Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics

Background Early detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients. Objective We aimed to develop a novel strategy for early CRC detection using the fragmentomic features of circulating cell-free mitochondrial DNA (ccf-mtDNA). Design Here, a total of 1147 participants, including 478 healthy controls (HCs), 112 patients with advanced adenomas (AAs) and 557 patients with CRC, were enrolled from five hospitals and plasma samples were collected for capture-based ccf-mtDNA sequencing. Results Our data analysis revealed significantly aberrant ccf-mtDNA fragmentomic features in patients with CRC and AA when compared with HCs. Then, a CRC detection (CD) model was constructed based on the fragmentomic features of ccf-mtDNA from 246 patients with CRC and 168 HC in the training cohort, showing area under the curve of 0.9863, sensitivity of 92.68% and specificity of 93.45%. Both internal and two external validation cohorts demonstrated the excellent capacity of CD model in distinguishing patients with early-stage CRC from HCs, greatly surpassing the performance of serum biomarkers. Furthermore, our CD model can also detect patients with AA with a sensitivity of 79.35% in AA cohort 1 and 85.00% in AA cohort 2. Conclusion In conclusion, based on aberrant ccf-mtDNA fragmentomic features, a novel and non-invasive approach was established for the detection of patients with early-stage CRC or AA, with high performance. Data are available upon reasonable request. The raw sequencing data underlying this article are available in BIG Data Center, Beijing Institute of Genomics (BIG) with access number PRJCA028508.