Microsatellite instability in colorectal cancer

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Microsatellite instability in colorectal cancer

Background. Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10-20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI-H) means MS differ in normal and cancer cells of an individual. The cause of MSI-H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6.

Conclusions. MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC.

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  • Weitz J Koch M Debus J Höhler T Galle PR Büchler MW. Colorectal cancer. Lancet 2005; 365: 153-65.

  • Primic-Žakelj M Zadnik V Žagar T Zakotnik B. Survival of cancer patients diagnosed in 1991-2005 in Slovenia. Ljubljana: Institute of Oncology Ljubljana Cancer Registry of Republic of Slovenia; 2009.

  • Cancer incidence in Slovenia 2007. Ljubljana: Institute of Oncology Ljubljana Cancer Registry of Republic of Slovenia; 2010.

  • Velenik V. Post-treatment surveillance in colorectal cancer. Radiol Oncol 2010; 44: 135-41.

  • Zhou YL Boardman LA Miller RC. Genetic testing for young-onset colorectal cancer: case report and evidence-based clinical guidelines. Radiol Oncol 2010; 44: 57-61.

  • Fearon ER Vogelstein B. A genetic model for colorectal tumourogenesis. Cell 1990; 61: 759-67.

  • West NJ Courtney EDY Poullis AP Leicester RJ. Apoptosis in the colonic crypt colorectal adenomata and manipulation by chemoprevention. Cancer Epidemiol Biomarkers Prev 2009; 18: 1680-7.

  • Duval A Hamelin R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res 2002; 62: 2447-54.

  • Lynch JP Hoops TC. The genetic pathogenesis of colorectal cancer. Hemat Oncol Clin N Am 2002; 16: 775-810.

  • Kondo Y Issa JPJ. Epigenetic changes in colorectal cancer. Cancer Met Rev 2004; 23: 29-39.

  • Kozuka S Nogaki M Ozeki T Masumori S. Premalignancy of the mucosal polyp in the large intestine. Estimation of the periods required for malignant transformation of mucosal polyps. Dis Colon Rectum 1975; 18: 494-500.

  • Kinzler K Vogelstein B. Gatekeepers and caretakers. Nature 1997; 386: 761-3.

  • Grady WM. Genomic instability and colon cancer. Cancer Metast Rev 2004; 23: 11-27.

  • Stoler DL Chen N Basik M Kahlenberg MS Rodriguez-Bigas MA Petrelli NJ et al. The onset and extent of genomic instability in sporadic colorectal tumour progression. Proc Natl Acad Sci USA 1999; 96: 15121-6.

  • Law DJ Olschwang S Monpezat J-P. Concerted nonsystemic allelic loss in human colorectal carcinoma. Science 1988; 241: 961-5.

  • Paulovich AG Toczyski DP Hartwell LH. When checkpoints fail. Cell 1997; 88: 315-21.

  • Vogelstein B Fearon ER Hamilton SR Kern SE Preisinger AC Leppert M et al. Genetic alterations during colorectal tumour development. N Engl J Med 1988; 319: 525-32.

  • Powell SM Zilz N Beazer-Barclay Y. APC mutations occur early during colorectal oncogenesis. Nature 1992; 359: 235-7.

  • Lenglauer C Kinzler KW Vogelstein B. Genetic instability in colorectal cancers. Nature 1997; 386: 623-7.

  • Jass JR Whitehall VLJ Young J Leggett BA. Emerging concepts in colorectal neoplasia. Gastroenterology 2002; 123: 862-76.

  • Thibodeau SN Bren G Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260: 816-9.

  • Worthley DL Leggett BA. Colorectal cancer: Molecular features and clinical opportunities. Clin Biochem Rev 2010; 31: 31-8.

  • De la Chapelle A Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 2010; 28: 3380-7.

  • Radman M Wagner R. Carcinogenesis. Missing mismatch repair. Nature 1993; 366: 722.

  • McClulloch SD Kunkel TA. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 2008; 18: 148-61.

