Aberrant fragmentomic features of circulating cell-free mitochondrial DNA as novel biomarkers in cancer patients

Abstract

Fragmentomic features of circulating cell free mitochondrial DNA (ccf-mtDNA) including fragmentation profile, 5’ end base preference and motif diversity are poorly understood. Here, we generated sequencing data in 788 plasma samples and found that fragmentomic features of ccf-mtDNA were remarkably different from those of circulating cell free nuclear DNA. Furthermore, region-specific fragmentomic features were observed, which was associated with protein binding, base composition and special structure of mitochondrial DNA. Aberrant fragmentomic features were observed in six cancer types compared to non-cancer controls. Highly accurate cancer detection models were built based on the fragmentomic features. The overall accuracy of tissue-of-origin was 90.59% for six cancer types. The fragmentation profile could also be used for effective monitoring of treatment efficacy in patients with hepatocellular carcinoma. Altogether, our study comprehensively describes cancer-specific fragmentomic features of ccf-mtDNA and provides a proof-of-principle for the ccf-mtDNA fragmentomics-based cancer detection and treatment monitoring.