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In EMBO molecular medicine

Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. We determined the glioma-derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient's tumor, we detected tumor-derived DNA in the majority of CSF (7/8), plasma (10/12), and urine samples (10/16), with a median tumor fraction of 6.4 × 10-3 , 3.1 × 10-5 , and 4.7 × 10-5 , respectively. We identified a shift in the size distribution of tumor-derived cfDNA fragments in these body fluids. We further analyzed cfDNA fragment sizes using whole-genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non-malignant brain disorders, and 26 healthy individuals. cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders (P = 1.7 × 10-2 ) and healthy individuals (P = 5.2 × 10-9 ). Machine learning models integrating fragment length could differentiate urine samples from glioma patients (AUC = 0.80-0.91) suggesting possibilities for truly non-invasive cancer detection.

Mouliere Florent, Smith Christopher G, Heider Katrin, Su Jing, van der Pol Ymke, Thompson Mareike, Morris James, Wan Jonathan C M, Chandrananda Dineika, Hadfield James, Grzelak Marta, Hudecova Irena, Couturier Dominique-Laurent, Cooper Wendy, Zhao Hui, Gale Davina, Eldridge Matthew, Watts Colin, Brindle Kevin, Rosenfeld Nitzan, Mair Richard


cell-free DNA, circulating tumor DNA, fragmentomics, gliomas, liquid biopsy