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OC-016 Human colorectal adenoma growth is characterised by periods of quiescence and rapid clonal expansion
  1. A Humphries1,
  2. T A Graham2,
  3. B Cereser3,
  4. S A McDonald3,
  5. N A Wright3
  1. 1Department of Gastroenterology, St Mark's Hospital, London, UK
  2. 2UCSF Medical Centre, San Francisco, USA
  3. 3Centre for Digestive Diseases, Barts and The London School of Medicine and Dentistry, London, UK

Abstract

Introduction Very little is known about the dynamics and rates of adenoma growth in the human colon. Longitudinal barium and endoscopic studies demonstrate most smaller adenomas to be static over many years, with a significant proportion even regressing.1 2 We have recently shown that methylation patterns at CpG loci within non-expressed genes can be used to infer the dynamics of clonal expansion in the normal human colon.3 By combining clonal mutational analysis with sampling of these methylation patterns for crypts within human adenomas, we aimed to learn more about how these important pre-malignant epithelial lesions grow.

Methods Fresh frozen human adenomas were screened for common tumourigenic mutations known to occur in adenoma progression. Multiple individual crypts spaced across the whole lesion were then laser-capture micro-dissected, the mutation(s) detected at screening confirmed and methylation tags at CpG islands of non-expressed genes sampled in order to infer dynamics and patterns of growth.

Results Crypts within adenomas clonal for APC and KRAS mutations demonstrated significantly less methylation pattern diversity than those from adenomas that were clonal for an APC mutation only, suggesting there had been a recent, rapid clonal expansion in the APC/KRAS mutated lesions. Genetically distinct sub-clones could be identified within adenomas, and analysis of methylation patterns showed them to be expanding rapidly. There was no correlation between the spatial separation of crypts and their respective epigenetic distances—as measured by comparisons of crypt methylation patterns—within the adenomas studied. Therefore, in those lesions that had not undergone a recent clonal expansion, there had been a sufficient time period of little or no growth to allow the methylation patterns of neighbouring crypts to diverge.

Conclusion The data collected here suggests that human adenomas display punctuated growth, characterised by periods of relative quiescence and rapid clonal expansion. Further data collection and analysis should allow the relative growth rates of genetically distinct lesions and sub-clones within adenomas to be estimated, and may help better inform our management and follow-up of patients with these lesions.

Competing interests None declared.

References 1. Hofstad B, et al. Gut 1996;39:449–56.

2. Welin, et al. Am J Roentgenol Radium Ther Nucl Med 1963;90:673–87.

3. Graham TA, et al. Gastroenterology 2011;140:1241–50.

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