Deficient mismatch repair system in patients with sporadic advanced colorectal cancer

M Koopman, G A M Kortman, L Mekenkamp, M J L Ligtenberg, N Hoogerbrugge, N F Antonini, C J A Punt, J H J M van Krieken, M Koopman, G A M Kortman, L Mekenkamp, M J L Ligtenberg, N Hoogerbrugge, N F Antonini, C J A Punt, J H J M van Krieken

Abstract

A deficient mismatch repair system (dMMR) is present in 10-20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2-18.8), 7.4 months (95% CI 3.7-16.9) and 10.2 months (95% CI 5.9-19.8), respectively. The disease control rate in pMMR and dMMR patients was 83% (95% CI 79-86%) and 56% (30-80%), respectively. We conclude that dMMR is rare in patients with sporadic advanced CRC. This supports the hypothesis that dMMR tumours have a reduced metastatic potential, as is observed in dMMR patients with early stage disease. The low incidence of dMMR does not allow drawing meaningful conclusions about the outcome of treatment in these patients.

Figures

Figure 1
Figure 1
IHC results, MSI analysis and hypermethylation MLH1 promoter.
Figure 2
Figure 2
OS by MMR status.
Figure 3
Figure 3
PFS by MMR status.

References

    1. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260: 812–816
    1. 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: 66–73
    1. Benatti P, Gafa R, Barana D, Marino M, Scarselli A, Pedroni M, Maestri I, Guerzoni L, Roncucci L, Menigatti M, Roncari B, Maffei S, Rossi G, Ponti G, Santini A, Losi L, Di GC, Oliani C, Ponz De LM, Lanza G (2005) Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res 11: 8332–8340
    1. Bettstetter M, Dechant S, Ruemmele P, Grabowski M, Keller G, Holinski-Feder E, Hartmann A, Hofstaedter F, Dietmaier W (2007) Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 13: 3221–3228
    1. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S (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: 5248–5257
    1. Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, Barrett JH, Selby P, Meade AM, Stephens RJ, Parmar MK, Seymour MT (2008) Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J Clin Oncol 26: 2690–2698
    1. 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
    1. 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
    1. Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58: 3455–3460
    1. Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh VC, Kubly V, Nelson H, Michels VV, Thibodeau SN (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69: 780–790
    1. Duffy MJ, van DA, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, Lamerz R, Peltomaki P, Sturgeon C, Topolcan O (2007) Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer 43: 1348–1360
    1. Elsaleh H, Iacopetta 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
    1. Fink D, Nebel S, Aebi S, Zheng H, Cenni B, Nehme A, Christen RD, Howell SB (1996) The role of DNA mismatch repair in platinum drug resistance. Cancer Res 56: 4881–4886
    1. 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
    1. Haddad R, Ogilvie RT, Croitoru M, Muniz V, Gryfe R, Pollet A, Shanmugathasan P, Fitzgerald T, Law CH, Hanna SS, Jothy S, Redston M, Gallinger S, Smith AJ (2004) Microsatellite instability as a prognostic factor in resected colorectal cancer liver metastases. Ann Surg Oncol 11: 977–982
    1. Hawkins N, Norrie M, Cheong K, Mokany E, Ku SL, Meagher A, O'Connor T, Ward R (2002) CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability. Gastroenterology 122: 1376–1387
    1. Hendriks Y, Franken P, Dierssen JW, De LW, Wijnen J, Dreef E, Tops C, Breuning M, Brocker-Vriends A, Vasen H, Fodde R, Morreau H (2003) Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol 162: 469–477
    1. 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
    1. Jass JR, Sobin LH, Wanatabe H (1990) The WHO classification of gastrointestinal tumors: a commentary on the second edition. Cancer 66: 2162–2167
    1. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50: 113–130
    1. Johnson V, Volikos E, Halford SE, Eftekhar Sadat ET, Popat S, Talbot I, Truninger K, Martin J, Jass J, Houlston R, Atkin W, Tomlinson IP, Silver AR (2005) Exon 3 beta-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome. Gut 54: 264–267
    1. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: 808–811
    1. Kochhar R, Halling KC, McDonnell S, Schaid DJ, French AJ, O'Connell MJ, Nagorney DM, Thibodeau SN (1997) Allelic imbalance and microsatellite instability in resected Duke's D colorectal cancer. Diagn Mol Pathol 6: 78–84
    1. Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van BA, Sinnige HA, Creemers GJ, Tesselaar ME, Slee PH, Werter MJ, Mol L, Dalesio O, Punt CJ (2007) Sequential vs combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370: 135–142
    1. Liang JT, Huang KC, Lai HS, Lee PH, Cheng YM, Hsu HC, Cheng AL, Hsu CH, Yeh KH, Wang SM, Tang C, Chang KJ (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
