Annals of Surgical Oncology

, Volume 17, Issue 11, pp 2839–2846 | Cite as

Absence of hMLH1 or hMSH2 Expression as a Stage-Dependent Prognostic Factor in Sporadic Colorectal Cancers

  • Ji Won Park
  • Hee Jin Chang
  • Sohee Park
  • Byung Chang Kim
  • Dae Yong Kim
  • Ji-Yeon Baek
  • Sun Young Kim
  • Jae Hwan Oh
  • Hyo Seong Choi
  • Sung Chan Park
  • Seung-Yong Jeong
Colorectal Cancer



The predictive role of mismatch repair (MMR) status for survival after sporadic colorectal cancer remains a point of controversy. This study was designed to test the prognostic value of MMR status in sporadic colorectal cancers.


The study included 318 patients with sporadic colorectal cancer who underwent primary tumor resection. MMR status was determined by the immunohistochemical analysis of hMLH1 and hMSH2 expression.


Thirty-six carcinomas (11.3%) showed abnormal MMR protein expression (22 hMLH1 negative and 14 hMSH2 negative) and were classified as MMR-defective tumors. An MMR defect was strongly associated with a reduced likelihood of lymph node (odds ratio, 0.32; 95% confidence interval [95% CI], 0.13–0.75) or distant organ metastases at diagnosis (odds ratio, 0.07; 95% CI, 0.01–0.62), independent of the clinicopathological features. Overall survival was significantly better in patients with MMR-defective tumors than in those with MMR-intact tumors (P = 0.013). In the subgroup analysis by stage, adjusted for other potential confounding variables, MMR status was not a statistically significant prognostic factor in stage I and II patients, while the MMR defect predicted a significantly better overall survival in stage III and IV patients (adjusted hazard ratio, 0.23; 95% CI, 0.06–0.97; P = 0.045).


At initial diagnosis, metastases were found at lower rates in MMR-defective tumors. MMR status may be a stage-dependent prognostic factor in patients with sporadic colorectal cancer.


