Mitochondrial DNA common deletion in cancer: Emerging evidence and methodological challenges

The 4977 bp common deletion of the mitochondrial DNA (mtDNA-CD) is a large-scale deletion that has been frequently observed in various cancers in humans. The common deletion mutation affects 7 key genes encoding for several complex subunits essential to the mitochondrial oxidative phosphorylation system. In the last 20 years, the evidence for the presence of mtDNA-CD in cancer has been elusive. This review aims to examine the evidence of the molecular mechanism and prevalence of mtDNA-CD in different cancers, and to discuss methodological challenges in detecting the presence of mtDNA-CD from clinical samples, and the estimation of prevalence in cancers. This is an attempt to perform a comprehensive literature review and evaluation of experimental evidence to determine whether there is sufficient evidence to suggest a link between mtDNA-CD and cancer. Our results suggest there is a lack of evidence across all cancers. Source of potential discrepancies depends on the quality of the experimental methods, statistical analyses and sampling strategy. Emerging evidence indicates the presence of mtDNA-CD may be cell-type- and cancer-specific. With advances in experimental and analytical techniques, such as single cell genomic and transcriptomic sequencing, spatial omics profiling, and long-read sequencing, we expect to see more comprehensive research that can better clarify the role and prevalence of mtDNA-CD in cancer.