Tumor Biology

, Volume 32, Issue 5, pp 977–983 | Cite as

Gene expression of the mismatch repair gene MSH2 in primary colorectal cancer

  • Lars Henrik Jensen
  • Hidekazu Kuramochi
  • Dorthe Gylling Crüger
  • Jan Lindebjerg
  • Steen Kolvraa
  • Peter Danenberg
  • Kathleen Danenberg
  • Anders Jakobsen
Research Article


Microsatellite instability (MSI) is caused by defective mismatch repair (MMR) and is one of the very few molecular markers with proven clinical importance in colorectal cancer with respect to heredity, prognosis, and treatment effect. The gene expression of the MMR gene MSH2 may be a quantitative marker for the level of MMR and a potential molecular marker with clinical relevance. The aim was to investigate the gene expression of MSH2 in primary operable colorectal cancer in correlation with MSI, protein expression, and promoter hypermethylation. In a cohort of 210 patients, the primary tumor and lymphnode metastases were analyzed with immunohistochemistry, methylation and MSI analyses, and quantitative polymerase chain reaction (PCR). The median gene expression of MSH2 was 1.00 (range 0.16–11.2, quartiles 0.70–1.51) and there was good agreement between the gene expression in primary tumor and lymph node metastasis (Spearman’s rho = 0.57, p < 0.001, n = 73). The validity of gene expression analysis was made probable by a significant correlation to protein expression (p = 0.005). MSI was most often caused by deficient MLH1 and was not correlated to MSH2 expression. Hypermethylation of the MSH2 gene promoter was only detected in 14 samples and only at a low level with no correlation to gene expression. MSH2 gene expression was not a prognostic factor for overall survival in univariate or multivariate analysis. The gene expression of MSH2 is a potential quantitative marker ready for further clinical validation.


Colorectal cancer Mismatch repair MSH2 Gene expression qPCR Methods MSI 


  1. 1.
    Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260(5109):812–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363(6429):558–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Duffy MJ, van Dalen A, Haglund C, Hansson L, Holinski-Feder E, Klapdor R, et al. Tumour markers in colorectal cancer: European Group on Tumour Markers (EGTM) guidelines for clinical use. Eur J Cancer. 2007;43(9):1348–60.PubMedCrossRefGoogle Scholar
  4. 4.
    NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Colon Cnacer. Version 2.2011 [Internet]. (Updated 2010; cited 2010) Available from: http://www.nccn.org.
  5. 5.
    Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23(3):609–18.PubMedCrossRefGoogle Scholar
  6. 6.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, 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(3):247–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, 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(20):3219–26.PubMedCrossRefGoogle Scholar
  8. 8.
    Drummond JT, Genschel J, Wolf E, Modrich P. DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair. Proc Natl Acad Sci USA. 1997;94(19):10144–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Jascur T, Boland CR. Structure and function of the components of the human DNA mismatch repair system. Int J Cancer. 2006;119(9):2030–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7(5):335–46.PubMedCrossRefGoogle Scholar
  11. 11.
    Li GM. The role of mismatch repair in DNA damage-induced apoptosis. Oncol Res. 1999;11(9):393–400.PubMedGoogle Scholar
  12. 12.
    Hawn MT, Umar A, Carethers JM, Marra G, Kunkel TA, Boland CR, et al. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res. 1995;55(17):3721–5.PubMedGoogle Scholar
  13. 13.
    Claij N, Te Riele H. Methylation tolerance in mismatch repair proficient cells with low MSH2 protein level. Oncogene. 2002;21(18):2873–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Seifert M, Reichrath J. The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer. J Mol Histol. 2006;37(5–7):301–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Chang DK, Ricciardiello L, Goel A, Chang CL, Boland CR. Steady-state regulation of the human DNA mismatch repair system. J Biol Chem. 2000;275(24):18424–31.PubMedCrossRefGoogle Scholar
  16. 16.
    Jensen L, Danenberg K, Danenberg P, Jakobsen A. Predictive value of MSH2 gene expression in colorectal cancer treated with capecitabine. Clin Colorectal Cancer. 2007;6(6):433–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Jensen L, Lindebjerg J, Byriel L, Kolvraa S, Crüger D. Strategy in clinical practice for classification of unselected colorectal tumours based on mismatch repair deficiency. Colorectal Dis. 2008;10(5):490–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, 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(22):5248–57.PubMedGoogle Scholar
  19. 19.
    Jeuken JWM, Cornelissen SJB, Vriezen M, Dekkers MMG, Errami A, Sijben A, et al. MS-MLPA: an attractive alternative laboratory assay for robust, reliable, and semiquantitative detection of MGMT promoter hypermethylation in gliomas. Lab Invest. 2007;87(10):1055–65.PubMedCrossRefGoogle Scholar
  20. 20.
    Jensen L, Dysager L, Lindebjerg J, Kølvrå S, Byriel L, Crüger D, et al. Molecular biology from bench-to-bedside—which colorectal cancer patients should be referred for genetic counselling and risk assessment. Eur J Cancer. 2010;46(10):1823–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Carethers JM, Chauhan DP, Fink D, Nebel S, Bresalier RS, Howell SB, et al. Mismatch repair proficiency and in vitro response to 5-fluorouracil. Gastroenterology. 1999;117(1):123–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Tajima A, Hess MT, Cabrera BL, Kolodner RD, Carethers JM. The mismatch repair complex hMutS alpha recognizes 5-fluorouracil-modified DNA: implications for chemosensitivity and resistance. Gastroenterology. 2004;127(6):1678–84.PubMedCrossRefGoogle Scholar
  23. 23.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Iacopetta B. Are there two sides to colorectal cancer? Int J Cancer. 2002;101(5):403–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95(12):6870–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, et al. 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. 1997;57(5):808–11.PubMedGoogle Scholar
  27. 27.
    Wheeler JM, Loukola A, Aaltonen LA, Mortensen NJ, Bodmer WF. The role of hypermethylation of the hMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers. J Med Genet. 2000;37(8):588–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Chan TL, Yuen ST, Kong CK, Chan YW, Chan ASY, Ng WF, et al. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet. 2006;38(10):1178–83.PubMedCrossRefGoogle Scholar
  29. 29.
    Ligtenberg MJL, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet. 2009;41(1):112–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Hayes DF, Trock B, Harris AL. Assessing the clinical impact of prognostic factors: when is “statistically significant” clinically useful? Breast Cancer Res Treat. 1998;52(1–3):305–19.PubMedCrossRefGoogle Scholar
  31. 31.
    André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350(23):2343–51.PubMedCrossRefGoogle Scholar
  32. 32.
    de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938–47.PubMedGoogle Scholar
  33. 33.
    Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343(13):905–14.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Lars Henrik Jensen
    • 1
    • 4
  • Hidekazu Kuramochi
    • 2
  • Dorthe Gylling Crüger
    • 1
  • Jan Lindebjerg
    • 1
  • Steen Kolvraa
    • 1
  • Peter Danenberg
    • 2
  • Kathleen Danenberg
    • 3
  • Anders Jakobsen
    • 1
  1. 1.Danish Colorectal Cancer Group SouthUniversity of Southern Denmark and Vejle HospitalVejleDenmark
  2. 2.Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos AngelesUSA
  3. 3.Response GeneticsLos AngelesUSA
  4. 4.Department of Oncology Vejle HospitalVejleDenmark

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