期刊
MOLECULAR CANCER THERAPEUTICS
卷 18, 期 1, 页码 204-212出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-0243
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资金
- Experimental Cancer Medicine Centre at King's College London
- Department of Health via the National Institute for Health Research Comprehensive Biomedical Research Centre award
- Cancer Research UK King's Health Partners Centre at King's College London
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas
- Breast Cancer Now Programme grant at King's College London
- Breast Cancer Now Programme grant at Institute of Cancer Research
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London
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 (similar to 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.
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