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Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models.

cam.issuedOnline2018-11-02
dc.contributor.authorMair, Richard
dc.contributor.authorMouliere, Florent
dc.contributor.authorSmith, Christopher G
dc.contributor.authorChandrananda, Dineika
dc.contributor.authorGale, Davina
dc.contributor.authorMarass, Francesco
dc.contributor.authorTsui, Dana WY
dc.contributor.authorMassie, Charles E
dc.contributor.authorWright, Alan J
dc.contributor.authorWatts, Colin
dc.contributor.authorRosenfeld, Nitzan
dc.contributor.authorBrindle, Kevin M
dc.contributor.orcidChandrananda, Dineika [0000-0002-8834-9500]
dc.contributor.orcidMarass, Francesco [0000-0002-8993-7320]
dc.contributor.orcidMassie, Charles E [0000-0003-2314-4843]
dc.contributor.orcidWright, Alan J [0000-0002-4577-5681]
dc.date.accessioned2018-12-07T00:31:11Z
dc.date.available2018-12-07T00:31:11Z
dc.date.issued2019-01-01
dc.description.abstractThe factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (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 GBM PDOX. Analysis of fragment length profiles by shallow genome-wide sequencing (<0.2× 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% vs. 24%) and allowed detection in cerebrospinal fluid 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 GBM, where current methods have largely failed. SIGNIFICANCE: These findings show that detection of tumor mitochondrial DNA is more sensitive than circulating tumor DNA analysis to detect and monitor tumor burden in patient-derived orthotopic xenografts of glioblastoma.
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-Electronic
dc.identifier.doi10.17863/CAM.33712
dc.identifier.eissn1538-7445
dc.identifier.issn0008-5472
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286401
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research (AACR)
dc.publisher.urlhttp://dx.doi.org/10.1158/0008-5472.can-18-0074
dc.subjectAnimals
dc.subjectBiomarkers, Tumor
dc.subjectBody Fluids
dc.subjectCirculating Tumor DNA
dc.subjectDNA, Mitochondrial
dc.subjectDNA, Neoplasm
dc.subjectFemale
dc.subjectGlioblastoma
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectHumans
dc.subjectMitochondria
dc.subjectRats
dc.subjectRats, Nude
dc.subjectTumor Cells, Cultured
dc.subjectXenograft Model Antitumor Assays
dc.titleMeasurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models.
dc.typeArticle
dcterms.dateAccepted2018-10-26
prism.endingPage230
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameCancer Res
prism.startingPage220
prism.volume79
pubs.funder-project-idCancer Research Uk (None)
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/A17197)
pubs.funder-project-idEuropean Research Council (337905)
pubs.funder-project-idCancer Research UK (unknown)
rioxxterms.licenseref.startdate2019-01
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/0008-5472.CAN-18-0074

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