title: The clonal origins of dysplasia from intestinal metaplasia in the human stomach.
abstract: OBJECTIVE
  Studies of the clonal architecture of gastric glands with intestinal metaplasia are important in our understanding of the progression from metaplasia to dysplasia. It is not clear if dysplasias are derived from intestinal metaplasia or how dysplasias expand. We investigated whether cells within a metaplastic gland share a common origin, whether glands clonally expand by fission, and determine if such metaplastic glands are genetically related to the associated dysplasia. We also examined the clonal architecture of entire dysplastic lesions and the genetic changes associated with progression within dysplasia.
  
  
  METHODS
  Cytochrome c oxidase-deficient (CCO⁻) metaplastic glands were identified using a dual enzyme histochemical assay. Clonality was assessed by laser capture of multiple cells throughout CCO⁻ glands and polymerase chain reaction sequencing of the entire mitochondrial DNA (mtDNA) genome. Nuclear DNA abnormalities in individual glands were identified by laser capture microdissection polymerase chain reaction sequencing for mutation hot spots and microsatellite loss of heterozygosity analysis.
  
  
  RESULTS
  Metaplastic glands were derived from the same clone-all lineages shared a common mtDNA mutation. Mutated glands were found in patches that had developed through gland fission. Metaplastic and dysplastic glands can be genetically related, indicating the clonal origin of dysplasia from metaplasia. Entire dysplastic fields contained a founder mutation from which multiple, distinct subclones developed.
  
  
  CONCLUSIONS
  There is evidence for a distinct clonal evolution from metaplasia to dysplasia in the human stomach. By field cancerization, a single clone can expand to form an entire dysplastic lesion. Over time, this field appears to become genetically diverse, indicating that gastric cancer can arise from a subclone of the founder mutation.
authors.affiliation: Histopathology Laboratory, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Gutierrez-Gonzalez
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Justo
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leedham
authors.forename: Marco R
authors.initials: MR
authors.lastname: Novelli
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Gay
authors.forename: Tania
authors.initials: T
authors.lastname: Ventayol-Garcia
authors.forename: Alicia
authors.initials: A
authors.lastname: Green
authors.forename: Ian
authors.initials: I
authors.lastname: Mitchell
authors.forename: David L
authors.initials: DL
authors.lastname: Stoker
authors.forename: Sean L
authors.initials: SL
authors.lastname: Preston
authors.forename: Shigeki
authors.initials: S
authors.lastname: Bamba
authors.forename: Eiji
authors.initials: E
authors.lastname: Yamada
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kishi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Jankowski
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Wright
authors.forename: Stuart A C
authors.initials: SA
authors.lastname: McDonald
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000368:Aged; D002455:Cell Division / Q000502:physiology; D002999:Clone Cells / Q000473:pathology* / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D018703:Founder Effect; D005753:Gastric Mucosa / Q000473:pathology* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008679:Metaplasia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV