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dc.contributor.authorMarkus, Hugh
dc.contributor.authorChandrananda, Dineika
dc.contributor.authorMoore, Elizabeth
dc.contributor.authorMouliere, Florent
dc.contributor.authorMorris, James
dc.contributor.authorBrenton, James
dc.contributor.authorSmith, Christopher
dc.contributor.authorRosenfeld, Nitzan
dc.description.abstractCirculating 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.
dc.description.sponsorshipThis study was supported by grants from CRUK Cambridge Institute (Core Grant, A29580) and by a funding from the ERC under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 337905
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.titleRefined characterization of circulating tumor DNA through biological feature integration.
dc.publisher.departmentCancer Research Uk Cambridge Institute
prism.publicationNameSci Rep
dc.contributor.orcidMarkus, Hugh [0000-0002-9794-5996]
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
dc.contributor.orcidSmith, Christopher [0000-0001-7357-2737]
dc.contributor.orcidRosenfeld, Nitzan [0000-0002-2825-4788]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (337905)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idNational Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
cam.orpheus.successThu Feb 24 18:06:39 GMT 2022 - Embargo updated
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International