  • Eshleman JR Markowitz SD. Mismatch repair defects in human carcinogenesis. Hum Mol Genet 1996; 5: 1489-94.

  • Umar A Boland CR Terdiman JP. Revised Bethesda guidelines for hereditary non-poliposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004; 96: 261-8.

  • Jover R Zapater P Castells A Llor X Andreu M Cubiella J et al. Mismatch repair status in the prediction of benefit from adjuvant Flourouracil chemotherapy in colorectal cancer. Gut 2006; 55: 848-55.

  • Niv Y. Microsatellite instability and MLH1 promoter hypermetalition in colorectal cancer. World J Gastroenterol 2007; 13: 1767-9.

  • Liang JT Huang KC Lai HS Lee PH Cheng YM Hsu HC et al. High frequency microsatellite instability predicts better chemosensitivity to high dose 5-fluorouracil plus Leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer 2002; 101: 519-25.

  • Markowitz S Wang J Myeroff L Parsons R Sun L Lutterbaugh J et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995; 268: 1336-8.

  • Lawes DA SenGupta S Boulos PB. The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol 2003; 29: 201-12.

  • Modrich P. Mechanisms and biological effects of mismatch repair. Ann Rev Genet 1991; 25: 229-53.

  • Joseph N Duppatla V Rao DN. Prokaryotic DNA mismatch repair. Prog Nucleic Acid Res 2006; 81: 1-49.

  • Iyer R Pluciennik A Modrich P Modrich PL. DNA mismatch repair: functions and mechanisms. Chem Rev 2006; 106: 302-23.

  • Hsieh P Yamane K. DNA mismatch repair: Molecular mechanisms cancer and ageing. Mech Ageing Dev 2008; 129: 391-407.

  • Shibata D Peinado MA Ionov Y Malkhosyan S Perucho M. Genomic instability in repeated sequences is an early somatic event in colorectal tumorogenesis that persists after transformation. Nat Genet 1994; 6: 273-81.

  • Warusavitarne J Schnitzler M. The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer. Int J Colorectal Dis 2007; 22: 739-48.

  • Aaltonen LA Peltomaki P Leach FS Sistonen P Pylkkänen L Mecklin JP et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260: 812-6.

  • Gryfe R Kim H Hsieh ETK Aronson MD Holowaty EJ Bull SB et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000; 342: 69-77.

  • Hemminki A Mecklin JP Jarvinen H Aaltonen LA Joensuu H. Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 2000; 119: 921-8.

  • Popat S Hubner R Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005; 23: 609-18.

  • Lim SB Jeong SY Lee MR Ku JL Shin YK Kim WH et al. Prognostic signifance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis 2004; 19: 533-7.

  • Fink D Nebel S Aebi S Zheng H Cenni B Nehmé A et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res 1996; 56: 4881-6.

  • Vaisman A Varchenko M Umar A Kunkel TA Risinger JI Barrett JC et al. The role of hMLH1 hMSH3 and hMSH6 defects in Cisplatin and Oxaliplatin resistance: correlation with replicative bypass of platinum-DNA adducts. Cancer Res 1998; 58: 3579-85.

  • Bras-Goncalves RA Rosty C Laurent-Puig P Soulié P Dutrillaux B Poupon MF. Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of microsatellite instability and p53 status. Br J Cancer 2000; 82: 913-23.

  • Aebi S Kurdi-Haidar B Gordon R Cenni B Zheng H Fink D et al. Loss of DNA mismatch repair in acquired resistance to Cisplatin. Cancer Res 1996; 56: 3087-90.

  • Fallik D Borrini F Boige V Viguier J Jacob S Miquel C et al. Microsatellite instability is a predictive factor of the tumor response to Irinotecan in patients with advanced colorectal cancer. Cancer Res 2003; 63: 5738-44.

  • Rothenberg ML Meropol NJ Poplin EA Van Cutsem E Wadler S. Mortality associated with Irinotecan plus bolus Flourouracil/Leucovorin. Summary findings of an independent panel. J Clin Oncol 2001; 19: 3801-7.

