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Molecular Pathology of Inflammatory Bowel Disease-Associated Neoplasia

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Molecular Pathology of Neoplastic Gastrointestinal Diseases

Part of the book series: Molecular Pathology Library ((MPLB,volume 7))

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Abstract

Patients with inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) have a greater risk of developing colorectal cancer (CRC) as compared to patients without colitis, requiring increased surveillance colonoscopy. Chronic colitis may progress to dysplasia and in turn dysplastic lesions carry a high risk of progression to adenocarcinoma.

Although many molecular players are common with sporadic colorectal carcinogenesis, since IBD-associated dysplasia and cancers are initiated in a specific inflammatory milieu, these lesions are significantly different at the molecular level. This chapter will review the most recent advances in molecular alterations observed in IBD-associated neoplastic lesions. Importantly, in view of these differences, approaches used for early detection and specific targeted therapies may differ between IBD-associated and sporadic forms of CRC and pre-cancer lesions.

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References

  1. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18(Suppl 2):1–5.

    Article  PubMed  Google Scholar 

  2. Harpaz N, Talbot IC. Colorectal cancer in idiopathic inflammatory bowel disease. Semin Diagn Pathol. 1996;13:339–57.

    PubMed  CAS  Google Scholar 

  3. Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory bowel diseases. Gastroenterology. 2004;126:1634–48.

    Article  PubMed  Google Scholar 

  4. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2004;99:1371–85.

    Article  PubMed  Google Scholar 

  5. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501–23. quiz 524.

    Article  PubMed  Google Scholar 

  6. Boland CR, Luciani MG, Gasche C, Goel A. Infection, inflammation, and gastrointestinal cancer. Gut. 2005;54:1321–31.

    Article  PubMed  CAS  Google Scholar 

  7. Karrasch T, Jobin C. NF-kappaB and the intestine: friend or foe? Inflamm Bowel Dis. 2008;14:114–24.

    Article  PubMed  Google Scholar 

  8. Rose-John S, Scheller J, Elson G, Jones SA. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80:227–36.

    Article  PubMed  CAS  Google Scholar 

  9. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol. 2011;90:484–94.

    Article  PubMed  CAS  Google Scholar 

  10. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  PubMed  CAS  Google Scholar 

  11. Stenson WF. Prostaglandins and epithelial response to injury. Curr Opin Gastroenterol. 2007;23:107–10.

    Article  PubMed  CAS  Google Scholar 

  12. Itzkowitz SH. Molecular biology of dysplasia and cancer in inflammatory bowel disease. Gastroenterol Clin North Am. 2006;35:553–71.

    Article  PubMed  Google Scholar 

  13. Maia L, Dinis J, Cravo M, et al. Who takes the lead in the development of ulcerative colitis-associated colorectal cancers: mutator, suppressor, or methylator pathway? Cancer Genet Cytogenet. 2005;162:68–73.

    Article  PubMed  CAS  Google Scholar 

  14. Willenbucher RF, Aust DE, Chang CG, et al. Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. Am J Pathol. 1999;154:1825–30.

    Article  PubMed  CAS  Google Scholar 

  15. Bronner MP, O’Sullivan JN, Rabinovitch PS, et al. Genomic biomarkers to improve ulcerative colitis neoplasia surveillance. Am J Pathol. 2008;173:1853–60.

    Article  PubMed  Google Scholar 

  16. Aust DE, Terdiman JP, Willenbucher RF, et al. The APC/beta-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis. Cancer. 2002;94:1421–7.

    Article  PubMed  CAS  Google Scholar 

  17. Redston MS, Papadopoulos N, Caldas C, Kinzler KW, Kern SE. Common occurrence of APC and K-ras gene mutations in the spectrum of colitis-associated neoplasias. Gastroenterology. 1995;108:383–92.

    Article  PubMed  CAS  Google Scholar 

  18. Tomlinson I, Ilyas M, Johnson V, et al. A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. J Pathol. 1998;184:148–52.

    Article  PubMed  CAS  Google Scholar 

  19. Greenwald BD, Harpaz N, Yin J, et al. Loss of heterozygosity affecting the p53, Rb, and mcc/apc tumor suppressor gene loci in dysplastic and cancerous ulcerative colitis. Cancer Res. 1992;52: 741–5.

    PubMed  CAS  Google Scholar 

  20. Lynch HT, Lynch JF. Hereditary cancer: family history, diagnosis, molecular genetics, ecogenetics, and management strategies. Biochimie. 2002;84:3–17.

    Article  PubMed  CAS  Google Scholar 

  21. Burmer GC, Rabinovitch PS, Haggitt RC, et al. Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology. 1992;103:1602–10.

