A Novel Blood-Based Test for Colorectal Cancer Detection Using Cell-Free DNA Fragmentomics

Background/Aim: Fragmentomic analysis of blood-derived cell-free DNA (cfDNA) has emerged as a promising approach for cancer screening. We aimed to develop a novel cfDNA-based blood test and evaluate its diagnostic performance for colorectal cancer (CRC) and advanced adenoma (AA). Methods: In this prospective case-control study, 1,677 participants were enrolled: 1,267 with normal colonoscopy, 302 with CRC, and 108 with AA. Participants were randomly assigned to either a development cohort (n=1,250) or a validation cohort (n=427). Whole-genome sequencing of cfDNA was performed to extract fragmentomic features, including end motifs, fragment lengths, and genome-wide coverage. A diagnostic model was developed using the Residual Enrichment From Independent Normal Ensemble method, and its performance was assessed in the validation cohort. Results: In the validation cohort, the sensitivities for CRC and AA were 90.4% (95% CI, 82.2–97.3) and 58.3% (95% CI, 48.1–67.6), respectively. Overall accuracy for advanced neoplasia was 84.8% (95% CI, 81.1–87.8), and specificity in individuals with normal colonoscopy was 94.7% (95% CI, 91.2–96.9). The areas under the ROC curve were 0.978 for CRC and 0.862 for AA. Sensitivities by CRC stage were 84.2% (stage I), 85.0% (stage II), 94.4% (stage III), and 100.0% (stage IV). Diagnostic performance was consistent across CRC locations (left vs. right colon), age of CRC patients (<60 vs. ≥60), and AA locations. Conclusion: This cfDNA-based blood test demonstrated high diagnostic accuracy for CRC and acceptable performance for AA. Its consistent performance across clinical subgroups suggests its potential as an effective noninvasive CRC screening tool.