Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA

Using whole-exome sequencing data, Gorelick et al. identify lineage-specific somatic mutations in mitochondrial DNA that affect cancer progression and patient prognosis. Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development.

Automated summary

Using whole-exome sequencing data, the study identified lineage-specific somatic mutations in mitochondrial DNA that impact cancer progression and patient prognosis. The findings suggest a clear functional relationship between pathogenic mtDNA mutations and overall survival of colorectal cancer patients, highlighting the disrupted nature of the mitochondrial genome across various cancers and its implications for patient stratification, prognosis, and therapeutic development.