Table 1.

The mitochondrial DNA mutations in cancers with the next-generation sequence (NGS) assay

Ju, et al. Elife. 2014;3:e02935	Grandhi, et al. Hum Mol Genet. 2017;26:2912–2922	Yuan, et al. Nat Genet. 2020;52:342–352
TCGA; 704 WGS; 971 WES; 31 tumor types	TCGA, 1,916 NGS; 24 tumor types	ICGC/TCGA-PCAWGC; 2,658 WGS; 38 tumor types
✓ Among 1675 cancer samples, 976 (58.3%) harbor at least one somatic substitution and 521 (31.1%) carry multiple substitutions, ranging from 2 to 7	✓ 64.3% of cancers harbor somatic mtDNA mutations	✓ Over 85% of somatic mtDNA substitutions are heteroplasmic
✓ Gastric, hepatocellular, prostate, and colorectal cancers are detected with the highest number of mtDNA substitutions. Hematologic cancers (acute lymphoblastic leukemia, myeloproliferative disease, and myelodysplastic syndrome) harbor fewer mutations	✓ Metastatic and recurrent tumors harbor a larger proportion of RNA variants vs. D-loop/unannotated variants than primary tumors	✓ MtDNA mutations are largely proportional to age
✓ Among the 1907 substitutions, 1153 (60.5%) are in the 13 protein-coding genes	✓ Higher numbers of tRNA, rRNA, and mRNA aberrations are detected in tumors than in normal cells ✓ Several recurrent mtDNA mutations occur within the genes of NADH dehydrogenase complex (Complex I)	✓ Variant allele fraction analysis showed that mutational hotspots are in the D-loop region and ND4 gene ✓ ND5 gene is the most frequently mutated in most cancer types; ND4 gene is the most frequently mutated in prostate and lung cancers; COX1 gene is the most frequently mutated in breast, cervical, and bladder cancers
✓ The vast majority of mtDNA mutations are passengers with no convincing evidence suggesting the existence of driver mitochondrial DNA mutations ✓ Mutations in tRNA anticodons and protein-truncating mutations confer a selective disadvantage ✓ No evidence of the mutational signatures characteristic of these carcinogens among the mtDNA mutations could be found	✓ There is no evidence for positive or negative selection for the somatic mtDNA mutations, except for KICH and thyroid carcinoma (dN/dS results most consistent with positive selection) ✓ Non-synonymous substitutions below 5% in the normal cell expand to a median allelic frequency of 58.8% in the tumor, as compared to 18.8% for synonymous substitutions, suggesting positive selection in the tumor	✓ Truncating mutations might be a negative selection

KICH kidney chromophobe, KIRC kidney renal clear cell carcinoma, KIRP kidney renal papillary cell carcinoma