Refined characterization of circulating tumor DNA through biological feature integration
Authors
Markus, Havell
Chandrananda, Dineika
Moore, Elizabeth
Mouliere, Florent
Morris, James
Brenton, James D
Smith, Christopher G
Rosenfeld, Nitzan
Publication Date
2022-12Journal Title
Scientific Reports
Publisher
Springer Science and Business Media LLC
Volume
12
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Markus, H., Chandrananda, D., Moore, E., Mouliere, F., Morris, J., Brenton, J. D., Smith, C. G., & et al. (2022). Refined characterization of circulating tumor DNA through biological feature integration. Scientific Reports, 12 (1) https://doi.org/10.1038/s41598-022-05606-z
Abstract
<jats:title>Abstract</jats:title><jats:p>Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection, recent studies have been focused on understanding the non-random fragmentation pattern of cfDNA. These studies have investigated fragment sizes, genomic position of fragment end points, and fragment end motifs. Although these features have been described and shown to be aberrant in cancer patients, there is a lack of understanding of how the individual and integrated analysis of these features enrich ctDNA fraction and enhance ctDNA detection. Using whole genome sequencing and copy number analysis of plasma samples from 5 high grade serious ovarian cancer patients, we observed that (1) ctDNA is enriched not only in fragments shorter than mono-nucleosomes (~ 167 bp), but also in those shorter than di-nucleosomes (~ 240–330 bp) (28–159% enrichment). (2) fragments that start and end at the border or within the nucleosome core are enriched in ctDNA (5–46% enrichment). (3) certain DNA motifs conserved in regions 10 bp up- and down- stream of fragment ends (i.e. cleavage sites) could be used to detect tumor-derived fragments (10–44% enrichment). We further show that the integrated analysis of these three features resulted in a higher enrichment of ctDNA when compared to using fragment size alone (additional 7–25% enrichment after fragment size selection). We believe these genome wide features, which are independent of genetic mutational changes, could allow new ways to analyze and interpret cfDNA data, as significant aberrations of these features from a healthy state could improve its utility as a diagnostic biomarker.</jats:p>
Keywords
Article, /631/67, /631/114/2785, /692/53/2421, article
Sponsorship
CRUK Cambridge Institute (A29580)
European Research Council (337905)
Identifiers
s41598-022-05606-z, 5606
External DOI: https://doi.org/10.1038/s41598-022-05606-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333650
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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