ArticleGastroenterology2021
A Diffusion-like Process Accommodates New Crypts During Clonal Expansion in Human Colonic Epithelium.
Article in Gastroenterology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
6 citing papers in PubMed, 13 citations in OpenAlex.
- Review
- Paired mutation calling and spatial transcriptomics identify cellular neighborhoods associated with the neoplastic outcome of mouse colitis.Nature genetics · 2026Article
- Clonal biases dictate availability of colonic cancer driver mutations for transformation.Nature communications · 2026Article
- Article
- Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets.Signal transduction and targeted therapy · 2024Review
- Colorectal Cancer Is Associated with the Presence of Cancer Driver Mutations in Normal Colon.Cancer research · 2022Article
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Authors and funding
15 authors at 8 institutions in 2 countries.
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Abstract
BACKGROUND &
aimsColorectal 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 determine how advantaged expansions can be accommodated in the human colon.
methodsImmunohistochemistry was used to visualize loss of the cancer driver KDM6A in formalin-fixed paraffin-embedded (FFPE) normal human colonic epithelium. Combining microscopy with neural network-based image analysis, we determined the frequencies of KDM6A-mutant crypts and fission/fusion intermediates as well as the spatial distribution of clones. Mathematical modeling then defined the dynamics of their fixation and expansion.
resultsInterpretation of the age-related behavior of KDM6A-negative clones revealed significant competitive advantage in intracrypt dynamics as well as a 5-fold increase in crypt fission rate. This was not accompanied by an increase in crypt fusion. Mathematical modeling of crypt spacing identifies 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.
conclusionsAdvantaged 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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