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Cell Stem Cell. 2018 Jun 1;22(6):909-918.e8. doi: 10.1016/j.stem.2018.04.020. Epub 2018 May 17.

Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium.

Author information

1
Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
2
Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute, Cambridge, UK.
3
Norwich Research Park BioRepository, James Watson Road, Norwich NR4 7UQ, UK.
4
Pathology and Tumour Biology, Level 4, Wellcome Trust Brenner Building, St. James University Hospital, Beckett Street, Leeds LS9 7TF, UK.
5
Department of Histopathology, Box 235, CUHFT, Cambridge, UK.
6
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala 751 85, Sweden.
7
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-120, 3900 NCTR Road, Jefferson, AR 72079, USA.
8
MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Electronic address: edward.morrissey@imm.ox.ac.uk.
9
Cancer Research-UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK. Electronic address: doug.winton@cruk.cam.ac.uk.

Abstract

We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred.

KEYWORDS:

clone; colon; crypt; dynamics; epithelium; expansion; fission; human; mutation; stem cells

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