Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer

Mitochondrial DNA (mtDNA) mutations are prevalent across cancer genomes, and growing evidence implicates their multifaceted role in energy metabolism with tumorigenesis. Ovarian cancer, in particular, demonstrates high mtDNA copy numbers and increased incidences of truncating and missense mtDNA mutations, with heteroplasmy levels predictive of prognosis. This review provides a comprehensive description of published mtDNA sequencing data in ovarian cancer, the majority being high-grade serous samples, encompassing both coding and non-coding regions. MtDNA mutations within non-coding regions, such as the D-loop control region, can affect mtDNA replication and transcription, hence affecting overall mtDNA copy numbers, while mtDNA mutations within coding regions can directly impact respiratory complex function and downstream metabolic pathways. MtDNA mutations may serve as clinically valuable diagnostic biomarkers for ovarian cancer and predictors for chemoresistance. We also explore ongoing efforts to deepen our understanding of mitochondrial oncogenetics through the creation of novel cancer models enabled by mitochondrial gene editing techniques. Developing robust human ovarian cancer cell models will be critical to elucidate mechanistic and phenotypic consequences of mtDNA mutations, assess drug response and resistance and identify new therapeutic targets to advance precision oncology in this emerging field.