Clonal expansion in the human gut: mitochondrial DNA mutations show us the way.
The mechanisms of how DNA mutations are fixed within the human gastrointestinal tract and how they spread are poorly understood and are hotly debated. It has been well documented that human colonic crypts are clonal units; one epithelial stem cell within the crypt becoming dominant and taking over the crypts' entire stem cell population--so called monoclonal conversion. Studies have revealed that crypts can exist as families and develop into patches. The questions have been how do such patches in the human colon develop? Does this have implications on how DNA mutations spread? We have previously shown that mitochondrial DNA (mtDNA) mutations, which result in the deficiency of cytochrome c oxidase, are established within a single colonic crypt stem cell, resulting in a crypt with a mixed phenotype. Over time that mutated stem cell can take over the entire stem cell population resulting in a wholly-mutated crypt. We have furthered this research by showing that entirely cytochrome c oxidase-deficient crypts are able to divide by a process called crypt fission, to form two cytochrome c oxidase-deficient daughter crypts, each sharing the exact parental mtDNA mutation. Furthermore, patches of these crypts also possess a founder mtDNA mutation suggesting that fission repeats itself to form patches, which increase in size with age. Here, we hypothesize that this can be expanded into other areas of the gastrointestinal tract, especially the stomach, where there is a paucity of data regarding clonality and the spread of DNA mutations. We ask if these mutated crypts expand at a different rate to wild type ones. We also discuss the implications for the spread of potential carcinogenic mutations within the gut.
McDonald
Stuart A C
SA
Histopathology Unit, London Research Institute, Cancer Research UK, London, UK. stuart.mcdonald@cancer.org.uk
Preston
Sean L
SL
Greaves
Laura C
LC
Leedham
Simon J
SJ
Lovell
Matthew A
MA
Jankowski
Janusz A Z
JA
Turnbull
Douglass M
DM
Wright
Nicholas A
NA
D003106:Colon / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D041981:Gastrointestinal Tract / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D013234:Stem Cells / Q000378:metabolism
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV