Analysis of fragment ends in plasma DNA from patients with cancer

Fragmentation patterns observed in plasma DNA reflect chromatin accessibility in contributing cells. Since DNA shed from cancer cells and blood cells may differ in fragmentation patterns, we investigated whether analysis of genomic positioning and nucleotide sequence at fragment ends can reveal the presence of tumor DNA in blood and aid cancer diagnostics. We analyzed whole genome sequencing data from >2700 plasma DNA samples including healthy individuals and patients with 11 different cancer types. We observed higher fractions of fragments with aberrantly positioned ends in patients with cancer, driven by contribution of tumor DNA into plasma. Genomewide analysis of fragment ends using machine learning showed overall area under the receiver operative characteristic curve of 0.96 for detection of cancer. Our findings remained robust with as few as 1 million fragments analyzed per sample, suggesting that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring. One-sentence summaryAnalyzing the positioning and nucleotide sequence at fragment ends in plasma DNA may enable cancer diagnostics.