    1. Lim SB, Jeong SY, Lee MR, Ku JL, Shin YK, Kim WH, Park JG (2004) Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis 19: 533–537
    1. Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, Walsh-Vockley C, Petersen GM, Walsh MD, Leggett BA, Young JP, Barker MA, Jass JR, Hopper J, Gallinger S, Bapat B, Redston M, Thibodeau SN (2002) Immunohistochemistry vs microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 20: 1043–1048
    1. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF, Bast RC (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24: 5313–5327
    1. Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, Pylkkanen L, Heimdal K, Andersen TI, Moller P, Rognum TO (1993) Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 53: 5849–5852
    1. Magrini R, Bhonde MR, Hanski ML, Notter M, Scherubl H, Boland CR, Zeitz M, Hanski C (2002) Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer 101: 23–31
    1. Malesci A, Laghi L, Bianchi P, Delconte G, Randolph A, Torri V, Carnaghi C, Doci R, Rosati R, Montorsi M, Roncalli M, Gennari L, Santoro A (2007) Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 13: 3831–3839
    1. McGivern A, Wynter CV, Whitehall VL, Kambara T, Spring KJ, Walsh MD, Barker MA, Arnold S, Simms LA, Leggett BA, Young J, Jass JR (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3: 101–107
    1. Mecklin JP (1987) Frequency of hereditary colorectal carcinoma. Gastroenterology 93: 1021–1025
    1. Melloni G, Doglioni C, Bandiera A, Carretta A, Ciriaco P, Arrigoni G, Zannini P (2006) Prognostic factors and analysis of microsatellite instability in resected pulmonary metastases from colorectal carcinoma. Ann Thorac Surg 81: 2008–2013
    1. Muller CI, Schulmann K, Reinacher-Schick A, Andre N, Arnold D, Tannapfel A, Arkenau H, Hahn SA, Schmoll SH, Porschen R, Schmiegel W, Graeven U (2008) Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing first-line chemotherapy. A report of the AIO Colorectal Study Group. Int J Colorectal Dis 23: 1033–1039
    1. Overbeek LI, Kets CM, Hebeda KM, Bodmer D, van der LE, Willems R, Goossens M, Arts N, Brunner HG, van Krieken JH, Hoogerbrugge N, Ligtenberg MJ (2007) Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. Br J Cancer 96: 1605–1612
    1. Overbeek LI, Ligtenberg MJ, Willems RW, Hermens RP, Blokx WA, Dubois SV, van der LH, Meijer JW, Mlynek-Kersjes ML, Hoogerbrugge N, Hebeda KM, van Krieken JH (2008) Interpretation of immunohistochemistry for mismatch repair proteins is only reliable in a specialized setting. Am J Surg Pathol 32: 1246–1251
    1. Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21: 1174–1179
    1. Popat S, Hubner R, Houlston RS (2005) Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 23: 609–618
    1. Poynter JN, Siegmund KD, Weisenberger DJ, Long TI, Thibodeau SN, Lindor N, Young J, Jenkins MA, Hopper JL, Baron JA, Buchanan D, Casey G, Levine AJ, Le ML, Gallinger S, Bapat B, Potter JD, Newcomb PA, Haile RW, Laird PW (2008) Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 17: 3208–3215
    1. Punt CJ (2004) New options and old dilemmas in the treatment of patients with advanced colorectal cancer. Ann Oncol 15: 1453–1459
    1. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, 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
    1. Ricciardiello L, Ceccarelli C, Angiolini G, Pariali M, Chieco P, Paterini P, Biasco G, Martinelli GN, Roda E, Bazzoli F (2005) High thymidylate synthase expression in colorectal cancer with microsatellite instability: implications for chemotherapeutic strategies. Clin Cancer Res 11: 4234–4240
    1. Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch H, Perucho M, Smyrk T, Sobin L, Srivastava S (1997) A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting hightlights and Bethesda guidelines. J Natl Cancer Inst 89: 1758–1762. Ref Type: Generic
    1. Samowitz WS, Curtin K, Ma KN, Schaffer D, Coleman LW, Leppert M, Slattery ML (2001) Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev 10: 917–923
    1. Samowitz WS, Slattery ML, Potter JD, Leppert MF (1999) BAT-26 and BAT-40 instability in colorectal adenomas and carcinomas and germline polymorphisms. Am J Pathol 154: 1637–1641
    1. Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP (1996) Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology 110: 682–687
    1. Sergent C, Franco N, Chapusot C, Lizard-Nacol S, Isambert N, Correia M, Chauffert B (2002) Human colon cancer cells surviving high doses of cisplatin or oxaliplatin in vitro are not defective in DNA mismatch repair proteins. Cancer Chemother Pharmacol 49: 445–452
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van GM, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216
    1. Ward R, Meagher A, Tomlinson I, O'Connor T, Norrie M, Wu R, Hawkins N (2001) Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut 48: 821–829
    1. 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

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner