Skip to main content
Springer Nature Link
Log in

Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that are characterized by concordant hypermethylation of multiple CpG island loci. CIMP+ CRCs have peculiar clinicopathological features. However, controversy exists over prognostic implications of CIMP in CRCs. We analyzed 320 cases of CRCs for their CIMP status using the MethyLight assay and determined clinicopathological features and prognostic implications of CIMP alone or in combination with microsatellite instability (MSI). With methylation of five or more markers among eight markers examined, CIMP+ tumors were significantly associated with female gender, proximal tumor location, poor differentiation, nodal metastasis, more advanced cancer, BRAF mutations, MSI, and poor prognosis (all P values <0.05). Ogino’s combined eight-marker panel outperformed the Ogino and the Laird five-marker panels in detecting these features. Of the four molecular subtypes generated by the combination of CIMP and MSI status, the CIMP+/MSI− subtype showed the worst clinical outcome (P = 0.0003). However, poor prognosis of CIMP+/MSI− subtype was found to be attributed to BRAF mutation. In conclusion, the CIMP+/MSI− subtype tends to present with distinct clinicopathological and molecular features and shows the worst clinical outcome among the four molecular subtypes of CRCs.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196

    Article  CAS  PubMed  Google Scholar 

  2. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

    CAS  PubMed  Google Scholar 

  3. Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99:451–454

    Article  CAS  PubMed  Google Scholar 

  4. Wood LD, Parsons DW, Jones S et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113

    Article  CAS  PubMed  Google Scholar 

  5. Schuebel KE, Chen W, Cope L et al (2007) Comparing the DNA hypermethylome with gene mutations in human colorectal cancer. PLoS Genet 3:1709–1723

    Article  CAS  PubMed  Google Scholar 

  6. Toyota M, Ahuja N, Ohe-Toyota M et al (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96:8681–8686

    Article  CAS  PubMed  Google Scholar 

  7. Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38:787–793

    Article  CAS  PubMed  Google Scholar 

  8. Ogino S, Cantor M, Kawasaki T et al (2006) CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 55:1000–1006

    Article  CAS  PubMed  Google Scholar 

  9. Nagasaka T, Koi M, Kloor M et al (2008) Mutations in both KRAS and BRAF may contribute to the methylator phenotype in colon cancer. Gastroenterology 134:1950–1960.e1

    Article  CAS  PubMed  Google Scholar 

  10. Shen L, Toyota M, Kondo Y et al (2007) Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA 104:18654–18659

    Article  CAS  PubMed  Google Scholar 

  11. Lee S, Cho NY, Yoo EJ, Kim JH, Kang GH (2008) CpG island methylator phenotype in colorectal cancers: comparison of the new and classic CpG island methylator phenotype marker panels. Arch Pathol Lab Med 132:1657–1665

    CAS  PubMed  Google Scholar 

  12. Ward RL, Cheong K, Ku SL et al (2003) Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J Clin Oncol 21:3729–3736

    Article  CAS  PubMed  Google Scholar 

  13. Shen L, Catalano PJ, Benson AB 3rd et al (2007) Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy. Clin Cancer Res 13:6093–6098

    Article  CAS  PubMed  Google Scholar 

  14. Barault L, Charon-Barra C, Jooste V et al (2008) Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. Cancer Res 68:8541–8546

    Article  CAS  PubMed  Google Scholar 

  15. Samowitz WS, Sweeney C, Herrick J et al (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65:6063–6069

    Article  CAS  PubMed  Google Scholar 

  16. Ogino S, Goel A (2008) Molecular classification and correlates in colorectal cancer. J Mol Diagnostics 10:13–27

    Article  CAS  Google Scholar 

  17. Yoo EJ, Park SY, Cho NY et al (2008) Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with polycomb repressive marks. Virchows Arch 452:515–524

    Article  CAS  PubMed  Google Scholar 

  18. Kang GH, Lee S, Cho NY et al (2008) DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest 88:161–170

    Article  CAS  PubMed  Google Scholar 

  19. Weisenberger DJ, Campan M, Long TI et al (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33:6823–6836

    Article  CAS  PubMed  Google Scholar 

  20. Lee S, Cho NY, Choi M et al (2008) Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation. Pathol Int 58:104–113

    Article  CAS  PubMed  Google Scholar 

  21. Ogino S, Kawasaki T, Kirkner GJ et al (2007) Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. J Mol Diagnostics 9:305–314

    Article  CAS  Google Scholar 

  22. Georgiades IB, Curtis LJ, Morris RM, Bird CC, Wyllie AH (1999) Heterogeneity studies identify a subset of sporadic colorectal cancers without evidence for chromosomal or microsatellite instability. Oncogene 18:7933–7940

