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Mitochondrial genome instability in human cancers
N O Bianchi1, M S Bianchi, S M Richard
1Instituto Multidisciplinario de Biología Celular (IMBICE), CC 403, 1900, La Plata, Argentina. bianchi@satlink.com
Abstract:
Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions of NGI. We present here data showing mitochondrial genome instability (mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase gamma (POLgamma) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLgamma, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.
Insights
Mitochondrial genome instability (mtGI) is observed in most human cancers, distinct from nuclear genome instability (NGI). This instability, characterized by various mtDNA mutations, appears specific to tumor type and may arise from replication errors or selective advantages of mutated mtDNA.
Area of Science:
- Genetics and Molecular Biology
- Cancer Research
- Mitochondrial Biology
Background:
- Malignant transformation is linked to nuclear genome instability (NGI), often involving mismatch repair (MMR) gene malfunction.
- Microsatellite instability (MSI), a marker of NGI, involves alterations in non-inherited microsatellite alleles within tumor cells.
- Mitochondrial DNA (mtDNA) plays a crucial role in cellular energy production and is susceptible to mutations.
Purpose of the Study:
- To investigate the presence and characteristics of mitochondrial genome instability (mtGI) across various human cancers.
- To compare mtGI patterns with nuclear genome instability (NGI) and explore potential correlations.
- To elucidate the mechanisms contributing to the origin and expansion of mtGI in tumor cells.
Main Methods:
- Analysis of mtDNA markers including point mutations, repeat instability, insertions/deletions, and long deletions in tumor versus normal tissues.
- Assessment of homoplasmic and heteroplasmic mutation states within tumor mtDNA.
- Correlation analysis between NGI markers and mtGI patterns in different cancer types.
Main Results:
- Mitochondrial genome instability (mtGI) was detected in most analyzed human cancers, with distinct mutation patterns for breast, colorectal, gastric, and kidney cancers.
- No consistent correlation between NGI and mtGI was observed in breast, colorectal, or kidney cancers; a positive correlation was found in gastric cancer.
- Germ cell testicular cancers were found to lack mtGI, suggesting tissue-specific mechanisms.
Conclusions:
- mtGI is a common feature in human cancers, driven by factors like reactive oxygen species (ROS), slipped-strand mispairing (SSM), and deficient repair.
- The polymerase gamma (POLgamma) enzyme, crucial for mtDNA synthesis, is implicated due to its error-prone nature and lack of proofreading.
- Expansion of specific mtDNA variants within tumors likely results from selective advantages or replicative benefits, possibly coupled with mitochondrial segregation bottlenecks during mitosis.