Comprehensive genome sequencing associates elevated mitochondrial DNA and homoplasmy with early stage I of pancreatic cancer.

Mitochondrial genome (mtDNA) presents higher fold mutation rates in cancers, creating heteroplasmy. While mtDNA mutations are drivers of cancers, heteroplasmic mutations appear theoretically unlikely drivers. However, whether high homoplasmy can characterize the early stage of cancers, along with high mtDNA genome coverage, has not yet been explored. Here, we directly profile stage I treatment naive pancreatic cancer patients' cfDNA using high throughput genome sequencing technology. Our analysis uncovered an elevated mitochondrial, not nuclear, genome coverage, correlating with high homoplasmy and rates of single-nucleotide variants. Heteroplasmy is the most expected and common biologically relevant mitochondrial genomic state in cells, but it can disrupt cellular phenotype and fitness. Conversely, homoplasmy is uncommon but can be selected for in certain cellular contexts. The high mtDNA coverage, along with a high mutation load at stage I of this cancer, concomitantly with a high homoplasmy, argues that mtDNA homoplasmy and its associated mutations accumulated non-passively.