Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection.

We introduce a cell-free DNA (cfDNA) fragmentation pattern: the fragment dispersity index (FDI), which integrates information on the distribution of cfDNA fragment ends with the variation in fragment coverage, enabling precise characterization of chromatin accessibility in specific regions. The FDI shows a strong correlation with chromatin accessibility and gene expression, and regions with high FDI are enriched in active regulatory elements. Using whole-genome cfDNA data from five datasets, we developed and validated the FDI-oncology model, which demonstrates robust performance in early cancer diagnosis, subtyping, and prognosis. Case studies reveal that key cancer genes such as HER2 and TP53 exhibit significantly different FDIs between cancer and control samples. Simulation experiments suggest that deep targeted sequencing of a small number of regions can achieve high diagnostic efficiency.