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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 in Colorectal Carcinoma Is Attributable to a Reduction in C∶G to T∶A Transitions.Mitochondrial DNA mutation spectrum (± s.e.m.) per Mb in human colorectal tissue. Mutant mtDNA amplicons (n = 796) spanning two restriction sites (1215–1218 and 7335–7338) were recovered from the RMC assay and subjected to DNA sequencing to generate the mutational signature of mtDNA isolated from normal (n = 297), adenoma (n = 275), and carcinoma (n = 224) colorectal tissues. * P<0.0001; two-tailed paired t-test.
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pgen-1002689-g003: Decreased mtDNA Mutagenesis in Colorectal Carcinoma Is Attributable to a Reduction in C∶G to T∶A Transitions.Mitochondrial DNA mutation spectrum (± s.e.m.) per Mb in human colorectal tissue. Mutant mtDNA amplicons (n = 796) spanning two restriction sites (1215–1218 and 7335–7338) were recovered from the RMC assay and subjected to DNA sequencing to generate the mutational signature of mtDNA isolated from normal (n = 297), adenoma (n = 275), and carcinoma (n = 224) colorectal tissues. * P<0.0001; two-tailed paired t-test.

Mentions: To gain further insight into possible mechanisms responsible for reducing mtDNA mutagenesis in tumor cells, we examined the mutation spectrum of 796 random mutation events (297 normal, 275 adenoma, 224 carcinoma). We found that in normal and adenoma tissues, C∶G to T∶A transitions predominated (Figure 3). Similar spectra have been previously reported in mice and are consistent with deamination of cytosine bases as the primary source of mutagenesis [10], a process that is driven by oxidative damage [15]. While all tissue types exhibited similar levels of T∶A to C∶G mutations, there was >3-fold decrease in C∶G to T∶A transitions among the tumor samples relative to normal colon, suggesting the source of these latter oxidatively-mediated mutations to be specifically reduced during carcinoma outgrowth. Interestingly, the majority of the clonally expanded mutations observed in carcinomas are C∶G to T∶A transitions (Table 1), which is similar to that previously reported in human colorectal tumors [16] and to the spectrum of random mutations in normal and adenoma tissue (Figure 3A), but is markedly different from the spectrum of mutations generated by polymerase γ on undamaged template [17], [18], [19]. This suggests that the biological change responsible for reducing the frequency of C∶G to T∶A mutations occurs after the initiation of neoplastic clonal expansion.


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 in Colorectal Carcinoma Is Attributable to a Reduction in C∶G to T∶A Transitions.Mitochondrial DNA mutation spectrum (± s.e.m.) per Mb in human colorectal tissue. Mutant mtDNA amplicons (n = 796) spanning two restriction sites (1215–1218 and 7335–7338) were recovered from the RMC assay and subjected to DNA sequencing to generate the mutational signature of mtDNA isolated from normal (n = 297), adenoma (n = 275), and carcinoma (n = 224) colorectal tissues. * P<0.0001; two-tailed paired t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1002689-g003: Decreased mtDNA Mutagenesis in Colorectal Carcinoma Is Attributable to a Reduction in C∶G to T∶A Transitions.Mitochondrial DNA mutation spectrum (± s.e.m.) per Mb in human colorectal tissue. Mutant mtDNA amplicons (n = 796) spanning two restriction sites (1215–1218 and 7335–7338) were recovered from the RMC assay and subjected to DNA sequencing to generate the mutational signature of mtDNA isolated from normal (n = 297), adenoma (n = 275), and carcinoma (n = 224) colorectal tissues. * P<0.0001; two-tailed paired t-test.
Mentions: To gain further insight into possible mechanisms responsible for reducing mtDNA mutagenesis in tumor cells, we examined the mutation spectrum of 796 random mutation events (297 normal, 275 adenoma, 224 carcinoma). We found that in normal and adenoma tissues, C∶G to T∶A transitions predominated (Figure 3). Similar spectra have been previously reported in mice and are consistent with deamination of cytosine bases as the primary source of mutagenesis [10], a process that is driven by oxidative damage [15]. While all tissue types exhibited similar levels of T∶A to C∶G mutations, there was >3-fold decrease in C∶G to T∶A transitions among the tumor samples relative to normal colon, suggesting the source of these latter oxidatively-mediated mutations to be specifically reduced during carcinoma outgrowth. Interestingly, the majority of the clonally expanded mutations observed in carcinomas are C∶G to T∶A transitions (Table 1), which is similar to that previously reported in human colorectal tumors [16] and to the spectrum of random mutations in normal and adenoma tissue (Figure 3A), but is markedly different from the spectrum of mutations generated by polymerase γ on undamaged template [17], [18], [19]. This suggests that the biological change responsible for reducing the frequency of C∶G to T∶A mutations occurs after the initiation of neoplastic clonal expansion.

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