI tumors have better stage independent prognosis compared to those with CIN, MMR deficient CRC appears to be resistant to fluorouracil based treatment, but sensitive to other therapeutic regimens. This review summarises current literature on differential chemosensitivity of MMR-deficient CRC.

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References

  1. Landis SH et al (1999) Cancer statistics. CA Cancer J Clin 49(1):8–31, 1

  2. Lynch HT (1985) Classics in oncology. Aldred Scott Warthin, M.D., Ph.D (1866–1931). CA Cancer J Clin 35(6):345–347

  3. Lynch HT et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549

    PubMed  CAS  Google Scholar 

  4. Fishel R et al (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75(5):1027–1038

    Article  PubMed  CAS  Google Scholar 

  5. Leach FS et al (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75(6):1215–1225

    Article  PubMed  CAS  Google Scholar 

  6. Peltomaki P et al (1993) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260(5109):810–812

    Article  PubMed  CAS  Google Scholar 

  7. Nishisho I et al (1991) Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253(5020):665–669

    Article  PubMed  CAS  Google Scholar 

  8. Parsons R et al (1995) Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res 55(23):5548–5550

    PubMed  CAS  Google Scholar 

  9. Rampino N et al (1997) Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275(5302):967–969

    Article  PubMed  CAS  Google Scholar 

  10. de la Chapelle A, Hampel H (2010) Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 28(20):3380–3387

    Article  PubMed  Google Scholar 

  11. Lindor NM et al (2002) Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20(4):1043–1048

    Article  PubMed  CAS  Google Scholar 

  12. Boland CR et al (1998) 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 58(22):5248–5257

    PubMed  CAS  Google Scholar 

  13. Poynter JN et al (2008) Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 17(11):3208–3215

    Article  PubMed  CAS  Google Scholar 

  14. Sinicrope FA (2010) DNA mismatch repair and adjuvant chemotherapy in sporadic colon cancer. Nat Rev Clin Oncol 7(3):174–177

    Article  PubMed  CAS  Google Scholar 

  15. Jass JR et al (1998) Morphology of sporadic colorectal cancer with DNA replication errors. Gut 42(5):673–679

    Article  PubMed  CAS  Google Scholar 

  16. Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260(5109):816–819

    Article  PubMed  CAS  Google Scholar 

  17. Lanza G et al (2006) Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol 24(15):2359–2367

    Article  PubMed  CAS  Google Scholar 

  18. Sinicrope FA et al (2006) Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131(3):729–737

    Article  PubMed  CAS  Google Scholar 

  19. Samowitz WS et al (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10(9):917–923

    PubMed  CAS  Google Scholar 

  20. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23(3):609–618

    Article  PubMed  CAS  Google Scholar 

  21. Gryfe R et al (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342(2):69–77

    Article  PubMed  CAS  Google Scholar 

  22. Hutchins G et al (2011) Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29(10):1261–1270

    Article  PubMed  Google Scholar 

  23. Moertel CG et al (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322(6):352–358

    Article  PubMed  CAS  Google Scholar 

  24. O’Connell MJ et al (1998) Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16(1):295–300

    PubMed  Google Scholar 

  25. Wolmark N et al (1993) The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11(10):1879–1887

    PubMed  CAS  Google Scholar 

  26. Wolmark N et al (1999) Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes’ B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 17(11):3553–3559

    PubMed  CAS  Google Scholar 

  27. Andre T et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350(23):2343–2351

    Article  PubMed  CAS  Google Scholar 

  28. Kuebler JP et al (2007) 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 25(16):2198–2204

    Article  PubMed  CAS  Google Scholar 

  29. Andre T et al (2009) Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27(19):3109–3116

    Article  PubMed  CAS  Google Scholar 

  30. Ribic CM et al (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257

    Article  PubMed  CAS  Google Scholar 

  31. Benson AB 3rd et al (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22(16):3408–3419

    Article  PubMed  Google Scholar 

  32. Kim GP et al (2007) 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 25(7):767–772

    Article  PubMed  CAS  Google Scholar 

  33. Elsaleh H et al (2000) Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355(9217):1745–1750

    Article  PubMed  CAS  Google Scholar 

  34. Hemminki A et al (2000) Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 119(4):921–928

    Article  PubMed  CAS  Google Scholar 

  35. Sargent DJ et al (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20):3219–3226

    Article  PubMed  CAS  Google Scholar 

  36. Meyers M et al (2001) Role of the hMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses. Cancer Res 61(13):5193–5201

