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  • Review Article
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Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis

Nature Reviews Gastroenterology & Hepatology volume 8, pages 395–404 (2011)Cite this article

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Abstract

One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses on the current understanding of the pathogenesis of ulcerative colitis-associated colorectal cancer and how this knowledge can be transferred into patient management to assist clinicians and pathologists in identifying patients with ulcerative colitis who have an increased risk of colorectal cancer. Inflammation-driven mechanisms of DNA damage, including the generation and effects of reactive oxygen species, microsatellite instability, telomere shortening and chromosomal instability, are reviewed, as are the molecular responses to genomic stress. We also discuss how these mechanisms can be translated into usable biomarkers. Although progress has been made in the understanding of inflammation-driven carcinogenesis, markers based on these findings possess insufficient sensitivity or specificity to be usable as reliable biomarkers for risk of colorectal cancer development in patients with ulcerative colitis. However, screening for mutations in p53 could be relevant in the surveillance of patients with ulcerative colitis. Several other new biomarkers, including senescence markers and α-methylacyl-CoA-racemase, might be future candidates for preneoplastic markers in ulcerative colitis.

Key Points

  • Pathogenesis of colorectal cancer in patients with ulcerative colitis is driven by inflammation-dependent mechanisms

  • The generation of reactive oxygen species in epithelial cells and the exposure of epithelial cell DNA to these molecules may be important for the development of colorectal cancer in ulcerative colitis

  • p53 mutations and chromosomal instability are the most promising biomarkers of premalignancy, and could be used in combination with histological evaluation to identify patients at high risk of developing colorectal cancer

  • Senescence and α-methylacyl-CoA-racemase are promising new candidates for preneoplastic biomarkers in ulcerative colitis

  • The clinical implications and reliability of biomarkers of premalignancy in ulcerative colitis remains to be established in prospective studies

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Figure 1: Mechanisms underlying carcinogenesis in ulcerative colitis. Ulcerative colitis is characterized by an increased number of immune cells in the mucosa.
Figure 2: Immunohistochemical staining of γ-H2A.x in a colonic biopsy sample from a patient with ulcerative colitis.

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Acknowledgements

This study was supported by grants from Fonden til Lægevidenskabens Fremme (the A. P. Møller Foundation), the Family Erichsen Memorial Foundation, the Lundbeck Foundation, the Axel Muusfeldts Foundation, and the Aase and Ejnar Danielsen Foundation.

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Authors and Affiliations

  1. Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 75 Herlev Ringvej, Herlev, DK-2730, Denmark

    Sigrun Thorsteinsdottir, Ole Haagen Nielsen & Jakob Benedict Seidelin

  2. Center for Genotoxic Stress Research, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen, DK-2100, Denmark

    Thorkell Gudjonsson

  3. Department of Pathology, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, Copenhagen, DK-2100, Denmark

    Ben Vainer

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  1. Sigrun Thorsteinsdottir
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  2. Thorkell Gudjonsson
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  3. Ole Haagen Nielsen
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  5. Jakob Benedict Seidelin
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All authors contributed equally to all aspects of preparation of the manuscript.

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Correspondence to Jakob Benedict Seidelin.

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Thorsteinsdottir, S., Gudjonsson, T., Nielsen, O. et al. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis. Nat Rev Gastroenterol Hepatol 8, 395–404 (2011). https://doi.org/10.1038/nrgastro.2011.96

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