A Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics.
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Date
2019-01-01Author
Quist, J
Mirza, H
Cheang, MCU
Telli, ML
O'Shaughnessy, JA
Lord, CJ
Tutt, ANJ
Grigoriadis, A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Humans
Platinum
DNA Repair Enzymes
Exodeoxyribonucleases
Transcription Factors
Bayes Theorem
Gene Expression Profiling
Genomics
Cell Survival
Gene Expression Regulation, Neoplastic
Allelic Imbalance
Decision Trees
Female
Apoptosis Regulatory Proteins
Clinical Trials, Phase II as Topic
Molecular Targeted Therapy
Triple Negative Breast Neoplasms
Forkhead Box Protein M1
Research team
Genomic Analysis – Clinical Trials
Gene Function
Language
eng
Date accepted
2018-10-05
License start date
2019-01
Citation
Molecular cancer therapeutics, 2019, 18 (1), pp. 204 - 212
Publisher
AMER ASSOC CANCER RESEARCH