    PubMed  CAS  Google Scholar 

  22. Yin J, Harpaz N, Tong Y, et al. p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology. 1993; 104:1633–9.

    PubMed  CAS  Google Scholar 

  23. Brentnall TA, Crispin DA, Rabinovitch PS, et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology. 1994;107:369–78.

    PubMed  CAS  Google Scholar 

  24. Hussain SP, Amstad P, Raja K, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 2000;60:3333–7.

    PubMed  CAS  Google Scholar 

  25. Yagishita H, Yoshida T, Ishiguro K, Numata Y, Okayasu I. Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis. Scand J Gastroenterol. 2008;43:559–66.

    Article  PubMed  CAS  Google Scholar 

  26. Holzmann K, Klump B, Borchard F, et al. Comparative analysis of histology, DNA content, p53 and Ki-ras mutations in colectomy specimens with long-standing ulcerative colitis. Int J Cancer. 1998;76:1–6.

    Article  PubMed  CAS  Google Scholar 

  27. Meek DW. The p53 response to DNA damage. DNA Repair (Amst). 2004;3:1049–56.

    Article  CAS  Google Scholar 

  28. Jen J, Kim H, Piantadosi S, et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med. 1994;331:213–21.

    Article  PubMed  CAS  Google Scholar 

  29. van Dieren JM, Wink JC, Vissers KJ, et al. Chromosomal and microsatellite instability of adenocarcinomas and dysplastic lesions (DALM) in ulcerative colitis. Diagn Mol Pathol. 2006;15:216–22.

    Article  PubMed  Google Scholar 

  30. van der Woude CJ, Moshage H, Homan M, Kleibeuker JH, Jansen PL, van Dekken H. Expression of apoptosis related proteins during malignant progression in chronic ulcerative colitis. J Clin Pathol. 2005;58:811–4.

    Article  PubMed  Google Scholar 

  31. Chen R, Bronner MP, Crispin DA, Rabinovitch PS, Brentnall TA. Characterization of genomic instability in ulcerative colitis neoplasia leads to discovery of putative tumor suppressor regions. Cancer Genet Cytogenet. 2005;162:99–106.

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi T, Shigematsu H, Shivapurkar N, et al. Aberrant promoter methylation of multiple genes during multistep pathogenesis of colorectal cancers. Int J Cancer. 2005;118:924–31.

    Article  Google Scholar 

  33. Fleisher AS, Esteller M, Harpaz N, et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res. 2000;60:4864–8.

    PubMed  CAS  Google Scholar 

  34. Schulmann K, Mori Y, Croog V, et al. Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability. Gastroenterology. 2005;129:74–85.

    Article  PubMed  CAS  Google Scholar 

  35. Hsieh CJ, Klump B, Holzmann K, Borchard F, Gregor M, Porschen R. Hypermethylation of the p16INK4a promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58:3942–5.

    PubMed  CAS  Google Scholar 

  36. Mikami T, Yoshida T, Numata Y, et al. Low frequency of promoter methylation of O6-methylguanine DNA methyltransferase and hMLH1 in ulcerative colitis-associated tumors: comparison with sporadic colonic tumors. Am J Clin Pathol. 2007;127:366–73.

    Article  PubMed  CAS  Google Scholar 

  37. Konishi K, Shen L, Wang S, Meltzer SJ, Harpaz N, Issa JP. Rare CpG island methylator phenotype in ulcerative colitis-associated neoplasias. Gastroenterology. 2007;132:1254–60.

    Article  PubMed  CAS  Google Scholar 

  38. Chang DK, Goel A, Ricciardiello L, et al. Effect of H(2)O(2) on cell cycle and survival in DNA mismatch repair-deficient and -proficient cell lines. Cancer Lett. 2003;195:243–51.

    Article  PubMed  CAS  Google Scholar 

  39. Hofseth LJ, Saito S, Hussain SP, et al. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA. 2003;100:143–8.

    Article  PubMed  CAS  Google Scholar 

  40. Kim J, Leung W, Wu L, Graham D, Sepulveda A. Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells: a link with gastric carcinogenesis. Gastroenterology. 2000;118:A867.

    Article  Google Scholar 

  41. Park DI, Park SH, Kim SH, et al. Effect of Helicobacter pylori infection on the expression of DNA mismatch repair protein. Helicobacter. 2005;10:179–84.

    Article  PubMed  CAS  Google Scholar 

  42. Sepulveda AR, Yao Y, Yan W, et al. CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection. Gastroenterology. 2010; 138:1836–44.

    Article  PubMed  CAS  Google Scholar 

  43. Souza RF, Lei J, Yin J, et al. A transforming growth factor beta 1 receptor type II mutation in ulcerative colitis-associated neoplasms [see comments]. Gastroenterology. 1997;112:40–5.