  • Braun MS Richman SD Thompson L Daly CL Meade AM Adlard JW et al. Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: The FOCUS trial. J Clin Oncol 2009; 27: 5519-28.

  • Ocvirk J. Advances in the treatment of metastatic colorectal carcinoma. Radiol Oncol 2009; 43: 1-8.

  • Adlard JW Richman SD Seymour MT Quirke P. Prediction of the response of colorectal cancer to systemic therapy. Lancet Oncol 2002; 8: 75-82.

  • Fischer F Baerenfaller K Jiricny J. 5-flourouracil is efficiently removed from DNA by the base excision and mismatch repair systems. Gastroenterology 2007; 133: 1858-68.

  • Ricciardiello L Ceccarelli C Angiolini G Pariali M Chieco P Paterini P et al. High tymidylate synthase expression in colorectal cancer with microsatellite instability: implications for chemotherapeutic strategies. Clin Cancer Res 2005; 11: 4234-40.

  • Tajima A Hess MT Cabrera BL Kolodner RD Carethers JM. The mismatch repair complex hMutS alpha recognizes 5-flourouracil modified DNA: implications for chemosensitivity and resistance. Gastroenterology 2004; 127: 1678-84.

  • Carethers JM Chauhan DP Fink D Nebel S Bresalier RS Howell SB et al. Mismatch repair proficiency and in vitro response to 5-flourouracil. Gastroenterology 1999; 117: 123-31.

  • Kirchner T Jung A. Pathologische Diagnostik fuer die individualisierte Therapie des Dickdarmkarzinoms. Pathologe 2010; 31: 16-21.

  • Jover R Zapater P Castells A Llor X Andreu M Cubiella J et al. The efficacy of adjuvant chemotherapy with 5-flourouracil in colorectal cancer depends on the mismatch repair status. Eur J Cancer 2009; 45: 365-73.

  • Ribic CM Sargent DJ Moore MJ Thibodeau SN French AJ Goldberg RM et al. Tumor microsatellite-instability status as a predictor of benefit from Flourouracil-based adjuvant chemotherapy for colon cancer. N Eng J Med 2003; 349: 247-57.

  • Magrini R Bhonde MR Hanski M Notter M Scherübl H Boland CR. Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 2002; 101: 23-31.

  • Chamara M Edmonston TB Burkholder S Walters R Anne P Mitchell E et al. Microsatellite status and cell cycle associated markers in rectal cancer patients undergoing combined regimen of 5-FU and CPT-11 chemotherapy and radiotherapy. Anticancer Res 2004; 24: 3161-7.

  • Fink D Aebi S Howell SB. The role of DNA mismatch repair in drug resistance. Cancer Res 1998; 4: 1-6.

  • Claij N te Riele H. Microsatellite instability in human cancer: a prognostic marker for chemotherapy? Exp Cell Res 1999; 246: 1-10.

  • Des Guetz G Schischmanoff O Nicolas P Perret GY Morere JF Uzzan B. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer 2009; 45: 1890-6.

  • Des Guetz G Uzzan B Nicolas P Schischmanoff O Perret GY Morere JF. Microsatellite instability does not predict the efficacy of chemotherapy in metastatic colorectal cancer. A systematic review and meta-analysis. Anticancer Res 2009; 29: 1615-20.

  • Des Guetz G Mariani P Cucherousset J Benamoun M Lagorce C Sastre X et al. Microsatellite instability and sensitivity to FOLFOX treatment in metastatic colorectal cancer. Anticancer Res 2007; 27: 2715-19.

  • Guastadisegni C Colafranceschi M Ottini L Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy. A meta analysis of colorectal cancer survival data. Eur J Cancer 2010; 46: 2788-98.

  • Sinicrope F Foster NR Sargent DJ Thibodeau SN Smyrk TC O'Connell MJ et al. Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients. Cancer 2010; 116: 1691-8.

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