  1. 1.
    Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet. 1999;36:801–18.PubMedGoogle Scholar
  2. 2.
    Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9:48–55.CrossRefPubMedGoogle Scholar
  3. 3.
    Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol. 2002;20:1043–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. 1996;56:4836–40.PubMedGoogle Scholar
  5. 5.
    Jass JR. Pathology of hereditary nonpolyposis colorectal cancer. Ann N Y Acad Sci. 2000;910:62–73.CrossRefPubMedGoogle Scholar
  6. 6.
    Sankila R, Aaltonen LA, Jarvinen HJ, Mecklin JP. Better survival rates in patients with MLH1-associated hereditary colorectal cancer. Gastroenterology. 1996;110:682–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Bubb VJ, Curtis LJ, Cunningham C, et al. Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer. Oncogene. 1996;12:2641–9.PubMedGoogle Scholar
  8. 8.
    Samowitz WS, Curtin K, Ma KN, et al. Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level. Cancer Epidemiol Biomarkers Prev. 2001;10:917–23.PubMedGoogle Scholar
  9. 9.
    Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342:69–77.CrossRefPubMedGoogle Scholar
  11. 11.
    Greene FL, Page DL, Fleming ID, et al. AJCC cancer staging manual. New York: Springer-Verlag, 2002.CrossRefGoogle Scholar
  12. 12.
    Jass JR, Love SB, Northover JM. A new prognostic classification of rectal cancer. Lancet. 1987;1:1303–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Gafa R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer. 2000;89:2025–37.CrossRefPubMedGoogle Scholar
  14. 14.
    Jeong SY, Shin KH, Shin JH, et al. Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers. Dis Colon Rectum. 2003;46:1069–77.CrossRefPubMedGoogle Scholar
  15. 15.
    Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Shia J, Ellis NA, Klimstra DS. The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch. 2004;445:431–41.CrossRefPubMedGoogle Scholar
  17. 17.
    Laghi L, Bianchi P, Malesci A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene 2008;27:6313–21.CrossRefPubMedGoogle Scholar
  18. 18.
    Müller W, Burgart LJ, Krause-Paulus R, et al. The reliability of immunohistochemistry as a prescreening method for the diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC)—results of an international collaborative study. Fam Cancer. 2001;1:87–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Cawkwell L, Gray S, Murgatroyd H, et al. Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair. Gut. 1999;45:409–15.CrossRefPubMedGoogle Scholar
  20. 20.
    Chaves P, Cruz C, Lage P, et al. Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype. J Pathol. 2000;191:355–60.CrossRefPubMedGoogle Scholar
  21. 21.
    Dieumegard B, Grandjouan S, Sabourin JC, et al. Extensive molecular screening for hereditary non-polyposis colorectal cancer. Br J Cancer. 2000;82:871–80.CrossRefPubMedGoogle Scholar
  22. 22.
    Iino H, Simms L, Young J, et al. DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer. Gut. 2000;47:37–42.CrossRefPubMedGoogle Scholar
  23. 23.
    Jass JR. hMLH1 and hMSH2 immunostaining in colorectal cancer. Gut. 2000;47:315–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Lanza G, Gafa R, Maestri I, et al. Immunohistochemical pattern of MLH1/MSH2 expression is related to clinical and pathological features in colorectal adenocarcinomas with microsatellite instability. Mod Pathol. 2002;15:741–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Rigau V, Sebbagh N, Olschwang S, et al. Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med. 2003;127:694–700.PubMedGoogle Scholar
  26. 26.
    Salahshor S, Koelble K, Rubio C, Lindblom A. Microsatellite instability and hMLH1 and hMSH2 expression analysis in familial and sporadic colorectal cancer. Lab Invest. 2001;81:535–41.PubMedGoogle Scholar
  27. 27.
    Ward R, Meagher A, Tomlinson I, et al. Microsatellite instability and the clinicopathological features of sporadic colorectal cancer. Gut. 2001;48:821–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Wahlberg SS, Schmeits J, Thomas G, et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families. Cancer Res. 2002;62:3485–92.PubMedGoogle Scholar
  29. 29.
    Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58:3455–60.PubMedGoogle Scholar
  30. 30.
    Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA. 1998;95:6870–5.CrossRefPubMedGoogle Scholar
  31. 31.
    Kane MF, Loda M, Gaida GM, 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;57:808–11.PubMedGoogle Scholar
  32. 32.
    Lim SB, Jeong SY, Lee MR, et al. Prognostic significance of microsatellite instability in sporadic colorectal cancer. Int J Colorectal Dis. 2004;19:533–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.CrossRefPubMedGoogle Scholar
  34. 34.
    Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.CrossRefPubMedGoogle Scholar
  35. 35.
    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. 2007;22:145–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Salahshor S, Kressner U, Fischer H, et al. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. Br J Cancer. 1999;81:190–3.CrossRefPubMedGoogle Scholar
  37. 37.
    Lanza G, Gafa R, Santini A, et al. Immunohistochemical test for MLH1 and MSH2 expression predicts clinical outcome in stage II and III colorectal cancer patients. J Clin Oncol. 2006;24:2359–67.CrossRefPubMedGoogle Scholar
  38. 38.
    Parc Y, Gueroult S, Mourra N, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res. 2007;13:3831–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Wright CM, Dent OF, Barker M, et al. Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer. Br J Surg. 2000;87:1197–202.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2010

Authors and Affiliations

  • Ji Won Park
    • 1
  • Hee Jin Chang
    • 1
  • Sohee Park
    • 2
  • Byung Chang Kim
    • 1
  • Dae Yong Kim
    • 1
  • Ji-Yeon Baek
    • 1
  • Sun Young Kim
    • 1
  • Jae Hwan Oh
    • 1
  • Hyo Seong Choi
    • 1
  • Sung Chan Park
    • 1
  • Seung-Yong Jeong
    • 3
  1. 1.Center for Colorectal Cancer, Research Institute and HospitalNational Cancer CenterGoyangRepublic of Korea
  2. 2.Cancer Biostatistics Branch, Research InstituteNational Cancer CenterGoyangRepublic of Korea
  3. 3.Department of SurgerySeoul National University College of MedicineSeoulRepublic of Korea

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