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Decreased mitochondrial DNA mutagenesis in human colorectal cancer.

Ericson NG, Kulawiec M, Vermulst M, Sheahan K, O'Sullivan J, Salk JJ, Bielas JH - PLoS Genet. (2012)

Bottom Line: 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 C:G to T:A 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Diagnostics Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

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 C:G to T:A 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.

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Decreased mtDNA Mutagenesis Is Coupled to a Shift in Glucose Metabolism.Normal (blue) and tumor (red) patient-matched colorectal tissue comparison of the mean mtDNA mutation burden (± s.e.m.) as a function of the tissue metabolic signature. This plot illustrates the inverse correlation between the level of mitochondrial respiration and mutagenesis (linear regression with 95% confidence intervals, slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71).
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pgen-1002689-g005: Decreased mtDNA Mutagenesis Is Coupled to a Shift in Glucose Metabolism.Normal (blue) and tumor (red) patient-matched colorectal tissue comparison of the mean mtDNA mutation burden (± s.e.m.) as a function of the tissue metabolic signature. This plot illustrates the inverse correlation between the level of mitochondrial respiration and mutagenesis (linear regression with 95% confidence intervals, slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71).

Mentions: Finally, to examine the relationship between energy metabolism and mtDNA mutation frequency, we plotted the random mutation frequency of all samples against the ratio of citrate to lactate (Figure 5). We found that in both normal and tumor tissue, mutation frequency decreases concomitantly with reduced mitochondrial respiration (linear regression: slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71). This is consistent with the hypothesis that a large fraction of mtDNA mutagenesis is a consequence of oxidative damage generated as a byproduct during OXPHOS and provides a plausible rationale for the decreased frequency of random mutations in tumor cells–specifically, a decrease in C∶G to T∶A transitions (Figure 3), the most commonly observed mutations resulting from oxidative damage [15].


Decreased mitochondrial DNA mutagenesis in human colorectal cancer.

Ericson NG, Kulawiec M, Vermulst M, Sheahan K, O'Sullivan J, Salk JJ, Bielas JH - PLoS Genet. (2012)

Decreased mtDNA Mutagenesis Is Coupled to a Shift in Glucose Metabolism.Normal (blue) and tumor (red) patient-matched colorectal tissue comparison of the mean mtDNA mutation burden (± s.e.m.) as a function of the tissue metabolic signature. This plot illustrates the inverse correlation between the level of mitochondrial respiration and mutagenesis (linear regression with 95% confidence intervals, slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369930&req=5

pgen-1002689-g005: Decreased mtDNA Mutagenesis Is Coupled to a Shift in Glucose Metabolism.Normal (blue) and tumor (red) patient-matched colorectal tissue comparison of the mean mtDNA mutation burden (± s.e.m.) as a function of the tissue metabolic signature. This plot illustrates the inverse correlation between the level of mitochondrial respiration and mutagenesis (linear regression with 95% confidence intervals, slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71).
Mentions: Finally, to examine the relationship between energy metabolism and mtDNA mutation frequency, we plotted the random mutation frequency of all samples against the ratio of citrate to lactate (Figure 5). We found that in both normal and tumor tissue, mutation frequency decreases concomitantly with reduced mitochondrial respiration (linear regression: slope −10.17±0.9894, significance of non-zero slope P<0.0001, R2 = 0.71). This is consistent with the hypothesis that a large fraction of mtDNA mutagenesis is a consequence of oxidative damage generated as a byproduct during OXPHOS and provides a plausible rationale for the decreased frequency of random mutations in tumor cells–specifically, a decrease in C∶G to T∶A transitions (Figure 3), the most commonly observed mutations resulting from oxidative damage [15].

Bottom Line: 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 C:G to T:A 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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Diagnostics Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

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 C:G to T:A 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.

Show MeSH
Related in: MedlinePlus