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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
Mutation Research
|February 27, 2001
Summary
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.