Abstract B054: Using FRAGILE score to capture context-dependent cfDNA fragmentation patterns for inference on their tissues-of-origin

Abstract Cell-free nucleic acids circulating in blood and other body fluids are usually highly fragmented and derived from multiple different tissue types, which makes it challenging to obtain information about their cellular and contextual origin. Analyzing low coverage cell-free DNA whole genome sequencing data from 243 healthy individuals, we showed that cfDNA fragmentation and degradation patterns vary depending on their underlying genomic and epigenomic contexts. We developed a composite index called FRAGILE Score (FRagment of Atypical GC and Irregular Length Enrichment Score) to capture the structure, sequence, and fragmentation-related properties of cell-free, and showed that the score carried information about the epigenomic contexts of the cfDNA fragments. A deconvolution approach based on the score predicts the cell type contribution in serum cfDNA from healthy individuals and cancer patients. We collected blood and urine of a cohort of 30 bladder urothelial carcinoma patients, and found that cfDNA derived from blood and urine had very different fragmentation characteristics. An analysis of cfDNA from paired urine and blood samples from this showcased utility of the score in predicting clinical and pathological characteristics non-invasively for clinical management of the patients. Citation Format: Subhajyoti De. Using FRAGILE score to capture context-dependent cfDNA fragmentation patterns for inference on their tissues-of-origin [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B054.