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dc.contributor.authorMansukhani, S
dc.contributor.authorBarber, LJ
dc.contributor.authorKleftogiannis, D
dc.contributor.authorMoorcraft, SY
dc.contributor.authorDavidson, M
dc.contributor.authorWoolston, A
dc.contributor.authorProszek, PZ
dc.contributor.authorGriffiths, B
dc.contributor.authorFenwick, K
dc.contributor.authorHerman, B
dc.contributor.authorMatthews, N
dc.contributor.authorO'Leary, B
dc.contributor.authorHulkki, S
dc.contributor.authorGonzalez De Castro, D
dc.contributor.authorPatel, A
dc.contributor.authorWotherspoon, A
dc.contributor.authorOkachi, A
dc.contributor.authorRana, I
dc.contributor.authorBegum, R
dc.contributor.authorDavies, MN
dc.contributor.authorPowles, T
dc.contributor.authorvon Loga, K
dc.contributor.authorHubank, M
dc.contributor.authorTurner, N
dc.contributor.authorWatkins, D
dc.contributor.authorChau, I
dc.contributor.authorCunningham, D
dc.contributor.authorLise, S
dc.contributor.authorStarling, N
dc.contributor.authorGerlinger, M
dc.date.accessioned2018-08-03T14:55:19Z
dc.date.issued2018-11
dc.identifier.citationClinical chemistry, 2018, 64 (11), pp. 1626 - 1635
dc.identifier.issn0009-9147
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2266
dc.identifier.eissn1530-8561
dc.identifier.doi10.1373/clinchem.2018.289629
dc.description.abstractBackground Circulating free DNA sequencing (cfDNA-Seq) can portray cancer genome landscapes, but highly sensitive and specific technologies are necessary to accurately detect mutations with often low variant frequencies.Methods We developed a customizable hybrid-capture cfDNA-Seq technology using off-the-shelf molecular barcodes and a novel duplex DNA molecule identification tool for enhanced error correction.Results Modeling based on cfDNA yields from 58 patients showed that this technology, requiring 25 ng of cfDNA, could be applied to >95% of patients with metastatic colorectal cancer (mCRC). cfDNA-Seq of a 32-gene, 163.3-kbp target region detected 100% of single-nucleotide variants, with 0.15% variant frequency in spike-in experiments. Molecular barcode error correction reduced false-positive mutation calls by 97.5%. In 28 consecutively analyzed patients with mCRC, 80 out of 91 mutations previously detected by tumor tissue sequencing were called in the cfDNA. Call rates were similar for point mutations and indels. cfDNA-Seq identified typical mCRC driver mutations in patients in whom biopsy sequencing had failed or did not include key mCRC driver genes. Mutations only called in cfDNA but undetectable in matched biopsies included a subclonal resistance driver mutation to anti-EGFR antibodies in KRAS , parallel evolution of multiple PIK3CA mutations in 2 cases, and TP53 mutations originating from clonal hematopoiesis. Furthermore, cfDNA-Seq off-target read analysis allowed simultaneous genome-wide copy number profile reconstruction in 20 of 28 cases. Copy number profiles were validated by low-coverage whole-genome sequencing.Conclusions This error-corrected, ultradeep cfDNA-Seq technology with a customizable target region and publicly available bioinformatics tools enables broad insights into cancer genomes and evolution.Clinicaltrialsgov identifier NCT02112357.
dc.formatPrint-Electronic
dc.format.extent1626 - 1635
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectHumans
dc.subjectColorectal Neoplasms
dc.subjectNeoplasm Metastasis
dc.subjectSensitivity and Specificity
dc.subjectDNA Mutational Analysis
dc.subjectMutation
dc.subjectGenome-Wide Association Study
dc.subjectDNA Copy Number Variations
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectBiomarkers, Tumor
dc.subjectCirculating Tumor DNA
dc.titleUltra-Sensitive Mutation Detection and Genome-Wide DNA Copy Number Reconstruction by Error-Corrected Circulating Tumor DNA Sequencing.
dc.typeJournal Article
dcterms.dateAccepted2018-07-17
rioxxterms.versionofrecord10.1373/clinchem.2018.289629
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2018-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical chemistry
pubs.issue11
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Gastrointestinal Cancers Clinical Trials/Gastrointestinal Cancers Clinical Trials (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume64
pubs.embargo.termsNo embargo
icr.researchteamMolecular Oncologyen_US
icr.researchteamGastrointestinal Cancers Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamTranslational Genomicsen_US
icr.researchteamTranslational Oncogenomicsen_US
dc.contributor.icrauthorGriffiths, Beatriceen
dc.contributor.icrauthorMansukhani, Soniaen
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorCunningham, Daviden
dc.contributor.icrauthorChau, Ianen
dc.contributor.icrauthorStarling, Naureenen
dc.contributor.icrauthorGerlinger, Marcoen
dc.contributor.icrauthorBarber, Louiseen
dc.contributor.icrauthorO'Leary, Benjaminen
dc.contributor.icrauthorLise, Stefanoen
dc.contributor.icrauthorWoolston, Andrewen
dc.contributor.icrauthorHubank, Michaelen


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