Decreased mitochondrial DNA mutagenesis in human colorectal cancer.
PLoS Genet
; 8(6): e1002689, 2012.
Article
em En
| MEDLINE
| ID: mdl-22685414
ABSTRACT
Genome instability is regarded as a hallmark of cancer. Human tumors frequently carry clonally expanded mutations in their mitochondrial DNA (mtDNA), some of which may drive cancer progression and metastasis. The high prevalence of clonal mutations in tumor mtDNA has commonly led to the assumption that the mitochondrial genome in cancer is genetically unstable, yet this hypothesis has not been experimentally tested. In this study, we directly measured the frequency of non-clonal (random) de novo single base substitutions in the mtDNA of human colorectal cancers. Remarkably, tumor tissue exhibited a decreased prevalence of these mutations relative to adjacent non-tumor tissue. The difference in mutation burden was attributable to a reduction in CG to TA transitions, which are associated with oxidative damage. We demonstrate that the lower random mutation frequency in tumor tissue was also coupled with a shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, as compared to non-neoplastic colon. Together these findings raise the intriguing possibility that fidelity of mitochondrial genome is, in fact, increased in cancer as a result of a decrease in reactive oxygen species-mediated mtDNA damage.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Neoplasias Colorretais
/
Mutagênese
/
Mutação Puntual
Tipo de estudo:
Risk_factors_studies
Limite:
Aged
/
Aged80
/
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
PLoS Genet
Assunto da revista:
GENETICA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos