TY - JOUR
T1 - Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients
AU - Mouliere, Florent
AU - Smith, Christopher G.
AU - Heider, Katrin
AU - Su, Jing
AU - van der Pol, Ymke
AU - Thompson, Mareike
AU - Morris, James
AU - Wan, Jonathan C. M.
AU - Chandrananda, Dineika
AU - Hadfield, James
AU - Grzelak, Marta
AU - Hudecova, Irena
AU - Couturier, Dominique-Laurent
AU - Cooper, Wendy
AU - Zhao, Hui
AU - Gale, Davina
AU - Eldridge, Matthew
AU - Watts, Colin
AU - Brindle, Kevin
AU - Rosenfeld, Nitzan
AU - Mair, Richard
PY - 2021/8/9
Y1 - 2021/8/9
N2 - 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.
AB - 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.
KW - cell-free DNA
KW - circulating tumor DNA
KW - fragmentomics
KW - gliomas
KW - liquid biopsy
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85110694200&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34291583
U2 - 10.15252/emmm.202012881
DO - 10.15252/emmm.202012881
M3 - Article
C2 - 34291583
VL - 13
JO - Embo Molecular Medicine
JF - Embo Molecular Medicine
SN - 1757-4676
IS - 8
M1 - e12881
ER -