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Risk stratification of triple-negative breast cancer with core gene signatures associated with chemoresponse and prognosis

  • Epidemiology
  • Published:
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Abstract

Purpose

Neoadjuvant chemotherapy studies have consistently reported a strong correlation between pathologic response and long-term outcome in triple-negative breast cancer (TNBC). We aimed to define minimal gene signatures for predicting chemoresponse by a three-step approach and to further develop a risk-stratification method of TNBC.

Methods

The first step involved the detection of genes associated with resistance to docetaxel in eight TNBC cell lines, leading to identification of thousands of candidate genes. Through subsequent second and third step analyses with gene set enrichment analysis and survival analysis using public expression profiles, the candidate gene list was reduced to prognostic core gene signatures comprising ten or four genes.

Results

The prognostic core gene signatures include three up-regulated (CEBPD, MMP20, and WLS) and seven down-regulated genes (ASF1A, ASPSCR1, CHAF1B, DNMT1, GINS2, GOLGA2P5, and SKA1). We further develop a simple risk-stratification method based on expression profiles of the core genes. Relative expression values of the up-regulated and down-regulated core genes were averaged into two scores, Up and Down scores, respectively; then samples were stratified by a diagonal line in a xy plot of the Up and Down scores. Based on this method, the patients were successfully divided into subgroups with distinct chemoresponse and prognosis. The prognostic power of the method was validated in three independent public datasets containing 230, 141, and 117 TNBC patients with chemotherapy. In multivariable Cox regression analysis, the core gene signatures were significantly associated with prognosis independent of tumor stage and age at diagnosis. In meta-analysis, we found that five core genes (CEBPD, WLS, CHAF1B, GINS2, and SKA1) play opposing roles, either tumor promoter or suppressor, in TNBC and non-TNBC tumors respectively, depending on estrogen receptor status.

Conclusions

The results may provide a promising prognostic tool for predicting chemotherapy responders among TNBC patients prior to initiation of chemotherapeutic treatment.

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Acknowledgements

We thank all the individuals who took part in the Translational Research Organization in Cancer (TROICA) project and all the researchers who have enabled this work to be carried out.

Funding

This research was funded by grants of the National Research Foundation (NRF) of Korea funded by the Korea government (MSIP), 2015R1A2A2A01008264 (to WH) and 2015R1A4A1041219 (to AKP).

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  1. Eun-Kyu Kim and Ae Kyung Park have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea

    Eun-Kyu Kim

  2. College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea

    Ae Kyung Park

  3. Department of Surgical Oncology, Oncology Center, Sheikh Khalifa Specialty Hospital, Ras Al-Khaimah, United Arab Emirates

    Eunyoung Ko

  4. Department of Molecular Cell Biology, Samsung Medical Center and Samsung Genome Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

    Woong-Yang Park

  5. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Kyung-Min Lee, Dong-Young Noh & Wonshik Han

  6. Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Dong-Young Noh & Wonshik Han

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Kim, EK., Park, A.K., Ko, E. et al. Risk stratification of triple-negative breast cancer with core gene signatures associated with chemoresponse and prognosis. Breast Cancer Res Treat 178, 185–197 (2019). https://doi.org/10.1007/s10549-019-05366-x

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