A diffusion-like process enables expansion of advantaged gene mutations in human colonic epithelium
Cora Olpe; Doran Khamis; Maria Chukanova; Richard Kemp; Kate Marks; Cerys Tatton; Cecilia Lindskog; Nefeli Skoufou-Papoutsaki; Anna M Nicholson; Roxanne Brunton-Sim; Shalini Malhotra; Rogier ten Hoopen; Rachel Stanley; Edward Morrissey; Douglas J Winton
Show abstract
Colorectal cancer is thought to arise when the mutational burden of the clonal population of stem cells within a colonic crypt exceeds a certain threshold. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in histologically normal epithelium is key to understanding colorectal cancer initiation. Here, using immunohistochemistry, loss of the histone demethylase KDM6A in normal human colonic epithelium is visualised. Interpretation of the age-related behaviour of KDM6A-negative clones revealed significant competitive advantage in intra-crypt dynamics. Further, subsequent clonal expansion into multi-crypt patches was quantified to reveal a significant 5-fold increase in crypt fission rate. To accomodate the local accumulation of new crypts, the role of crypt fusion was considered. However, no compensatory increase in fusion rate was found. Instead, evidence for crypt diffusion is presented and proposed as a means of accommodating clonal expansions. The threshold fission rate at which diffusion fails to accommodate new crypts, and which may promote polyp growth, is defined.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.