Skip to main content

Advertisement

SpringerLink
Log in

An Alternative Pathway in Colorectal Carcinogenesis Based on the Mismatch Repair System and p53 Expression in Korean Patients with Sporadic Colorectal Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Microsatellite instability (MSI) and chromosomal instability are main mechanisms underlying colorectal carcinogenesis. We determined the features and prognosis of colorectal cancer based on MSI including mismatch repair genes and expression of p53.

Methods

Between 1999 and 2008, a total of 2,649 colorectal cancer patients were analyzed using a prospective database. A mismatch repair defect (MMR-D) was defined as a loss of expression of more than one MMR protein and/or MSI-high. MMR-proficiency (MMR-P) was defined as expression of all MMR proteins and microsatellite stable (MSS)/MSI-low. Groups 1 (G1), 2 (G2), 3 (G3), and 4 (G4) were defined as MMR-D and p53-positive expression, MMR-D and p53-negative expression, MMR-P and p53-positive expression, MMR-P and p53-negative expression, respectively.

Results

Eighty-two (3.0 %), 181 (6.8 %), 1,368 (51.7 %), and 1,018 (38.5 %) patients were classified into groups 1–4, respectively. Comparison between G1 and G2 showed differences in location (p < 0.001), size (p = 0.030), node metastasis (p = 0.027), distant metastasis (p = 0.009), and stage (p = 0.040). Comparison between G3 and G4 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G1 and G3 showed differences in location (p < 0.001) and histology (p < 0.001). Comparison between G2 and G4 showed differences in age (p < 0.001), location (p < 0.001), size (p = 0.006), histology (p < 0.001), node metastasis (p < 0.001), distant metastasis (p < 0.001), and stage (p < 0.001). On multivariate analysis, stage (p = 0.007) and histology (p < 0.001) were associated with improved overall survival, and stage (p < 0.001) was associated with disease-free survival.

Conclusions

According to the MSI and p53 subsets, colorectal cancers showed different clinicopathologic features, but these subsets had no prognostic impact on overall and disease-free survival rate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Rodriquez J, Frigola J, Vendrell E, et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 2006;66:8462–8.

    Article  Google Scholar 

  2. Smith G, Carey FA, Beattie J, et al. Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA. 2002;99:9433–8.

    Article  PubMed  CAS  Google Scholar 

  3. Söreide K, Janssen EAM, Söiland H, Körner H, Baak JP. Microsatellite instability in colorectal cancer. Br J Surg. 2006;93:395–406.

    Article  PubMed  Google Scholar 

  4. Clark AJ, Barneston R, Farrington SM, Dunlop MG. Prognosis in DNA mismatch repair deficient colorectal cancer: are all MSI tumours equivalent? Fam Cancer. 2004;3:85–91.

    Article  PubMed  CAS  Google Scholar 

  5. Samowitz WS, Curtin K, Ma KN, et al. Prognostic significance of p53 mutations in colon cancer at the population level. Int J Cancer. 2002;99:597–602.

    Article  PubMed  CAS  Google Scholar 

  6. Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009;9:489–99.

    Article  PubMed  CAS  Google Scholar 

  7. Ogino S, Goel A. Molecular classification and correlate in colorectal cancer. J Mol Diagn. 2008;10:13–27.

    Article  PubMed  CAS  Google Scholar 

  8. Munro AJ, Lain S, Lane DP. p53 abnormalities and outcomes in colorectal cancer: a systematic review. Br J Cancer. 2005;92:434–44.

    PubMed  CAS  Google Scholar 

  9. Hendriks Y, Franken P, Dierssen JW, et al. Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors. Am J Pathol. 2003;162:469–7.

    Article  PubMed  CAS  Google Scholar 

  10. Rashid A, Zahurak M, Goodman SN, Hamilton SR. Genetic epidemiology of mutated K-ras proto-oncogene, suppressor genes, and microsatellite instability in colorectal adenomas. Gut. 1999;44:826–33.

    Article  PubMed  CAS  Google Scholar 

  11. Lawes DA, Pearson T, Sengupta S, Boulos PB. The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. Br J Cancer. 2005;93:472–7.

    Article  PubMed  CAS  Google Scholar 

  12. Hatch SB, Lightfoot HM Jr, Garwacki CP, et al. Microsatellite instability testing in colorectal carcinoma: choice of markers affects sensitivity of detection of mismatch repair-deficient tumors. Clin Cancer Res. 2005;11:2180–7.

    Article  PubMed  CAS  Google Scholar 

  13. Rigau V, Sebbagh N, Olschwang S, et al. Microsatellite instability testing in colorectal carcinoma: the comparison of immunohistochemistry and molecular biology suggests a role for hMLH6 immunostaining. Arch Pathol Lab Med. 2003;127:694–700.

    PubMed  CAS  Google Scholar 

  14. Sinicrope FA, Rego RL, Halling KC, et al. Prognostic impact of microsatellite instability and DNA ploidy in human colorectal carcinoma patients. Gastroenterology. 2006;131:729–37.

    Article  PubMed  CAS  Google Scholar 

  15. Mead LJ, Jenkins MA, Young J, et al. Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes. Clin Cancer Res. 2007;13:2865–9.