    PubMed  CAS  Google Scholar 

  37. Arnold CN, Goel A, Boland CR (2003) Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int J Cancer 106(1):66–73

    Article  PubMed  CAS  Google Scholar 

  38. Pocard M et al (2000) Response to 5-fluorouracil of orthotopically xenografted human colon cancers with a microsatellite instability: influence of P53 status. Anticancer Res 20(1A):85–90

    PubMed  CAS  Google Scholar 

  39. Parker WB, Cheng YC (1990) Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther 48(3):381–395

    Article  PubMed  CAS  Google Scholar 

  40. Nehme A et al (1997) Differential induction of c-Jun NH2-terminal kinase and c-Abl kinase in DNA mismatch repair-proficient and -deficient cells exposed to cisplatin. Cancer Res 57(15):3253–3257

    PubMed  CAS  Google Scholar 

  41. Fink D et al (1997) In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res 57(10):1841–1845

    PubMed  CAS  Google Scholar 

  42. des Guetz G et al (2007) Microsatellite instability and sensitivitiy to FOLFOX treatment in metastatic colorectal cancer. Anticancer Res 27(4C):2715–2719

    PubMed  Google Scholar 

  43. Kim ST et al (2010) Clinical impact of microsatellite instability in colon cancer following adjuvant FOLFOX therapy. Cancer Chemother Pharmacol 66(4):659–667

    Article  PubMed  CAS  Google Scholar 

  44. Kim ST et al (2010) The effect of DNA mismatch repair (MMR) status on oxaliplatin-based first-line chemotherapy as in recurrent or metastatic colon cancer. Med Oncol 27(4):1277–1285

    Article  PubMed  CAS  Google Scholar 

  45. Zaanan A et al (2010) 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 21(4):772–780

    Article  PubMed  CAS  Google Scholar 

  46. Jacob S et al (2001) The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res 61(17):6555–6562

    PubMed  CAS  Google Scholar 

  47. Magrini R et al (2002) Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 101(1):23–31

    Article  PubMed  CAS  Google Scholar 

  48. Charara M et al (2004) Microsatellite status and cell cycle associated markers in rectal cancer patients undergoing a combined regimen of 5-FU and CPT-11 chemotherapy and radiotherapy. Anticancer Res 24(5B):3161–3167

    PubMed  CAS  Google Scholar 

  49. Fallik D et al (2003) Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res 63(18):5738–5744

    PubMed  CAS  Google Scholar 

  50. Vincent F et al (2009) Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. Cancer Res 69(7):2853–2860

    Article  PubMed  CAS  Google Scholar 

  51. Bolderson E et al (2004) ATM is required for the cellular response to thymidine induced replication fork stress. Hum Mol Genet 13(23):2937–2945

    Article  PubMed  CAS  Google Scholar 

  52. Martin SA et al (2009) Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol Med 1(6–7):323–337

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

    N. Devaud & S. Gallinger

  2. Toronto General Hospital, University Health Network (UHN), Toronto, Canada

    S. Gallinger

  3. Hepatobiliary/Pancreatic Surgical Oncology Program, Toronto General Hospital, University of Toronto, 200 Elizabeth St, 10EN, Room 206, Toronto, ON, M5G2C4, Canada

    S. Gallinger

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  1. N. Devaud
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Correspondence to S. Gallinger.

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Devaud, N., Gallinger, S. Chemotherapy of MMR-deficient colorectal cancer. Familial Cancer 12, 301–306 (2013). https://doi.org/10.1007/s10689-013-9633-z

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