Abstract
Introduction
High microsatellite instability (MSI-H) occurs in about 15% of colorectal cancers (CRC) and clinical as well as pathological features differ from tumours exhibiting low microsatellite instability (MSI-L) or microsatellite stability (MSS). Conflicting data exists about the relevance of MSI in predicting the prognosis and benefit of 5-fluorouracil (5-FU) based chemotherapy in patients with CRC. We investigated the usefulness of MSI as a predictor of distinct clinical attributes influencing recurrence rate and disease-free survival (DFS) subject to the use of adjuvant or palliative chemotherapy with 5-FU in stage II- stage IV CRC.
Methods
We collected data and tumours of 416 consecutive stage I to IV CRC patients from 2000 to 2002, and followed them for a median time of 33 months. Microsatellite loci recommended by the National Cancer Institute were analysed. Cox proportional hazard modelling was used to compare clinical data and survival as well as associations for MSI and 5-FU treatment status of patients with MSI-H, MSI-L or MSS CRC.
Results
We identified 52 MSI-H (13%), 21 MSI-L (5%) and 343 MSS (82%) tumours. CRC with MSI-H tended to have a decreased likelihood of metastasising to regional lymph nodes (p=0.055), whilst age of diagnosis and tumour location did not differ. In an analysis that did not take into account the use of chemotherapy, univariate and multivariate analyses failed to show a difference between MSI-H and MSS groups with respect to disease-free and overall survival. Furthermore, survival under application of 5-FU did not correlate with MSI status.
Conclusion
No clear influence of MSI status on overall survival and response to 5-FU chemotherapy was found.
Similar content being viewed by others
References
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532
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
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR et al (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260:812–816
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB, Vertino PM (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Alterations in DNA methylation: a fundamental aspect of neoplasia. Proc Natl Acad Sci USA 95:6870–6875
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 95:8698–8702
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819
Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342:69–77
Bubb VJ, Curtis LJ, Cunningham C, Dunlop MG, Carothers AD, Morris RG, White S, Bird CC, Wyllie AH (1996) Microsatellite instability and the role of hMSH2 in sporadic colorectal cancer. Oncogene 12:2641–2649
Brueckl W, Moesch C, Brabletz T, Koebnick C, Riedel C, Jung A, Merkel S, Schaber S, Boxberger F, Kirchner T, Hohenberger W, Hahn E, Wein A (2003) Relationship between microsatellite instability, response and survival in palliative patients with colorectal cancer undergoing first-line chemotherapy. Anticancer Res 23:1773–1777
Gafa R, Maestri I, Matteuzzi M, Santini A, Ferretti S, Cavazzini L, Lanza G, Calin GA, Tibiletti MG, Herlea V, Becheanu G, Barbanti-Brodano G, Nenci I, Negrini M, Dubini A, Gilli G (2000) Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 89:2025–2037
Garrity MM, Burgart LJ, Mahoney MR, Windschitl HE, Salim M, Wiesenfeld M, Krook JE, Michalak JC, Goldberg RM, O’Connell MJ, Furth AF, Sargent DJ, Murphy LM, Hill E, Riehle DL, Meyers CH, Witzig TE; NCCT Group (2004) Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes’ B2 or C colon cancer: a North Central Cancer Treatment Group Study. J Clin Oncol 22:1572–1582
Halling KC, French AJ, McDonnell SK, Burgart LJ, Schaid DJ, Peterson BJ, Moon-Tasson L, Mahoney MR, Sargent DJ, O’Connell MJ, Witzig TE, Farr GH Jr, Goldberg RM, Thibodeau SN (1999) Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 91:1295–1303
Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO et al (1993) Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53:5849–5852
Lukish JR, Muro K, DeNobile J, Katz R, Williams J, Cruess DF, Drucker W, Kirsch I, Hamilton SR (1998) Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 227:51–56
