DNA Methylation in Colorectal Cancer

  • Jeremy R. Jass
  • Vicki L. J. Whitehall
  • Joanne Young
  • Barbara A. Leggett
Part of the Medical Intelligence Unit book series (MIUN)


In this chapter, it is pointed out that colorectal cancer is a heterogeneous disease. The case is made for a ‘serrated pathway’ of neoplasia that would evolve relatively rapidly through the early acquisition of DNA instability. DNA hypermethylation is likely to be of critical importance in driving this pathway. Inhibition of apoptosis is conceived as the first step. Thereafter, methylation of one of several DNA repair genes would result in a state of tolerated hypermutability. It remains to be shown whether this model applies to a small subset of colorectal cancers or in fact explains the great majority given the overall low risk of progression for an individual adenoma initiated by mutation of APC.


Colorectal Cancer Familial Adenomatous Polyposis Lynch Syndrome Microsatellite Instability Hyperplastic Polyp 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bussey HJR. Familial Polyposis Coli. Baltimore: Johns Hopkins Press; 1975.Google Scholar
  2. 2.
    Lynch HT, Smyrk T, Lynch JF. Overview of natural history, pathology, molecular genetics and mangement of HNPCC (Lynch syndrome). Int J Cancer 1996; 69:38–43.PubMedCrossRefGoogle Scholar
  3. 3.
    Järvinen HJ, Aarnio M, Mustonen H et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118:829–834.PubMedCrossRefGoogle Scholar
  4. 4.
    Pollock AM, Quirke P. Adenoma screening and colorectal cancer. The need for screening and polypectomy is unproved. Br J Med 1991; 303:3–4.Google Scholar
  5. 5.
    Jass JR. Serrated route to colorectal cancer: back street or super highway? J Pathol 2001; 193:283–285.PubMedCrossRefGoogle Scholar
  6. 6.
    Takayama T, Ohi M, Hayashi T et al. Analysis of K-ras, APC, and beta-catenin in aberrant crypt foci in sporadic adenoma, cancer, and familial adenomatous polyposis. Gastroenterology 2001; 121:599–611.PubMedCrossRefGoogle Scholar
  7. 7.
    Lamlum H, Papadopoulou A, Ilyas M et al. APC mutations are sufficient for the growth of early colorectal adenomas. Proc Natl Acad Sci USA 2000; 97:2225–2228.PubMedCrossRefGoogle Scholar
  8. 8.
    Fishel R. The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. Cancer Res 2001; 61:7369–7374.PubMedGoogle Scholar
  9. 9.
    Boland CR, Thibodeau SN, Hamilton SR 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; 58:5248–5257.PubMedGoogle Scholar
  10. 10.
    Dietmaier W, Wallinger S, Bocker T et al. Diagnostic microsatellite instability: Definition and correlation with mismatch repair protein expression. Cancer Res 1997; 57:4749–4756.PubMedGoogle Scholar
  11. 11.
    Young J, Simms LA, Biden KG et al. Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: Parallel pathways of tumorigenesis. Am J Pathol 2001; 159:2107–2116.PubMedGoogle Scholar
  12. 12.
    Halford S, Sasieni P, Rowan A et al. Low-level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative trait. Cancer Res 2002; 62:53–57.PubMedGoogle Scholar
  13. 13.
    Jass JR, Biden KG, Cummings M et al. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 1999; 52:455–460.PubMedCrossRefGoogle Scholar
  14. 14.
    Jass JR, Young J, Leggett BA. Evolution of colorectal cancer: Change of pace and change of direction. J Gastroenterol Hepatol 2002; 17:17–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Tomlinson I, Bodmer W. Selection, the mutation rate and cancer: Ensuring that the tail does not wag the dog. Nature Med 1999; 5:11–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Fenton RG, Hixon JA, Wright PW et al. Inhibition of Fas (CD95) expression and Fas-mediated apoptosis by oncogenic. Ras Cancer Res 1998; 58:3391–3400.Google Scholar
  17. 17.
    Jass JR, Iino H, Ruszkiewicz A et al. Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 2000; 47:43–49.PubMedCrossRefGoogle Scholar
  18. 18.
    Esteller M, Hamilton SR, Burger PC et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999; 59:793–797.PubMedGoogle Scholar
  19. 19.
    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; 57:808–811.PubMedGoogle Scholar
  20. 20.
    Esteller M, Toyota M, Sanchez-Cespedes M et al. Inactivation of the DNA repair gene 06-Methylguanine-DNA Methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 2000; 60:2368–2371.PubMedGoogle Scholar
  21. 21.
    Toyota M, Ahuja N, Ohe-Toyota M et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999; 96:8681–8686.PubMedCrossRefGoogle Scholar
  22. 22.
    Toyota M, Ohe-Toyota M, Ahuja N et al. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA 2000; 97:710–715.PubMedCrossRefGoogle Scholar
  23. 23.
    Hawkins N, Norrie M, Cheong K et al. CpG island methylation in sporadic colorectal cancer and its relationship to microsatellite instability. Gastroenterology 2002; 122:1376–1387.PubMedCrossRefGoogle Scholar
