title: Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells.
abstract: OBJECTIVE
  How mutations are established and spread through the human stomach is unclear because the clonal structure of gastric mucosal units is unknown. Here we investigate, using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion, the clonality of the gastric unit and show how mutations expand in normal mucosa and gastric mucosa showing intestinal metaplasia. This has important implications in gastric carcinogenesis.
  
  
  METHODS
  Mutated units were identified by a histochemical method to detect activity of cytochrome c oxidase. Negative units were laser-capture microdissected, and mutations were identified by polymerase chain reaction sequencing. Differentiated epithelial cells were identified by immunohistochemistry for lineage markers.
  
  
  RESULTS
  We show that mtDNA mutations establish themselves in stem cells within normal human gastric body units, and are passed on to all their differentiated progeny, thereby providing evidence for clonal conversion to a new stem cell-derived unit-monoclonal conversion, encompassing all gastric epithelial lineages. The presence of partially mutated units indicates that more than one stem cell is present in each unit. Mutated units can divide by fission to form patches, with each unit sharing an indentical, mutant mtDNA genotype. Furthermore, we show that intestinal metaplastic crypts are clonal, possess multiple stem cells, and that fission is a mechanism by which intestinal metaplasia spreads.
  
  
  CONCLUSIONS
  These data show that human gastric body units are clonal, contain multiple multipotential stem cells, and provide definitive evidence for how mutations spread within the human stomach, and show how field cancerization develops.
authors.affiliation: Histopathology Unit, London Research Institute, Cancer Research UK, London, United Kingdom. stuart.mcdonald@cancer.org.uk
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
authors.forename: Laura C
authors.initials: LC
authors.lastname: Greaves
authors.forename: Lydia
authors.initials: L
authors.lastname: Gutierrez-Gonzalez
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.forename: Maesha
authors.initials: M
authors.lastname: Deheragoda
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leedham
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Chung Yin
authors.initials: CY
authors.lastname: Lee
authors.forename: Sean L
authors.initials: SL
authors.lastname: Preston
authors.forename: Matthew
authors.initials: M
authors.lastname: Lovell
authors.forename: Toby
authors.initials: T
authors.lastname: Hunt
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.forename: Dahmane
authors.initials: D
authors.lastname: Oukrif
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.forename: Marco R
authors.initials: MR
authors.lastname: Novelli
authors.forename: Ian
authors.initials: I
authors.lastname: Mitchell
authors.forename: David L
authors.initials: DL
authors.lastname: Stoker
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.forename: Janusz A Z
authors.initials: JA
authors.lastname: Jankowski
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D005753:Gastric Mucosa / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D008679:Metaplasia / Q000473:pathology; D039902:Multipotent Stem Cells / Q000201:enzymology / Q000473:pathology*; D009154:Mutation; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D013270:Stomach / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D013274:Stomach Neoplasms / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV