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Breast Cancer Research and Treatment

, Volume 178, Issue 2, pp 251–261 | Cite as

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

  • Zhe-Bin Liu
  • Nader E. Ezzedine
  • Agda K. Eterovic
  • Joe E. Ensor
  • Helen J. Huang
  • Joan Albanell
  • Dong S. Choi
  • Ana Lluch
  • Yi Liu
  • Federico Rojo
  • Helen Wong
  • Eduardo Martínez-Dueñas
  • Ángel Guerrero-Zotano
  • Zhi-Min Shao
  • Jorge G. Darcourt
  • Gordon B. Mills
  • Bhuvanesh Dave
  • Jenny C. ChangEmail author
Preclinical study
  • 238 Downloads

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.

Keywords

Breast carcinoma Stem cell Mutation Droplet digital polymerase chain reaction Metastasis 

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

Notes

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.

Author 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.

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.

Compliance with ethical standards

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.

Animal subjects

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

Supplementary material

10549_2019_5374_MOESM1_ESM.docx (16 kb)
Supplementary material 1 (DOCX 16 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Zhe-Bin Liu
    • 1
    • 2
    • 13
  • Nader E. Ezzedine
    • 3
  • Agda K. Eterovic
    • 3
  • Joe E. Ensor
    • 4
  • Helen J. Huang
    • 5
  • Joan Albanell
    • 6
    • 7
    • 8
  • Dong S. Choi
    • 2
    • 4
  • Ana Lluch
    • 6
    • 7
    • 9
  • Yi Liu
    • 2
    • 4
  • Federico Rojo
    • 6
    • 7
    • 10
  • Helen Wong
    • 2
    • 4
  • Eduardo Martínez-Dueñas
    • 6
    • 11
  • Ángel Guerrero-Zotano
    • 6
    • 12
  • Zhi-Min Shao
    • 1
    • 13
  • Jorge G. Darcourt
    • 4
  • Gordon B. Mills
    • 3
  • Bhuvanesh Dave
    • 2
    • 4
  • Jenny C. Chang
    • 2
    • 4
    Email author
  1. 1.Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Houston Methodist Research InstituteHoustonUSA
  3. 3.Department of Systems Biology and Institute of Personalized Cancer TherapyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Houston Methodist Cancer CenterHoustonUSA
  5. 5.Division of Cancer Medicine, Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.GEICAM (Spanish Breast Cancer Group)San Sebastián de los ReyesMadridSpain
  7. 7.Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIIIMadridSpain
  8. 8.Hospital del MarBarcelonaSpain
  9. 9.Hospital Clínico Universitario de ValenciaValenciaSpain
  10. 10.Fundación Jiménez DíazMadridSpain
  11. 11.Hospital Provincial de CastellónCastellónSpain
  12. 12.Instituto Valenciano de OncologíaValenciaSpain
  13. 13.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina

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