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PTH-083 Methylation Signatures of Non-Expressed Genes Reveal Insights into the Effects of Inflammation on Stem Cell Dynamics and Crypt Fission in Inflammatory Bowel Disease
  1. N Jawad1,
  2. T Graham2,
  3. M Novelli3,
  4. M Rodriguez-Justo3,
  5. N Wright1,
  6. S McDonald1
  1. 1Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  2. 2Centre for Evolution and Cancer, University of California at San Francisco, San Francisco, United States
  3. 3Histopathology Department, University College Hospital, London, UK

Abstract

Introduction Inflammatory bowel disease (IBD) confers a high risk of development of colitis-associated colorectal cancer (CACRC) in patients with extensive colitis. Crypt fission (a crypt bifurcating into two) has been shown to be a mechanism of clonal expansion in the intestinal epithelium. Although fission is rare in normal colon, many crypts in patients with colitis appear to be in the process of fission. A recent study from the host laboratory demonstrated that protumourigenic mutations can spread through the entire inflamed colon suggesting that this occurs at a considerable rate indicating stem cell dynamics are altered in IBD1.

Methods Somatic mitochondrial DNA (mtDNA) mutations are a reliable marker of clonal expansion in human colon. Combining mtDNA mutations with additional markers of clonal expansion that change over time, such as methylation patterns of non-expressed genes, reveals whether populations of cells show a recent ancestry. This is measured by evaluating methylation pattern diversity between samples. Methylation patterns of CSX and MYOD1 genes were examined in clonally related and unrelated crypts from multiple areas in IBD patients by laser capture microdissection bisulphite sequencing. Clonality was demonstrated by cytochrome c oxidase deficient (CCO-) cells sharing an identical somatic mtDNA mutation.

Results In active inflammation, both adjacent clonally related CCO- crypts and adjacent unrelated crypts had similar methylation patterns, indicating recent crypt fission. In contrast, adjacent unrelated crypts in quiescent disease had dissimilar methylation patterns, indicating that crypt fission rates are slow and resemble that of normal colon. The number of unique methylation patterns in crypts from active IBD were significantly less than those obtained from normal patients suggesting that niche succession (a stem cell populating the niche) is elevated in IBD.

Conclusion Elevated crypt fission in active IBD may explain the extensive dispersion of protumourigenic clones previously observed in IBD. Subsequent cycles of crypt atrophy and mucosal healing by crypt fission, may provide a key growth stimulus in the inflamed colon. Furthermore, there appears to be an increased rate at which a single stem cell populates the niche within IBD crypts. Such expansion facilitates the establishment of protumourgenic mutations within crypts.

Disclosure of Interest None Declared.

Reference

  1. Galandiuk S, Rodriguez-Justo M, Jeffery R, Nicholson AM, Cheng Y, Oukrif D, Elia G, Leedham SJ, McDonald SA, Wright NA et al. 2012. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis. Gastroenterology 142: 855–864 e858

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