    Article  PubMed  CAS  Google Scholar 

  44. Issa JP, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 2001;61:3573–7.

    PubMed  CAS  Google Scholar 

  45. Sato F, Shibata D, Harpaz N, et al. Aberrant methylation of the HPP1 gene in ulcerative colitis-associated colorectal carcinoma. Cancer Res. 2002;62:6820–2.

    PubMed  CAS  Google Scholar 

  46. Azarschab P, Porschen R, Gregor M, Blin N, Holzmann K. Epigenetic control of the E-cadherin gene (CDH1) by CpG methylation in colectomy samples of patients with ulcerative colitis. Genes Chromosomes Cancer. 2002;35:121–6.

    Article  PubMed  CAS  Google Scholar 

  47. Matsumura S, Oue N, Ito R, et al. The promoter methylation status of the DNA repair gene O6-methylguanine-DNA methyltransferase in ulcerative colitis. Virchows Arch. 2003;443:518–23.

    Article  PubMed  CAS  Google Scholar 

  48. Petko Z, Ghiassi M, Shuber A, et al. Aberrantly methylated CDKN2A, MGMT, and MLH1 in colon polyps and in fecal DNA from patients with colorectal polyps. Clin Cancer Res. 2005;11:1203–9.

    PubMed  CAS  Google Scholar 

  49. Dhir M, Montgomery EA, Glockner SC, et al. Epigenetic regulation of WNT signaling pathway genes in inflammatory bowel disease (IBD) associated neoplasia. J Gastrointest Surg. 2008;12:1745–53.

    Article  PubMed  Google Scholar 

  50. Lin Z, Hegarty JP, Cappel JA, et al. Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease. Clin Genet. 2011;80:59–67.

    Article  PubMed  CAS  Google Scholar 

  51. Gloria L, Cravo M, Pinto A, et al. DNA hypomethylation and proliferative activity are increased in the rectal mucosa of patients with long-standing ulcerative colitis. Cancer. 1996;78:2300–6.

    Article  PubMed  CAS  Google Scholar 

  52. Sepulveda AR, Jones D, Ogino S, et al. CpG methylation analysis–current status of clinical assays and potential applications in molecular diagnostics: a report of the Association for Molecular Pathology. J Mol Diagn. 2009;11:266–78.

    Article  PubMed  CAS  Google Scholar 

  53. Aust DE, Haase M, Dobryden L, et al. Mutations of the BRAF gene in ulcerative colitis-related colorectal carcinoma. Int J Cancer. 2005;115:673–7.

    Article  PubMed  CAS  Google Scholar 

  54. Benhattar J, Saraga E. Molecular genetics of dysplasia in ulcerative colitis. Eur J Cancer. 1995;31A:1171–3.

    Article  PubMed  CAS  Google Scholar 

  55. Wu F, Zhang S, Dassopoulos T, et al. Identification of microRNAs associated with ileal and colonic Crohn’s disease. Inflamm Bowel Dis. 2010;16:1729–38.

    Article  PubMed  Google Scholar 

  56. Dalal SR, Kwon JH. The role of MicroRNA in inflammatory bowel disease. Gastroenterol Hepatol (N Y). 2010;6:714–22.

    Google Scholar 

  57. Olaru AV, Selaru FM, Mori Y. et al. Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation. Inflamm Bowel Dis. 2011;17:221–31.

    Article  PubMed  Google Scholar 

  58. Garrity-Park MM, Loftus EV Jr, Sandborn WJ, Bryant SC, Smyrk TC. Methylation status of genes in non-neoplastic mucosa from patients with ulcerative colitis-associated colorectal cancer. Am J Gastroenterol. 2010;105:1610–9.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan

    Takeshi Uehara M.D.

  2. Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive BT6008GH, Iowa City, 52242, IA, USA

    Deqin Ma M.D., Ph.D.

  3. Department of Pathology & Cell Biology, Columbia University, 630 W 168th Street, VC-14 RM 212, New York, NY, 10032, USA

    Antonia R. Sepulveda M.D., Ph.D.

Authors
  1. Takeshi Uehara M.D.
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  2. Deqin Ma M.D., Ph.D.
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  3. Antonia R. Sepulveda M.D., Ph.D.
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Corresponding author

Correspondence to Antonia R. Sepulveda M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Pathology & Cell Biology, Columbia University, New York, 10032, New York, USA

    Antonia R. Sepulveda

  2. Division of Gastroenterology, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    John P. Lynch

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Uehara, T., Ma, D., Sepulveda, A.R. (2013). Molecular Pathology of Inflammatory Bowel Disease-Associated Neoplasia. In: Sepulveda, A., Lynch, J. (eds) Molecular Pathology of Neoplastic Gastrointestinal Diseases. Molecular Pathology Library, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-6015-2_10

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  • DOI: https://doi.org/10.1007/978-1-4614-6015-2_10

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