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BACKGROUND & AIMS: Colorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads to clonal expansion and ultimately neoplastic transformation. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in normal epithelium is key to understanding colorectal cancer initiation. The aim of the present study was to understand how advantaged expansions can be accommodated in the human colon. METHODS: We used immunohistochemistry to visualise loss of the cancer driver KDM6A in formalin-fixed paraffin embedded (FFPE) normal human colonic epithelium. Using microscopy combined with neural network-based image analysis we determined the frequencies of KDM6A-mutant crypts as well as the expansion of clones into large areas by fission and fusion. We then used mathematical modelling to define the dynamics of fixation and expansion. RESULTS: Interpretation of the age-related behaviour of KDM6A-negative clones revealed significant competitive advantage in intra-crypt dynamics as well as a 5-fold increase in crypt fission rate. This was not accompanied by an increase in crypt fusion. Using mathematical modelling of crypt spacing we present evidence for a crypt diffusion process. We define the threshold fission rate at which diffusion fails to accommodate new crypts, which can be exceeded by KRAS activating mutations. CONCLUSIONS: Advantaged gene mutations in KDM6A expand dramatically by crypt fission but not fusion. The crypt diffusion process enables accommodation of the additional crypts up to a threshold value, beyond which polyp growth may occur. The fission rate associated with KRAS mutations offers a potential explanation for KRAS-initiated polyps.

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colorectal cancer initiation, crypt fission, crypt fusion, intestinal crypt