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dc.contributor.authorQuist, J
dc.contributor.authorMirza, H
dc.contributor.authorCheang, MCU
dc.contributor.authorTelli, ML
dc.contributor.authorO'Shaughnessy, JA
dc.contributor.authorLord, CJ
dc.contributor.authorTutt, ANJ
dc.contributor.authorGrigoriadis, A
dc.date.accessioned2018-11-06T09:19:24Z
dc.date.issued2019-01
dc.identifier.citationMolecular cancer therapeutics, 2019, 18 (1), pp. 204 - 212
dc.identifier.issn1535-7163
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2911
dc.identifier.eissn1538-8514en_US
dc.identifier.doi10.1158/1535-7163.mct-18-0243en_US
dc.description.abstractThe molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (<i>n</i> = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (<i>EXO1, TP53BP2, FOXM1</i>, and <i>RSU1</i>) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors (∼50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4<sup>+</sup> and CD8<sup>+</sup> immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.
dc.formatPrint-Electronic
dc.format.extent204 - 212
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectPlatinum
dc.subjectDNA Repair Enzymes
dc.subjectExodeoxyribonucleases
dc.subjectTranscription Factors
dc.subjectBayes Theorem
dc.subjectGene Expression Profiling
dc.subjectGenomics
dc.subjectCell Survival
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectAllelic Imbalance
dc.subjectDecision Trees
dc.subjectFemale
dc.subjectApoptosis Regulatory Proteins
dc.subjectClinical Trials, Phase II as Topic
dc.subjectMolecular Targeted Therapy
dc.subjectTriple Negative Breast Neoplasms
dc.subjectForkhead Box Protein M1
dc.titleA Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics.
dc.typeJournal Article
dcterms.dateAccepted2018-10-05
rioxxterms.versionofrecord10.1158/1535-7163.mct-18-0243
rioxxterms.licenseref.startdate2019-01en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfMolecular cancer therapeutics
pubs.issue1
pubs.notesNot known
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/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
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/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Genomic Analysis – Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume18en_US
pubs.embargo.termsNot known
icr.researchteamGenomic Analysis – Clinical Trialsen_US
icr.researchteamGene Functionen_US
dc.contributor.icrauthorCheang, Chonen
dc.contributor.icrauthorLord, Christopheren
dc.contributor.icrauthorTutt, Andrewen


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