    Article  PubMed  CAS  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. Kim YH, Min BH, Choi HK, et al. Sporadic colorectal carcinomas with low-level microsatellite instability in Korea: do they form a distinct subgroup with distinguished clinicopathological features? J Surg Oncol. 2009;99:351–5.

    Article  PubMed  CAS  Google Scholar 

  18. Jung SH, Kim HC, Kim JS, Choi J, Yu CS, Kim JC. Efficacy of hMLH1/hMSH2 immunohistochemical staining as representative index for microsatellite instability status in sporadic colorectal cancer. J Korean Soc Coloproctol. 2006;22:184–91.

    Google Scholar 

  19. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancers: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713–8.

    PubMed  CAS  Google Scholar 

  20. Ashktorah H, Smooth DT, Carethers JM, et al. High incidence of microsatellite instability in colorectal cancer from African Americans. Clin Cancer Res. 2003;9:1112–7.

    Google Scholar 

  21. Tomlinson IP, Ilyas M, Bodmer WF. Allele loss occurs frequently at hMLH1, but rarely at hMSH2 in sporadic colorectal cancer with microsatellite instability. Br J Cancer. 1996;74:1514–7.

    Article  PubMed  CAS  Google Scholar 

  22. Kuismanen SA, Hoimberg MT, Salovaara R, de la Chapelle A, Peltomäki P. Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol. 2000;156:1773–9.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    Article  PubMed  CAS  Google Scholar 

  24. Poynter JN, Siegmund KD, Weisenberger DJ, et al. Molecular characterization of MSI-H colorectal cancer by MLH1 promoter methylation, immunohistochemistry and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev. 2008;17:3208–15.

    Article  PubMed  CAS  Google Scholar 

  25. Kakar S, Burgart LJ, Thibodeau SN, et al. Frequency of loss of hMLH1 expression in colorectal carcinoma increases with advancing age. Cancer. 2003;97:1421–7.

    Article  PubMed  CAS  Google Scholar 

  26. Iacopetta B. TP53 mutation in colorectal cancer. Hum Mutat. 2003;21:271–6.

    Article  PubMed  CAS  Google Scholar 

  27. Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N. The TP53 Colorectal Cancer International Collaborative Study on the prognosis and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol. 2005;23:7518–28.

    Article  PubMed  CAS  Google Scholar 

  28. Samowitz WS, Holden JA, Curtin K, et al. Inverse relationship between microsatellite instability and K-ras and p53 gene alteration in colon cancer. Am J Pathol. 2001;158:1517–24.

    Article  PubMed  CAS  Google Scholar 

  29. Elsaleh H, Powell B, McCaul K, et al. p53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res. 2001;7:1343–9.

    PubMed  CAS  Google Scholar 

  30. Cripps KJ, Purdie CA, Carder PJ, et al. A study of stabilization of p53 protein versus point mutation in colorectal carcinoma. Oncogene. 1994;9:2739–43.

    PubMed  CAS  Google Scholar 

  31. Dix B, Robbins P, Carrello S, House A, Iacopetta B. Comparison of p53 gene mutation and protein overexpression in colorectal carcinoma. Br J Cancer. 1994;70:585–90.

    Article  PubMed  CAS  Google Scholar 

  32. Veloso M, Wrbra F, Kaserer K, et al. p53 gene status and expression of p53, mdm2, and p21Waf1/Cip1 proteins in colorectal cancer. Virchows Arch. 2000;437:241–7.

    Article  PubMed  CAS  Google Scholar 

  33. Laghi L, Bianchi P, Malesci A. Differences and evolution of the methods for the assessment of microsatellite instability. Oncogene. 2008;27:6313–21.

    Article  PubMed  CAS  Google Scholar 

  34. Jones AM, Douglas EJ, Halford S, et al. Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma. Oncogene. 2005;24:118–29.

    Article  PubMed  CAS  Google Scholar 

  35. Burgart LJ. Testing for defective DNA mismatch repair in colorectal carcinoma: a practical guide. Arch Pathol Lab Med. 2005;129:1385–9.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0016765). We thank Sun Woo Kim, Sook Young Woo, and Jung Hyeon Ahn of the Biostatistics Team, Samsung Biomedical Research Institute, for the statistical analysis of this study.

Author information

Authors and Affiliations

  1. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Hyoung Ran Kim MD, PhD, Hee Cheol Kim MD, PhD, Hae-Ran Yun MD, Yong Beom Cho MD, PhD, Seong Hyeon Yun MD, PhD, Woo Yong Lee MD, PhD & Ho-Kyung Chun MD, PhD

  2. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Seok Hyung Kim MD, PhD & Cheol Keun Park MD, PhD

Authors
  1. Hyoung Ran Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hee Cheol Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hae-Ran Yun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seok Hyung Kim MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheol Keun Park MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Beom Cho MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seong Hyeon Yun MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Woo Yong Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ho-Kyung Chun MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hee Cheol Kim MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, H.R., Kim, H.C., Yun, HR. et al. An Alternative Pathway in Colorectal Carcinogenesis Based on the Mismatch Repair System and p53 Expression in Korean Patients with Sporadic Colorectal Cancer. Ann Surg Oncol 20, 4031–4040 (2013). https://doi.org/10.1245/s10434-012-2455-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-012-2455-7

Keywords

Search

Navigation