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Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Smith, Christopher G  ORCID logo  https://orcid.org/0000-0001-7357-2737
Heider, Katrin 
Su, Jing 

Abstract

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.

Description

Keywords

cell-free DNA, circulating tumor DNA, fragmentomics, gliomas, liquid biopsy, Biomarkers, Tumor, Cell-Free Nucleic Acids, Glioma, Humans, Liquid Biopsy, Mutation, Plasma, Sequence Analysis, DNA

Journal Title

EMBO Mol Med

Conference Name

Journal ISSN

1757-4676
1757-4684

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (unknown)
Cancer Research UK (C14303/A17197)
European Research Council (337905)
Cancer Research UK (20240)
Cancer Research UK (11906)
Cancer Research UK (EDDCPT\100013)