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dc.contributor.authorHudecova, Irena
dc.contributor.authorSmith, Christopher
dc.contributor.authorHänsel-Hertsch, Robert
dc.contributor.authorChilamakuri, Chandra S
dc.contributor.authorMorris, James A
dc.contributor.authorVijayaraghavan, Aadhitthya
dc.contributor.authorHeider, Katrin
dc.contributor.authorChandrananda, Dineika
dc.contributor.authorCooper, Wendy
dc.contributor.authorGale, Davina
dc.contributor.authorGarcia-Corbacho, Javier
dc.contributor.authorPacey, Simon
dc.contributor.authorBaird, Richard
dc.contributor.authorRosenfeld, Nitzan
dc.contributor.authorMouliere, Florent
dc.description.abstractCurrent evidence suggests that plasma cell-free DNA (cfDNA) is fragmented around a mode of 166 bp. Data supporting this view has been mainly acquired through the analysis of double-stranded cfDNA. The characteristics and diagnostic potential of single-stranded and damaged double-stranded cfDNA in healthy individuals and cancer patients remain unclear. Here, through a combination of high-affinity magnetic bead-based DNA extraction and single-stranded DNA sequencing library preparation (MB-ssDNA), we report the discovery of a large proportion of cfDNA fragments centered at ∼50 bp. We show that these "ultrashort" cfDNA fragments have a greater relative abundance in plasma of healthy individuals (median = 19.1% of all sequenced cfDNA fragments, n = 28) than in plasma of patients with cancer (median = 14.2%, n = 21, P < 0.0001). The ultrashort cfDNA fragments map to accessible chromatin regions of blood cells, particularly in promoter regions with the potential to adopt G-quadruplex (G4) DNA secondary structures. G4-positive promoter chromatin accessibility is significantly enriched in ultrashort plasma cfDNA fragments from healthy individuals relative to patients with cancers (P < 0.0001), in whom G4-cfDNA enrichment is inversely associated with copy number aberration-inferred tumor fractions. Our findings redraw the landscape of cfDNA fragmentation by identifying and characterizing a novel population of ultrashort plasma cfDNA fragments. Sequencing of MB-ssDNA libraries could facilitate the characterization of gene regulatory regions and DNA secondary structures via liquid biopsy. Our data underline the diagnostic potential of ultrashort cfDNA through classification for cancer patients.
dc.publisherCold Spring Harbor Laboratory Press
dc.rightsAttribution-NonCommercial 4.0 International
dc.titleCharacteristics, origin, and potential for cancer diagnostics of ultrashort plasma cell-free DNA.
dc.publisher.departmentCancer Research Uk Cambridge Institute
dc.publisher.departmentDepartment of Oncology
prism.publicationNameGenome Research
dc.contributor.orcidSmith, Christopher [0000-0001-7357-2737]
dc.contributor.orcidCooper, Wendy [0000-0003-3416-9982]
dc.contributor.orcidPacey, Simon [0000-0002-3303-7577]
dc.contributor.orcidBaird, Richard [0000-0001-7071-6483]
dc.contributor.orcidRosenfeld, Nitzan [0000-0002-2825-4788]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (C37096/A16673)
pubs.funder-project-idEuropean Research Council (337905)
cam.orpheus.success2022-03-01: VoR added to Apollo record
pubs.licence-display-nameApollo Repository Deposit Licence Agreement

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