Abstract
Many studies have suggested that mitochondria and mitochondrial DNA (mtDNA) might be functionally associated with tumor genesis and development. Although the heterogeneity of tumors is well known, most studies were based on the analysis of a single tumor sample. The extent of mtDNA diversity in the same tumor is unclear, as is whether the diversity is influenced by selection pressure. Here, we analyzed the whole exon data from 1 nontumor sample and 23 tumor samples from different locations of one single tumor tissue from a hepatocellular carcinoma (HCC) patient. Among 18 heteroplasmic sites identified in the tumor, only 2 heteroplasmies were shared among all tumor samples. By investigating the correlations between the occurrence and frequency of heteroplasmy (Het) and sampling locations (Coordinate), relative mitochondrial copy numbers, and single-nucleotide variants in the nuclear genome, we found that the Coordinate was significantly correlated with Het, suggesting no strong purifying selection or positive selection acted on the mtDNA in HCC. By further investigating the allele frequency and proportion of nonsynonymous mutations in the tumor mtDNA, we found that mtDNA in HCC did not undergo extra selection compared with mtDNA in the adjacent nontumor tissue, and they both likely evolved under neutral selection.
Highlights
Mitochondria play a pivotal role in eukaryotic cells
We further compared our results (105 heteroplasmy sites) with those obtained with the DREEP method (89 heteroplasmy sites) (Li and Stoneking 2012), which applied a similar algorithm but was slower (>1 min), We found that all heteroplasmic sites identified by DREEP were reported by our method, but not vice versa
We found that the Coordinate dendrogram was significantly similar to the Het dendrogram, but less similar when compared with the mtDNA copy number (mtCN) dendrogram and single-nucleotide variants (SNV) dendrogram
Summary
Mitochondria play a pivotal role in eukaryotic cells. Mitochondria are involved in other important functions, including cell signaling and cell death, and they are the key component in innate immunity (West et al 2015; Van Houten et al 2016). Mitochondria have their own genetic materials named mitochondrial DNA (mtDNA), which is characterized as multicopy, lacking genetic recombination, and prone to mutations. The number of mitochondria per cell varies from a few hundred to tens of thousands in different cell types. The coexistence of wild-type and mutant mtDNA in the same cell is called mitochondrial heteroplasmy. MtDNA mutations have been reported to be associated with multiple diseases, including Leber’s hereditary optic neuropathy, deafness, autism, and Parkinson’s disease, as well as tumors, and these mutations always occur in the heteroplasmic state (Wallace et al 1999; Farrar et al 2013)
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