A primary breast cancer with distinct foci of estrogen receptor-alpha positive and negative cells derived from the same clonal origin as revealed by whole exome sequencing

Brief Report



Tumor heterogeneity is a now well-recognized phenomenon that can affect the classification, prognosis and treatment of human cancers. Heterogeneity is often described in primary breast cancers based upon histologic subtypes, hormone- and HER2-receptor status, and immunolabeling for various markers, which can be seen within a single tumor as mixed cellular populations, or as separate discrete foci.

Experimental design/methods

Here, we present a case report of a patient’s primary breast cancer that had two separate but adjacent histologic components, one that was estrogen receptor (ER) positive, and the other ER negative. Each component was subjected to whole exome sequencing and compared for gene identity to determine clonal origin.


Using prior bioinformatic tools, we demonstrated that both the ER positive and negative components shared many variants, including passenger and driver alterations. Copy number variations also supported the two components were derived from a single common clone.


These analyses strongly suggest that the two ER components of this patient’s breast cancer were derived from the same clonal origin. Our results have implications for the evolution of breast cancers with mixed histologies, and how they might be best managed for optimal therapy.


Whole exome sequencing Breast cancer Estrogen receptor 



We thank various members of the Park and Wheelan lab for helpful thoughts and discussions. This work was supported by NIH R01CA194024, NIH P30CA006973, Susan G. Komen, the Commonwealth Foundation, the Breast Cancer Research Foundation, the Marcie Ellen Foundation, The Helen Golde Trust, and The Canney Foundation. None of the funding sources influenced the design, interpretation or submission of this manuscript.


B.H.P. is a paid member of scientific advisory boards for Loxo Oncology, and has ownership interest in Loxo Oncology. B.H.P. has research contracts with Foundation Medicine, Inc. Under separate licensing agreements between Horizon Discovery, LTD and The Johns Hopkins University, B.H.P. is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by the Johns Hopkins University, in accordance with its conflict of interest policies. No potential conflicts of interest were disclosed by the other authors.

Supplementary material

10549_2018_4742_MOESM1_ESM.pdf (529 kb)
Supplementary material 1 (PDF 528 kb)
10549_2018_4742_MOESM2_ESM.xlsx (36 kb)
Supplementary material 2 (XLSX 35 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Oncology, The Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Anatomic Pathology, Northwell PathologyNorthshore University Hospital Long Island Jewish Medical Center, Cohen Children HospitalLake SuccessUSA
  3. 3.Department of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Department of BiostatisticsThe Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  5. 5.Department of Chemical and Biomolecular Engineering, The Whiting School of EngineeringJohns Hopkins UniversityBaltimoreUSA
  6. 6.BaltimoreUSA
  7. 7.BaltimoreUSA
  8. 8.BaltimoreUSA

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