    Article  CAS  PubMed  Google Scholar 

  23. Goel A, Arnold CN, Niedzwiecki D et al (2003) Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res 63:1608–1614

    CAS  PubMed  Google Scholar 

  24. Cheng YW, Pincas H, Bacolod MD et al (2008) CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clin Cancer Res 14:6005–6013

    Article  CAS  PubMed  Google Scholar 

  25. Goel A, Nagasaka T, Arnold CN et al (2007) The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer. Gastroenterology 132:127–138

    Article  CAS  PubMed  Google Scholar 

  26. Ogino S, Nosho K, Kirkner GJ et al (2009) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58:90–96

    Article  PubMed  Google Scholar 

  27. Herman JG, Umar A, Polyak K et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875

    Article  CAS  PubMed  Google Scholar 

  28. Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomaki P (2000) Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 156:1773–1779

    CAS  PubMed  Google Scholar 

  29. Cunningham JM, Christensen ER, Tester DJ et al (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58:3455–3460

    CAS  PubMed  Google Scholar 

  30. Cunningham JM, Kim CY, Christensen ER et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69:780–790

    Article  CAS  PubMed  Google Scholar 

  31. Yuen ST, Davies H, Chan TL et al (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455

    CAS  PubMed  Google Scholar 

  32. Chang SC, Lin JK, Yang SH et al (2006) Relationship between genetic alterations and prognosis in sporadic colorectal cancer. Int J Cancer 118:1721–1727

    Article  CAS  PubMed  Google Scholar 

  33. Nagasaka T, Sasamoto H, Notohara K et al (2004) Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. J Clin Oncol 22:4584–4594

    Article  CAS  PubMed  Google Scholar 

  34. Fransen K, Klintenas M, Osterstrom A et al (2004) Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis 25:527–533

    Article  CAS  PubMed  Google Scholar 

  35. Vilkin A, Niv Y, Nagasaka T et al (2009) Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel. Cancer 115:760–769

    Article  CAS  PubMed  Google Scholar 

  36. Young J, Barker MA, Simms LA et al (2005) Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer. Clin Gastroenterol Hepatol 3:254–263

    Article  CAS  PubMed  Google Scholar 

  37. Samowitz WS, Slattery ML, Sweeney C et al (2007) APC mutations and other genetic and epigenetic changes in colon cancer. Mol Cancer Res 5:165–170

    Article  CAS  PubMed  Google Scholar 

  38. Tanaka H, Deng G, Matsuzaki K et al (2006) BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer. Int J Cancer 118:2765–2771

    Article  CAS  PubMed  Google Scholar 

  39. Rajagopalan H, Bardelli A, Lengauer C et al (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934

    Article  CAS  PubMed  Google Scholar 

  40. Oliveira C, Pinto M, Duval A et al (2003) BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene 22:9192–9196

    Article  CAS  PubMed  Google Scholar 

  41. Ogino S, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS (2006) CpG island methylator phenotype-low (CIMP-low) in colorectal cancer: possible associations with male sex and KRAS mutations. J Mol Diagnostics 8:582–588

    Article  CAS  Google Scholar 

  42. Rashid A, Shen L, Morris JS, Issa JP, Hamilton SR (2001) CpG island methylation in colorectal adenomas. Am J Pathol 159:1129–1135

    CAS  PubMed  Google Scholar 

  43. Jass JR, Baker K, Zlobec I et al (2006) Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer. Histopathology 49:121–131

    Article  CAS  PubMed  Google Scholar 

  44. Kakar S, Deng G, Cun L, Sahai V, Kim YS (2008) CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component. Hum Pathol 39:30–36

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the 21C Frontier Functional Human Genome Project from the Ministry of Science & Technology in Korea (FG09-11-02) and by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (0720540).

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Jongno-gu, Seoul, 110-744, South Korea

    Jung Ho Kim, Hyeong Ju Kwon & Gyeong Hoon Kang

  2. Laboratory of Epigenetics, Cancer Research Institute and 2nd Stage Brain Korea, Seoul National University College of Medicine, Seoul, South Korea

    So Hyun Shin, Nam Yun Cho & Gyeong Hoon Kang

Authors
  1. Jung Ho Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. So Hyun Shin
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Hyeong Ju Kwon
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Nam Yun Cho
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Gyeong Hoon Kang
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Gyeong Hoon Kang.

ELECTRONIC SUPPLEMENTARY MATERIAL

Below is the link to the electronic supplementary material.

Supplementary Table 1

(DOC 43 kb)

Supplementary Table 2

(DOC 58.5 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J.H., Shin, S.H., Kwon, H.J. et al. Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers. Virchows Arch 455, 485–494 (2009). https://doi.org/10.1007/s00428-009-0857-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-009-0857-0

Keywords