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dc.contributor.authorMouliere, Florent
dc.contributor.authorChandrananda, Sandunie
dc.contributor.authorPiskorz, Anna M
dc.contributor.authorMoore, Elizabeth K
dc.contributor.authorMorris, James
dc.contributor.authorAhlborn, Lise Barlebo
dc.contributor.authorMair, Richard
dc.contributor.authorGoranova, Teodora
dc.contributor.authorMarass, Francesco
dc.contributor.authorHeider, Katrin
dc.contributor.authorWan, Jonathan
dc.contributor.authorSupernat, Anna
dc.contributor.authorHudecova, Irena
dc.contributor.authorGounaris, Ioannis
dc.contributor.authorRos, Susana
dc.contributor.authorJimenez-Linan, Mercedes
dc.contributor.authorGarcia-Corbacho, Javier
dc.contributor.authorPatel, Keval
dc.contributor.authorØstrup, Olga
dc.contributor.authorMurphy, Suzanne
dc.contributor.authorEldridge, Matthew
dc.contributor.authorGale, Davina
dc.contributor.authorStewart, Grant
dc.contributor.authorBurge, Johanna
dc.contributor.authorCooper, Wendy
dc.contributor.authorvan der Heijden, Michiel S
dc.contributor.authorMassie, Charles
dc.contributor.authorWatts, Colin
dc.contributor.authorCorrie, Pippa
dc.contributor.authorPacey, Simon
dc.contributor.authorBrindle, Kevin
dc.contributor.authorBaird, Richard
dc.contributor.authorMau-Sørensen, Morten
dc.contributor.authorParkinson, Christine A
dc.contributor.authorSmith, Christopher
dc.contributor.authorBrenton, James
dc.contributor.authorRosenfeld, Nitzan
dc.date.accessioned2018-12-07T00:31:46Z
dc.date.available2018-12-07T00:31:46Z
dc.date.issued2018-11-07
dc.identifier.issn1946-6234
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286423
dc.description.abstractExisting methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
dc.description.sponsorshipWe would like to acknowledge the support of The University of Cambridge, Cancer Research UK and the EPSRC (CRUK grant numbers A11906 (NR), A20240 (NR), A22905 (JDB), A15601 (JDB), A25177 (CRUK Cancer Centre Cambridge), A17242 (KMB), A16465 (CRUK-EPSRC Imaging Centre in Cambridge and Manchester)). The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 337905. The research was supported by the National Institute for Health Research Cambridge, National Cancer Research Network, Cambridge Experimental Cancer Medicine Centre and Hutchison Whampoa Limited. This research is also supported by Target Ovarian Cancer and the Medical Research Council through their Joint Clinical Research Training Fellowship for Dr Moore. The CALIBRATE study was supported by funding from AstraZeneca.
dc.format.mediumPrint
dc.languageeng
dc.publisherAmerican Association for the Advancement of Science (AAAS)
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMutation
dc.subjectGenome, Human
dc.subjectDNA Copy Number Variations
dc.subjectMachine Learning
dc.subjectWhole Genome Sequencing
dc.subjectCirculating Tumor DNA
dc.titleEnhanced detection of circulating tumor DNA by fragment size analysis.
dc.typeArticle
prism.issueIdentifier466
prism.publicationDate2018
prism.publicationNameSci Transl Med
prism.volume10
dc.identifier.doi10.17863/CAM.33732
dcterms.dateAccepted2018-10-17
rioxxterms.versionofrecord10.1126/scitranslmed.aat4921
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidMouliere, Florent [0000-0001-7043-0514]
dc.contributor.orcidChandrananda, Sandunie [0000-0002-8834-9500]
dc.contributor.orcidPiskorz, Anna M [0000-0002-7171-1120]
dc.contributor.orcidMoore, Elizabeth K [0000-0002-2728-3202]
dc.contributor.orcidMair, Richard [0000-0001-8235-5689]
dc.contributor.orcidGoranova, Teodora [0000-0003-3848-2968]
dc.contributor.orcidMarass, Francesco [0000-0002-8993-7320]
dc.contributor.orcidHeider, Katrin [0000-0003-4035-1668]
dc.contributor.orcidWan, Jonathan [0000-0003-0001-1802]
dc.contributor.orcidHudecova, Irena [0000-0003-3823-9896]
dc.contributor.orcidEldridge, Matthew [0000-0002-5799-8911]
dc.contributor.orcidGale, Davina [0000-0002-4521-8199]
dc.contributor.orcidStewart, Grant [0000-0003-3188-9140]
dc.contributor.orcidCooper, Wendy [0000-0003-3416-9982]
dc.contributor.orcidMassie, Charles [0000-0003-2314-4843]
dc.contributor.orcidWatts, Colin [0000-0003-3531-8791]
dc.contributor.orcidCorrie, Pippa [0000-0003-4875-7021]
dc.contributor.orcidPacey, Simon [0000-0002-3303-7577]
dc.contributor.orcidBrindle, Kevin [0000-0003-3883-6287]
dc.contributor.orcidBaird, Richard [0000-0001-7071-6483]
dc.contributor.orcidMau-Sørensen, Morten [0000-0003-2235-1250]
dc.contributor.orcidSmith, Christopher [0000-0001-7357-2737]
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
dc.contributor.orcidRosenfeld, Nitzan [0000-0002-2825-4788]
dc.identifier.eissn1946-6242
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L017415/1)
pubs.funder-project-idCancer Research UK (CB4150)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idEuropean Research Council (337905)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (CRUK-A22905)
pubs.funder-project-idCancer Research UK (CRUK-A15601)
pubs.funder-project-idCancer Research UK (C96/A25177)


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