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dc.contributor.authorMair, Richarden
dc.contributor.authorMouliere, Florenten
dc.contributor.authorSmith, Christopheren
dc.contributor.authorChandrananda, Sandunieen
dc.contributor.authorGale, Davinaen
dc.contributor.authorMarass, Francescoen
dc.contributor.authorTsui, Dana WYen
dc.contributor.authorMassie, Charlesen
dc.contributor.authorWright, Alanen
dc.contributor.authorWatts, Colinen
dc.contributor.authorRosenfeld, Nitzanen
dc.contributor.authorBrindle, Kevinen
dc.date.accessioned2018-12-07T00:31:11Z
dc.date.available2018-12-07T00:31:11Z
dc.date.issued2019-01en
dc.identifier.issn0008-5472
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286401
dc.description.abstractThe factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of glioblastoma (GB) patients are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GB (n=64) and show that tumor size and cell proliferation, but not the integrity of the blood-brain barrier or cell death, affect the release of ctDNA in treatment naïve GB PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (<0.2x coverage) of host (rat) and tumor (human) circulating DNA identified a peak at 145 bp in the human DNA fragments, indicating a difference in the origin or processing of the ctDNA. The concentration of ctDNA correlated with cell death only after treatment with Temozolomide and radiotherapy. Digital PCR detection of plasma tumor mitochondrial DNA (tmtDNA), an alternative to detection of nuclear ctDNA, improved plasma DNA detection rate (82% versus 24%) and allowed detection in cerebrospinal fluid (CSF) and urine. Mitochondrial mutations are prevalent across all cancers and can be detected with high sensitivity, at low cost and without prior knowledge of tumor mutations via capture-panel sequencing. Coupled with the observation that mitochondrial copy number increases in glioma, these data suggest analyzing tmtDNA as a more sensitive method to detect and monitor tumor burden in cancer, specifically in GB where current methods have largely failed.
dc.description.sponsorshipN. Rosenfeld and K. Brindle are supported by the University of Cambridge, Cancer Research UK (grant numbers A11906, A20240, 17242, 16465) and Hutchison Whampoa Limited. N. Rosenfeld has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n. 337905. C. Watts is supported by The Brain Tumour Charity grant 10/136.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Association for Cancer Research
dc.subjectTumor Cells, Cultureden
dc.subjectMitochondriaen
dc.subjectBody Fluidsen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subjectRatsen
dc.subjectRats, Nudeen
dc.subjectGlioblastomaen
dc.subjectDNA, Mitochondrialen
dc.subjectDNA, Neoplasmen
dc.subjectXenograft Model Antitumor Assaysen
dc.subjectFemaleen
dc.subjectHigh-Throughput Nucleotide Sequencingen
dc.subjectBiomarkers, Tumoren
dc.subjectCirculating Tumor DNAen
dc.titleMeasurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models.en
dc.typeArticle
prism.endingPage230
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameCancer researchen
prism.startingPage220
prism.volume79en
dc.identifier.doi10.17863/CAM.33712
dcterms.dateAccepted2018-10-26en
rioxxterms.versionofrecord10.1158/0008-5472.can-18-0074en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-01en
dc.contributor.orcidMair, Richard [0000-0001-8235-5689]
dc.contributor.orcidMouliere, Florent [0000-0001-7043-0514]
dc.contributor.orcidSmith, Christopher [0000-0001-7357-2737]
dc.contributor.orcidChandrananda, Sandunie [0000-0002-8834-9500]
dc.contributor.orcidGale, Davina [0000-0002-4521-8199]
dc.contributor.orcidMarass, Francesco [0000-0002-8993-7320]
dc.contributor.orcidMassie, Charles [0000-0003-2314-4843]
dc.contributor.orcidWright, Alan [0000-0002-4577-5681]
dc.contributor.orcidRosenfeld, Nitzan [0000-0002-2825-4788]
dc.contributor.orcidBrindle, Kevin [0000-0003-3883-6287]
dc.identifier.eissn1538-7445
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (16465)
pubs.funder-project-idCancer Research UK (C48525/A18345)
pubs.funder-project-idAddenbrooke's Charitable Trust (ACT) (unknown)
pubs.funder-project-idCancer Research UK (CB4100)
pubs.funder-project-idCancer Research UK (C14303_do not transfer)
pubs.funder-project-idEuropean Research Council (337905)
pubs.funder-project-idCancer Research UK (unknown)
rioxxterms.freetoread.startdate2019-11-02


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