Popat S, Hubner R, Houlston R (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23:609–618
Ribic C, Sargent D, Moore M, Thibodeau S, French A, Goldberg R, Hamilton S, Laurent-Puig P, Gryfe R, Shepherd L, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247–257
Ward RL, Cheong K, Ku SL, Meagher A, O’Connor T, Hawkins NJ (2003) Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21:3729–3736
Wright C, Dent O, Barker M, Newland R, Chapuis P, Bokey E, Young J, Leggett B, Jass J, Macdonald G (2000) Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg 87:1197–1202
Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR (2004) Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology 126:394–401
Curran B, Lenehan K, Mulcahy H, Tighe O, Bennett M, Kay E, O’Donoghue D, Leader M, Croke D (2000) Replication error phenotype, clinicopathological variables, and patient outcome in Dukes’ B stage II (T3,N0,M0) colorectal cancer. Gut 46:200–204
Diep CB, Thorstensen L, Meling GI, Skovlund E, Rognum TO, Lothe RA (2003) Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J Clin Oncol 21:820–829
Feeley KM, Fullard JF, Heneghan MA, Smith T, Maher M, Murphy RP, O’Gorman TA (1999) Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis. J Pathol 188:14–17
Johannsdottir J, Bergthorsson J, Gretarsdottir S, Kristjansson A, Ragnarsson G, Jonasson J, Egilsson V, Ingvarsson S (1999) Replication error in colorectal carcinoma: association with loss of heterozygosity at mismatch repair loci and clinicopathological variables. Anticancer Res 19:1821–1826
Jover R, Zapater P, Castells A, Llor X, Andreu M, Cubiella J, Pinol V, Xicola.RM, Bujanda L, Rene JM, Clofent J, Bessa X, Morillas JD, Nicolas-Perez D, Paya A, Alenda C (2006) Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55(6):848–855
Ko JM, Cheung MH, Kwan MW, Wong CM, Lau KW, Tang CM, Lung ML (1999) Genomic instability and alterations in Apc, Mcc and Dcc in Hong Kong patients with colorectal carcinoma. Int J Cancer 84:404–409
Messerini L, Ciantelli M, Baglioni S, Palomba A, Zampi G, Papi L (1999) Prognostic significance of microsatellite instability in sporadic mucinous colorectal cancers. Hum Pathol 30:629–634
Salahshor S, Kressner U, Fischer H, Lindmark G, Glimelius B, Pahlman L, Lindblom A (1999) Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer 81:190–193
Wang C, van Rijnsoever M, Grieu F, Bydder S, Elsaleh H, Joseph D, Harvey J, Iacopetta B (2003) Prognostic significance of microsatellite instability and Ki-ras mutation type in stage II colorectal cancer. Oncology 64:259–265
Kim H, Jen J, Vogelstein B, Hamilton S (1994) Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 148–156
Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K, Chiba M, Nomizu S, Konishi F, Utsunomiya J, Miyaki M (1996) Molecular nature of colon tumours in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111:307–317
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, Fan R, Zborowska E, Kinzler K, Vogelstein B et al (1995) Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 268:1336–1338
Morin P, Sparks A, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790
Sparks A, Morin P, Vogelstein B, Kinzler K (1998) Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 58:1130–1134
Young J, Simms LA, Biden KG, Wynter C, Whitehall V, Karamatic R, George J, Goldblatt J, Walpole I, Robin SA, Borten MM, Stitz R, Searle J, McKeone D, Fraser L, Purdie D, Podger K, Price R, Buttenshaw R, Walsh MD, Barker M, Leggett BA, Jass JR (2001) Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 159:2107–2116
Boland CR, Sinicrope FA, Brenner DE, Carethers JM (2000) Colorectal cancer prevention and treatment. Gastroenterology 118:115–128
Laurie JA, Moertel CG, Fleming TR, Wieand HS, Leigh JE, Rubin J, McCormack GW, Gerstner JB, Krook JE, Malliard J, Poon MA, O’Connell MJ, Cullinan SA, Everson LK, Mailliard JA, Tschetter LK (1989) Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7:1447–1456
Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH et al (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358
Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Tangen CM, Ungerleider JS, Emerson WA, Tormey DC, Glick JH et al (1995) Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 122:321–326
Aebi S, Fink D, Gordon R, Kim HK, Zheng H, Fink JL, Howell SB (1997) Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res 3:1763–1767
Arnold CN, Goel A, Boland CR, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM (2003) Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Characterization of sporadic colon cancer by patterns of genomic instability. Int J Cancer 106:66–73
Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, Boland CR (1999) Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 117:123–131
Carethers JM, Hawn MT, Chauhan DP, Luce MC, Marra G, Koi M, Boland CR (1996) Competency in mismatch repair prohibits clonal expansion of cancer cells treated with N-methyl-N′-nitro-N-nitrosoguanidine. J Clin Invest 98:199–206
Hawn MT, Umar A, Carethers JM, Marra G, Kunkel TA, Boland CR, Koi M (1995) Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res 55:3721–3725
Elsaleh H, Iacopetta B, Powell B, McCaul K, Grieu F, Grant R, Joseph D, Shannon B (2001) Microsatellite instability is a predictive marker for survival benefit from adjuvant chemotherapy in a population-based series of stage III colorectal carcinoma. Clin Colorectal Cancer 1:104–109
Hemminki A, Mecklin JP, Jarvinen H, Aaltonen LA, Joensuu H (2000) Microsatellite instability is a favorable prognostic indicator in patients with colorectal cancer receiving chemotherapy. Gastroenterology 119:921–928
Liang J, Huang K, Lai H, Lee P, Cheng Y, Hsu H, Cheng A, Hsu C, Yeh K, Wang S, Tang C, Chang K (2002) 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 101:519–525
Barratt PL, Seymour MT, Stenning SP, Georgiades I, Walker C, Birbeck K, Quirke P; Study. UKCCCR AXIS trial collaborators (2002) DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study. Lancet 360:1381–1391
Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425
Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268
Kruse R, Rutten A, Schweiger N, Jakob E, Mathiak M, Propping P, Mangold E, Bisceglia M, Ruzicka T (2003) Frequency of microsatellite instability in unselected sebaceous gland neoplasias and hyperplasias. J Invest Dermatol 120:858–864
Faivre-Finn C, Bouvier-Benhamiche AM, Phelip JM, Manfredi S, Dancourt V, Faivre J (2002) Colon cancer in France: evidence for improvement in management and survival. Gut 51:60–64
Gatta G, Ciccolallo L, Capocaccia R, Coleman MP, Hakulinen T, Moller H, Berrino F (2003) Differences in colorectal cancer survival between European and US populations: the importance of sub-site and morphology. Eur J Cancer 39:2214–2222
Sant M, Aareleid T, Berrino F, Bielska Lasota M, Carli PM, Faivre J, Grosclaude P, Hedelin G, Matsuda T, Moller H, Moller T, Verdecchia A, Capocaccia R, Gatta G, Micheli A, Santaquilani M, Roazzi P, Lisi D (2003) EUROCARE-3: survival of cancer patients diagnosed 1990–94—results and commentary. Ann Oncol 14:V61–V118
Westra J, Schaapveld M, Hollema H, de Boer J, Kraak M, de Jong D, ter Elst A, Mulder N, Buys C, Hofstra R, Plukker J (2005) Determination of TP53 mutation is more relevant than microsatellite instability status for the prediction of disease-free survival in adjuvant-treated stage III colon cancer patients. J Clin Oncol 23:5635–5643
Tajima A, Hess M, Cabrera B, Kolodner R, Carethers J (2004) The mismatch repair complex hMutS alpha recognizes 5-fluorouracil-modified DNA: implications for chemosensitivity and resistance. Gastroenterology 127:1678–1684
Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B (2000) Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 355:1745–1750
Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB (2004) Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology 126:394–401
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lamberti, C., Lundin, S., Bogdanow, M. et al. Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer. Int J Colorectal Dis 22, 145–152 (2007). https://doi.org/10.1007/s00384-006-0131-8
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-006-0131-8