Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells.
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.
McDonald
Stuart A C
SA
Histopathology Unit, London Research Institute, Cancer Research UK, London, United Kingdom. stuart.mcdonald@cancer.org.uk
Greaves
Laura C
LC
Gutierrez-Gonzalez
Lydia
L
Rodriguez-Justo
Manuel
M
Deheragoda
Maesha
M
Leedham
Simon J
SJ
Taylor
Robert W
RW
Lee
Chung Yin
CY
Preston
Sean L
SL
Lovell
Matthew
M
Hunt
Toby
T
Elia
George
G
Oukrif
Dahmane
D
Harrison
Rebecca
R
Novelli
Marco R
MR
Mitchell
Ian
I
Stoker
David L
DL
Turnbull
Douglass M
DM
Jankowski
Janusz A Z
JA
Wright
Nicholas A
NA
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*
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV