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Clinicopathological Features of Triple-Negative Breast Cancer Epigenetic Subtypes

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background/Objective

Triple-negative breast cancer (TNBC) is a heterogeneous collection of breast tumors with numerous differences including morphological characteristics, genetic makeup, immune-cell infiltration, and response to systemic therapy. DNA methylation profiling is a robust tool to accurately identify disease-specific subtypes. We aimed to generate an epigenetic subclassification of TNBC tumors (epitypes) with utility for clinical decision-making.

Methods

Genome-wide DNA methylation profiles from TNBC patients generated in the Cancer Genome Atlas project were used to build machine learning-based epigenetic classifiers. Clinical and demographic variables, as well as gene expression and gene mutation data from the same cohort, were integrated to further refine the TNBC epitypes.

Results

This analysis indicated the existence of four TNBC epitypes, named as Epi-CL-A, Epi-CL-B, Epi-CL-C, and Epi-CL-D. Patients with Epi-CL-B tumors showed significantly shorter disease-free survival and overall survival [log rank; P = 0.01; hazard ratio (HR) 3.89, 95% confidence interval (CI) 1.3–11.63 and P = 0.003; HR 5.29, 95% CI 1.55–18.18, respectively]. Significant gene expression and mutation differences among the TNBC epitypes suggested alternative pathway activation that could be used as ancillary therapeutic targets. These epigenetic subtypes showed complementarity with the recently described TNBC transcriptomic subtypes.

Conclusions

TNBC epigenetic subtypes exhibit significant clinical and molecular differences. The links between genetic make-up, gene expression programs, and epigenetic subtypes open new avenues in the development of laboratory tests to more efficiently stratify TNBC patients, helping optimize tailored treatment approaches.

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Acknowledgment

This work was supported by the Associates for Breast and Prostate Cancer Studies (ABCs) Foundation, the Fashion Footwear Association of New York (FFANY) Foundation, and the John Wayne Cancer Institute Translational Research Fund.

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Author notes

  1. Maggie L. DiNome and Javier I. J. Orozco have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, David Geffen School of Medicine, University California Los Angeles (UCLA), Los Angeles, CA, USA

    Maggie L. DiNome MD

  2. Cancer Epigenetics Laboratory, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, USA

    Javier I. J. Orozco MD, Ayla O. Manughian-Peter MSc & Diego M. Marzese PhD

  3. Computational Biology Laboratory, John Wayne Cancer Institute at Providence St. John’s Health Center, Santa Monica, CA, USA

    Chikako Matsuba PhD & Matthew P. Salomon PhD

  4. Cancer Cell Biology Group, Balearic Islands Health Research Institute (IdISBa), Palma, Islas Baleares, Spain

    Miquel Ensenyat-Mendez MSc

  5. Medical Data Research Center, Providence Saint Joseph Health, Portland, OR, USA

    Shu-Ching Chang PhD

  6. Department of Pathology, Providence Saint John’s Health Center, Santa Monica, CA, USA

    John R. Jalas MD

Authors
  1. Maggie L. DiNome MD
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  2. Javier I. J. Orozco MD
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Correspondence to Diego M. Marzese PhD.

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DiNome, M.L., Orozco, J.I.J., Matsuba, C. et al. Clinicopathological Features of Triple-Negative Breast Cancer Epigenetic Subtypes. Ann Surg Oncol 26, 3344–3353 (2019). https://doi.org/10.1245/s10434-019-07565-8

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  • DOI: https://doi.org/10.1245/s10434-019-07565-8

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