Abstract
BackgroundMutations in the mitochondrial genome (mtgenome) have been associated with cancer and many other disorders. These mutations can be point mutations or deletions, or admixtures (heteroplasmy). The detection of mtDNA mutations in body fluids using resequencing microarrays, which are more sensitive than other sequencing methods, could provide a strategy to measure mutation loads in remote anatomical sites.MethodsWe determined the mtDNA mutation load in the entire mitochondrial genome of 26 individuals with different early stage cancers (lung, bladder, kidney) and 12 heavy smokers without cancer. MtDNA was sequenced from three matched specimens (blood, tumor and body fluid) from each cancer patient and two matched specimens (blood and sputum) from smokers without cancer. The inherited wildtype sequence in the blood was compared to the sequences present in the tumor and body fluid, detected using the Affymetrix Genechip® Human Mitochondrial Resequencing Array 1.0 and supplemented by capillary sequencing for noncoding region.ResultsUsing this high-throughput method, 75% of the tumors were found to contain mtDNA mutations, higher than in our previous studies, and 36% of the body fluids from these cancer patients contained mtDNA mutations. Most of the mutations detected were heteroplasmic. A statistically significantly higher heteroplasmy rate occurred in tumor specimens when compared to both body fluid of cancer patients and sputum of controls, and in patient blood compared to blood of controls. Only 2 of the 12 sputum specimens from heavy smokers without cancer (17%) contained mtDNA mutations. Although patient mutations were spread throughout the mtDNA genome in the lung, bladder and kidney series, a statistically significant elevation of tRNA and ND complex mutations was detected in tumors.ConclusionOur findings indicate comprehensive mtDNA resequencing can be a high-throughput tool for detecting mutations in clinical samples with potential applications for cancer detection, but it is unclear the biological relevance of these detected mitochondrial mutations. Whether the detection of tumor-specific mtDNA mutations in body fluidsy this method will be useful for diagnosis and monitoring applications requires further investigation.
Highlights
IntroductionMutations in the mitochondrial genome (mtgenome) have been associated with cancer and many other disorders
Mutations in the mitochondrial genome have been associated with cancer and many other disorders
Our results suggest that mitochondrial DNA (mtDNA) mutations in body fluids can partially distinguish lung cancer patients from heavy smokers
Summary
Mutations in the mitochondrial genome (mtgenome) have been associated with cancer and many other disorders. The mitochondrial genome has an accelerated mutation rate in comparison to the nuclear genome [2], and DNA repair is less efficient in the mitochondria than in the nuclear genome [3] This high frequency of mutation and the high copy number of mitochondria per cell suggest that mtDNA mutations may be useful markers for personalized assessment of cancer. The utility of a mtDNA deletion for molecular definition of benign, malignant and proximal to malignant prostate needle biopsies was reported [23] These mitochondrial mutations may be linked to a field effect [24], which suggests that mutations in the mitochondrial genome may represent sensitive markers for neoplastic transformation [25]. MtDNA instabilities have been reported in degenerative diseases [26,27,28,29], neurodegenerative diseases [30,31], macular degeneration [32], aging and longevity [28,33,34,35,36] and cardiovascular disease [37]
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