title: Quantification of crypt and stem cell evolution in the normal and neoplastic human colon.
abstract: Human intestinal stem cell and crypt dynamics remain poorly characterized because transgenic lineage-tracing methods are impractical in humans. Here, we have circumvented this problem by quantitatively using somatic mtDNA mutations to trace clonal lineages. By analyzing clonal imprints on the walls of colonic crypts, we show that human intestinal stem cells conform to one-dimensional neutral drift dynamics with a "functional" stem cell number of five to six in both normal patients and individuals with familial adenomatous polyposis (germline APC(-/+)). Furthermore, we show that, in adenomatous crypts (APC(-/-)), there is a proportionate increase in both functional stem cell number and the loss/replacement rate. Finally, by analyzing fields of mtDNA mutant crypts, we show that a normal colon crypt divides around once every 30-40 years, and the division rate is increased in adenomas by at least an order of magnitude. These data provide in vivo quantification of human intestinal stem cell and crypt dynamics.
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Baker
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Biancastella
authors.initials: B
authors.lastname: Cereser
authors.affiliation: Cavendish Laboratory, Department of Physics, J.J. Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Melton
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford OX2 6GG, UK.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Fletcher
authors.affiliation: Department of Histopathology, University College London, London WC1E 6BT, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.affiliation: Cellular Pathology, Northwest London Hospitals NHS Trust, London HA1 3UJ, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tadrous
authors.affiliation: St. Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Humphries
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.affiliation: Cavendish Laboratory, Department of Physics, J.J. Thomson Avenue, University of Cambridge, Cambridge CB3 0HE, UK; The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; The Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Simons
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Department of Pathology, Academic Medical Centre, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; Center for Evolution and Cancer, 2340 Sutter Street, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: t.graham@qmul.ac.uk.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
mesh_terms: D058739:Aberrant Crypt Foci / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology*; D053687:Adult Stem Cells / Q000502:physiology; D001483:Base Sequence; D016022:Case-Control Studies; D002454:Cell Differentiation; D049109:Cell Proliferation; D003106:Colon / Q000473:pathology*; D004252:DNA Mutational Analysis; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D009154:Mutation