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

Abstract

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). 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. 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 receiver operating characteristic 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 patients with CRC (<60 vs ≥60), and AA locations. 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.