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Detection of breast cancer stem cell gene mutations in circulating free DNA during the evolution of metastases

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications.

Methods

We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer.

Results

Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy.

Conclusion

BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.

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Data availability

The datasets supporting the conclusions for the current study are stored in secured shared drive and will be shared by the corresponding author upon reasonable request.

Abbreviations

BCSC:

Breast cancer stem cell

cfDNA:

Circulating free DNA

ddPCR:

Droplet digital polymerase chain reaction

HN1L:

Hematological and neurological expressed 1-like

RPL39:

Ribosomal protein L39

MLF2:

Myeloid leukemia factor 2

RNA-Seq:

RNA deep sequencing

SIFT:

Sorting intolerant from tolerant

HER2:

Human epidermal growth factor receptor 2

TTM:

Time-to-metastasis

NOS:

Nitric oxide synthase

ER:

Estrogen receptor

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Acknowledgements

Any opinions, findings, and conclusions expressed in this materials are those of the author(s) and do not necessarily reflect those of the American Society of Clinical Oncology® or the Conquer Cancer Foundation, or The Breast Cancer Research Foundation. We would like to thank Dr. Ana María González-Angulo from MD Anderson Hospital who identified the samples from GEICAM investigators.

Funding

This work was supported by a 2013 Conquer Cancer Foundation of ASCO Long-term International Fellowship (LIFe) in Breast Cancer, supported by The Breast Cancer Research Foundation.

Author information

Author notes

  1. Zhe-Bin Liu, Bhuvanesh Dave, and Jenny C. Chang have contributed equally to this work.

Authors and Affiliations

  1. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, China

    Zhe-Bin Liu & Zhi-Min Shao

  2. Houston Methodist Research Institute, Houston, TX, 77030, USA

    Zhe-Bin Liu, Dong S. Choi, Yi Liu, Helen Wong, Bhuvanesh Dave & Jenny C. Chang

  3. Department of Systems Biology and Institute of Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Nader E. Ezzedine, Agda K. Eterovic & Gordon B. Mills

  4. Houston Methodist Cancer Center, 6445 Main St P21-34, Houston, TX, 77030, USA

    Joe E. Ensor, Dong S. Choi, Yi Liu, Helen Wong, Jorge G. Darcourt, Bhuvanesh Dave & Jenny C. Chang

  5. Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Helen J. Huang

  6. GEICAM (Spanish Breast Cancer Group), San Sebastián de los Reyes, 28703, Madrid, Spain

    Joan Albanell, Ana Lluch, Federico Rojo, Eduardo Martínez-Dueñas & Ángel Guerrero-Zotano

  7. Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28029, Madrid, Spain

    Joan Albanell, Ana Lluch & Federico Rojo

  8. Hospital del Mar, 08003, Barcelona, Spain

    Joan Albanell

  9. Hospital Clínico Universitario de Valencia, 46010, Valencia, Spain

    Ana Lluch

  10. Fundación Jiménez Díaz, 28040, Madrid, Spain

    Federico Rojo

  11. Hospital Provincial de Castellón, 12002, Castellón, Spain

    Eduardo Martínez-Dueñas

  12. Instituto Valenciano de Oncología, 46009, Valencia, Spain

    Ángel Guerrero-Zotano

  13. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Zhe-Bin Liu & Zhi-Min Shao

Authors
  1. Zhe-Bin Liu
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  2. Nader E. Ezzedine
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Contributions

Conceptualization, ZBL, BD, and JCC; Methodology, ZBL, NEE, AKE, BD, HW, and JCC; Investigation, ZBL, DSC, YL, HW, and BD; Formal Analysis, ZBL, NEE, JEE, and BD.; Resources, AKE, HJH, ZMS, JGD, GBM, and JCC; Writing—Original Draft, ZBL; Writing—Review and Editing, ZBL, JGD, DK, BD, and JCC; Supervision, BD and JCC; Funding Acquisition, JCC.

Corresponding author

Correspondence to Jenny C. Chang.

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Conflict of interests

The authors declare no potential conflicts of interest with the material reported in this manuscript and have no financial relationship with the organization that funded this study. Individual conflict of interest unrelated to the data presented here are listed in the conflict of interest form.

Research involving human participants and informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board at the Houston Methodist Hospital (IRB protocol numbers 0908-0265, 0811-0147, and 0208-0033) and written informed consent was obtained from all patients before sample and data collection.

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This article does not contain any studies with animals performed by any of the authors.

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Liu, ZB., Ezzedine, N.E., Eterovic, A.K. et al. Detection of breast cancer stem cell gene mutations in circulating free DNA during the evolution of metastases. Breast Cancer Res Treat 178, 251–261 (2019). https://doi.org/10.1007/s10549-019-05374-x

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