dc.contributor.author | Quist, J | |
dc.contributor.author | Mirza, H | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | Telli, ML | |
dc.contributor.author | O'Shaughnessy, JA | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Tutt, ANJ | |
dc.contributor.author | Grigoriadis, A | |
dc.date.accessioned | 2018-11-06T09:19:24Z | |
dc.date.issued | 2019-01-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2019, 18 (1), pp. 204 - 212 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2911 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-18-0243 | |
dc.description.abstract | The 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 (n = 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 (EXO1, TP53BP2, FOXM1, and RSU1) 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+ and CD8+ 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.format | Print-Electronic | |
dc.format.extent | 204 - 212 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Platinum | |
dc.subject | DNA Repair Enzymes | |
dc.subject | Exodeoxyribonucleases | |
dc.subject | Transcription Factors | |
dc.subject | Bayes Theorem | |
dc.subject | Gene Expression Profiling | |
dc.subject | Genomics | |
dc.subject | Cell Survival | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Allelic Imbalance | |
dc.subject | Decision Trees | |
dc.subject | Female | |
dc.subject | Apoptosis Regulatory Proteins | |
dc.subject | Clinical Trials, Phase II as Topic | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.subject | Forkhead Box Protein M1 | |
dc.title | A Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-10-05 | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-18-0243 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 18 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Genomic Analysis – Clinical Trials | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Cheang, Chon | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Tutt, Andrew | |