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Mitochondrial mutations in human cancer: Curation of translation
Maϊwen Caudron-Herger1, Sven Diederichs1,2,3,4
1a Division of RNA Biology & Cancer , German Cancer Research Center (DKFZ) , Heidelberg , Germany.
Abstract:
As a genetic disease, cancer is caused by the activation of oncogenes and the inhibition of tumor suppressor genes via genetic and epigenetic mechanisms. Given the important role of energy metabolism in tumors, we analyzed the cancer-derived mutations occurring in the DNA of the mitochondrion. Mutations in the mitochondrial DNA (mtDNA) compared to nuclear DNA are 62% decreased relative to the coding length per chromosome. We find that the majority of these mutations affects highly conserved nucleotides - significantly exceeding the conservation of the mtDNA - and are devoid of single nucleotide polymorphisms (SNPs). Surprisingly, the leading resources for tumor genetics information universally use the standard genetic code for translation of nucleotide into amino acid sequences in their online resources. However, the nuclear and mitochondrial genetic codes differ for four codons and the usage of incomplete STOP codons. Hence, we analyze and curate the consequences for all mutations in the mtDNA and comprehensively reclassify missense, nonsense and synonymous mutations accordingly. In total, 10% of the mutations are incorrectly translated leading to significant changes in the distribution of mutation types with tripling of nonsense and 69% loss of nonstop extension mutations. Lastly, we provide a curated dataset of coding and non-coding mitochondrial mutations in cancer merged, standardized, duplicate-free and aggregated from two databases as a resource including orthogonal data on their high conservation and SNPs. This study generally highlights the need to universally regard the important differences between the standard and mitochondrial genetic code in life science research.
Insights
Cancer research must account for mitochondrial DNA (mtDNA) genetic code differences. Incorrect translation of mtDNA mutations leads to misclassified cancer mutation types, impacting genetic disease understanding.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Biology
Background:
- Cancer arises from genetic and epigenetic alterations affecting oncogenes and tumor suppressor genes.
- Mitochondrial DNA (mtDNA) plays a crucial role in cellular energy metabolism, and its mutations are implicated in cancer.
- Existing cancer genetics databases often overlook the distinct genetic code used by mitochondria.
Purpose of the Study:
- To analyze cancer-derived mutations in mitochondrial DNA (mtDNA).
- To reclassify mtDNA mutations based on the unique mitochondrial genetic code, correcting for inaccuracies in standard genetic code translations.
- To provide a curated, comprehensive dataset of mitochondrial mutations in cancer.
Main Methods:
- Analysis of cancer-derived mutations within the mitochondrial genome.
- Comparison of mutation frequencies and conservation patterns between mtDNA and nuclear DNA.
- Reclassification of missense, nonsense, and synonymous mutations using the mitochondrial genetic code.
- Aggregation and curation of mitochondrial mutation data from public databases.
Main Results:
- Mitochondrial DNA mutations are significantly less frequent per coding length compared to nuclear DNA.
- The majority of mtDNA mutations affect highly conserved nucleotides and lack single nucleotide polymorphisms (SNPs).
- Utilizing the mitochondrial genetic code revealed that 10% of mutations were incorrectly translated, altering mutation type distributions (e.g., tripling nonsense mutations).
Conclusions:
- There is a critical need to apply the distinct mitochondrial genetic code when analyzing mtDNA mutations in cancer.
- Incorrect translation due to the use of the standard genetic code leads to significant misclassification of mutation types.
- The study provides a valuable, curated resource of cancer-associated mitochondrial mutations, highlighting their conservation and SNP status.