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Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer

Nature Medicine volume 22, pages 298–305 (2016)Cite this article

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Abstract

An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.

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Figure 1: Clinical and mutational profile of the cohort.
Figure 2: Tracing CRPC-NE emergence through allele-specific analysis.
Figure 3: Methylation analysis of CRPC-NE and CRPC-Adeno tumors.
Figure 4: Integrative DNA, RNA and methylation analysis.

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  • 18 February 2016

    In the version of this article initially published online, the affiliation “Center for Cancer Precision Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA.” was incorrectly attributed to Francesca Demichelis and should have been attributed to Levi A Garraway. The error has been corrected for all versions of this article.

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Acknowledgements

We thank our patients and their families for participation in this study. We would also like to acknowledge R. Montgomery, A. Armstrong and R. Szmulewitz for contributing samples and S.S. Chae for his technical assistance. H.B. is the Damon Runyon-Gordon Family Clinical Investigator and is supported (in part) by the Damon Runyon Cancer Research Foundation (award no. CI-67-13). This work was also supported by the Ann and William Bresnan Foundation (H.B. and D.M.N.), the Department of Defense (grant no. PC121341; H.B.), the US National Institutes of Health (NIH) (grant no. R01 CA116337 (H.B., F.D. and M.A.R.), R01CA157845 (S.V.), R01 CA183857 (S.A.T.), 1K08CA188615 (E.M.V.A.), U54 HG003067 (L.A.G.), U01CA162148 (L.A.G.), 5U01 CA111275-09 (J.M.M., M.A.R. and F.D.), the Starr Cancer Consortium (H.B., L.A.G. and M.A.R), the American-Italian Cancer Foundation (L.P.), the Nuovo Soldati Foundation (J.C.), the A. Alfred Taubman Medical Institute (S.A.T.), a Prostate Cancer Foundation Young Investigator Award (E.M.V.A.), the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant no. IG 13562; F.D.), the European Research Council (consolidator grant (CoG) SPICE (Synthetic lethal phenotype identification through cancer evolution analysis); F.D.) and the Prostate Cancer Foundation (H.B., S.A.T., M.A.R. and F.D.). H.B., J.M.M., S.A.T., D.M.N., S.T.T., E.M.V.A., O.E., A.S., L.A.G., M.A.R and F.D. are supported by a Stand Up To Cancer–Prostate Cancer Foundation Prostate Dream Team translational cancer research grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation that is administered by the American Association for Cancer Research (grant no. SU2C-AACR-DT0712).

Author information

Author notes

  1. Himisha Beltran and Davide Prandi: These authors contributed equally to this work.

  2. Levi A Garraway, Mark A Rubin and Francesca Demichelis: These authors jointly directed this work.

Authors and Affiliations

  1. Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital–Weill Cornell Medicine, New York, New York, USA

    Himisha Beltran, Juan Miguel Mosquera, Loredana Puca, Joanna Cyrta, Clarisse Marotz, Olivier Elemento, Andrea Sboner, Mark A Rubin & Francesca Demichelis

  2. Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York, USA

    Himisha Beltran, David M Nanus & Scott T Tagawa

  3. Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, New York, New York, USA

    Himisha Beltran, David M Nanus, Scott T Tagawa & Mark A Rubin

  4. Centre for Integrative Biology, University of Trento, Trento, Italy

    Davide Prandi, Matteo Benelli & Francesca Demichelis

  5. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA

    Juan Miguel Mosquera, Andrea Sboner & Mark A Rubin

  6. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA

    Eugenia Giannopoulou & Olivier Elemento

  7. Department of Pathology, University of Alabama, Birmingham, Alabama, USA

    Balabhadrapatruni V S K Chakravarthi & Sooryanarayana Varambally

  8. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Scott A Tomlins

  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Eliezer M Van Allen & Levi A Garraway

  10. Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, Massachusetts, USA

    Eliezer M Van Allen & Levi A Garraway

  11. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA

    Andrea Sboner & Francesca Demichelis

  12. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts, USA

    Levi A Garraway

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  1. Himisha Beltran
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Contributions

H.B., M.A.R., L.A.G. and F.D. initiated and designed the study; H.B., S.A.T., D.M.N. and S.T.T. enrolled subjects and contributed samples and clinical data; J.M.M., L.P., J.C., C.M., B.V.S.K.C. and S.V. performed experiments; D.P., M.B., E.G., E.M.V.A., O.E., A.S. and F.D. did the statistical and bioinformatics analyses; H.B., M.A.R., L.A.G. and F.D. supervised the research; H.B., M.A.R., L.A.G. and F.D. wrote the first draft of the manuscript; and all authors contributed to the writing and editing of the revised manuscript, and approved the manuscript.

Corresponding authors

Correspondence to Himisha Beltran, Mark A Rubin or Francesca Demichelis.

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The authors declare no competing financial interests.

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Beltran, H., Prandi, D., Mosquera, J. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med 22, 298–305 (2016). https://doi.org/10.1038/nm.4045

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