  24. 24.
    Robertson KD, Jones PA. The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol Cell Biol 1998; 18:6457–6473.PubMedGoogle Scholar
  25. 25.
    Young JP, Biden KG, Simms LA et al. HPP1: A transmembrane protein commonly methylated in colorectal polyps and cancers. Proc Natl Acad Sci USA 2001; 98:265–270.PubMedCrossRefGoogle Scholar
  26. 26.
    Toyota M, Shen L, Ohe-Toyota M et al. Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res 2000; 60:4044–4048.PubMedGoogle Scholar
  27. 27.
    Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319:525–532.PubMedCrossRefGoogle Scholar
  28. 28.
    Whitehall VLJ, Wynter CVA, Walsh MD et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res 2002; 62:6011–6014.PubMedGoogle Scholar
  29. 29.
    Whitehall VLJ, Walsh MD, Young J et al. Methylation of 0-6-Methylguanine DNA Methyltransferase characterises a subset of colorectal cancer with low level DNA microsatellite instability. Cancer Res 2001; 61:827–830.PubMedGoogle Scholar
  30. 30.
    Esteller M, Risques RA, Toyota M et al. Promoter hypermethylation of the DNA repair gene O6-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 2001; 61:4689–4692.PubMedGoogle Scholar
  31. 31.
    Fink D, Aebi S, Howell SB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res 1998; 4:1–6.PubMedGoogle Scholar
  32. 32.
    Berardini M, Mazurek A, Fishel R. The effect of O6-methylguanine DNA adducts on the adenosine nucleotide switch functions of hMSH2-hMSH6 and hMSH2-hMSH3. J Biol Chem 2000; 275:27851–27857.PubMedGoogle Scholar
  33. 33.
    Issa J-PJ, Ottaviano YL, Celano P et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994; 7:536–540.PubMedCrossRefGoogle Scholar
  34. 34.
    Yatabe Y, Tavare S, Shibata D. Investigating stem cells in human colon by using methylation patterns. Proc Natl Acad Sci USA 2001; 98:10839–10844.PubMedCrossRefGoogle Scholar
  35. 35.
    Chan AO-O, Issa J-PJ, Morris JS et al. Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 2002; 160:529–536.PubMedGoogle Scholar
  36. 36.
    Rashid A, Shen L, Morris JS et al. CpG island methylation in colorectal adenomas. Am J Pathol 2001; 159:1129–1135.PubMedGoogle Scholar
  37. 37.
    Jeevaratnam P, Cottier DS, Browett PJ et al. Familial giant hyperplastic polyposis predisposing to colorectal cancer: A new hereditary bowel cancer syndrome. J Pathol 1996; 179:20–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Jass JR, Cottier DS, Pokos V et al. Mixed epithelial polyps in association with hereditary nonpolyposis colorectal cancer providing an alternative pathway of cancer histogenesis. Pathology 1997; 29:28–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Rashid A, Houlihan S, Booker S et al. Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 2000; 119:323–332.PubMedCrossRefGoogle Scholar
  40. 40.
    Biemer-Hüttmann A-E, Walsh MD, McGuckin MA et al. Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum. J Histochem Cytochem 1999; 47:1039–1047.PubMedGoogle Scholar
  41. 41.
    Biemer-Hüttmann A-E, Walsh MD, McGuckin MA et al. Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin Cancer Res 2000; 6:1909–1916.PubMedGoogle Scholar
  42. 42.
    Jass JR, Young J, Leggett BA. Hyperplastic polyps and DNA microsatellite unstable cancers of the colorectum. Histopathology 2000; 37:295–301.PubMedCrossRefGoogle Scholar
  43. 43.
    Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J. Natl Cancer Inst 2001; 93:1307–1313.PubMedCrossRefGoogle Scholar
  44. 44.
    Mäkinen MJ, George SMC, Jernvall P et al. Colorectal carcinoma associated with serrated adenoma-prevalence, histological features, and prognosis. J Pathol 2001; 193:286–294.PubMedCrossRefGoogle Scholar
  45. 45.
    Park S-J, Rashid A, Lee J-H et al. Frequent CpG island methylation in serrated adenomas of the colorectum. Am J Pathol 2003; 162:815–822.PubMedGoogle Scholar
  46. 46.
    Pfeifer GP, Steigerwald SD, Hansen RS et al. Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. Proc Natl Acad Sci USA 1990; 87:8252–8256.PubMedCrossRefGoogle Scholar
  47. 47.
    Nasr AF, Nutini M, Palombo B et al. Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene. Oncogene 2003; 22:1668–1677.PubMedCrossRefGoogle Scholar
  48. 48.
    Shen L, Yutaka K, Hamilton SR et al. p14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53. Gastroenterology 2003; 124:626–633.PubMedCrossRefGoogle Scholar

Copyright information

© and Kluwer Academic/Plenum Publishers 2005

Authors and Affiliations

  • Jeremy R. Jass
    • 1
  • Vicki L. J. Whitehall
    • 2
  • Joanne Young
    • 2
  • Barbara A. Leggett
    • 2
  1. 1.Department of PathologyMcGill UniversityMontrealCanada
  2. 2.Conjoint Gastroenterology LaboratoryBancroft CentreBrisbaneAustralia

Personalised recommendations