Original Paper

From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer†

  1. Anna V Lapuk1,‡,
  2. Chunxiao Wu1,‡,
  3. Alexander W Wyatt1,
  4. Andrew McPherson2,3,
  5. Brian J McConeghy1,
  6. Sonal Brahmbhatt1,
  7. Fan Mo1,
  8. Amina Zoubeidi1,
  9. Shawn Anderson1,
  10. Robert H Bell1,
  11. Anne Haegert1,
  12. Robert Shukin1,
  13. Yuzhuo Wang1,
  14. Ladan Fazli1,
  15. Antonio Hurtado-Coll1,
  16. Edward C Jones4,
  17. Faraz Hach3,
  18. Fereydoun Hormozdiari3,
  19. Iman Hajirasouliha3,
  20. Paul C Boutros5,
  21. Robert G Bristow6,
  22. Yongjun Zhao2,7,
  23. Marco A Marra7,
  24. Andrea Fanjul8,
  25. Christopher A Maher9,
  26. Arul M Chinnaiyan9,
  27. Mark A Rubin10,
  28. Himisha Beltran11,
  29. S Cenk Sahinalp3,
  30. Martin E Gleave1,
  31. Stanislav V Volik1,
  32. Colin C Collins1,*

Article first published online: 6 JUN 2012

DOI: 10.1002/path.4047

Issue

The Journal of Pathology

The Journal of Pathology

Volume 227, Issue 3, pages 286–297, July 2012

Additional Information

How to Cite

Lapuk, A. V., Wu, C., Wyatt, A. W., McPherson, A., McConeghy, B. J., Brahmbhatt, S., Mo, F., Zoubeidi, A., Anderson, S., Bell, R. H., Haegert, A., Shukin, R., Wang, Y., Fazli, L., Hurtado-Coll, A., Jones, E. C., Hach, F., Hormozdiari, F., Hajirasouliha, I., Boutros, P. C., Bristow, R. G., Zhao, Y., Marra, M. A., Fanjul, A., Maher, C. A., Chinnaiyan, A. M., Rubin, M. A., Beltran, H., Sahinalp, S. C., Gleave, M. E., Volik, S. V. and Collins, C. C. (2012), From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J. Pathol., 227: 286–297. doi: 10.1002/path.4047

Author Information

  1. 1

    Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

  2. 2

    Centre for Translational and Applied Genomics, BC Cancer Agency, Vancouver, BC, Canada

  3. 3

    School of Computing Science, Simon Fraser University, Burnaby, BC, Canada

  4. 4

    Department of Pathology and Laboratory Medicine and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

  5. 5

    Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, ON, Canada

  6. 6

    Division of Applied Molecular Oncology, Ontario Institute for Cancer Research, Toronto, ON, Canada

  7. 7

    Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada

  8. 8

    Pfizer Global Research and Development, La Jolla Laboratories, California, USA

  9. 9

    Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA

  10. 10

    Department of Pathology and Laboratory Medicine, Weill Cornell Cancer Center, New York, NY, USA

  11. 11

    Department of Medicine, Weill Cornell Cancer Center, New York, NY, USA

  1. ‡

    These authors contributed equally to this work.Data availability: Illumina sequence data are available from the Vancouver Prostate Centre website at http://www.lagapc.ca/FTP_Lapuk.html

*2660 Oak St, Vancouver, BC, V6H 3Z6, Canada.

  1. †

    Conflict of interest statement: There is a possible conflict of interest as Andrea Fanjul is a Pfizer employee.

  2. ‡

    These authors contributed equally to this work.Data availability: Illumina sequence data are available from the Vancouver Prostate Centre website at http://www.lagapc.ca/FTP_Lapuk.html

Publication History

  1. Issue published online: 6 JUN 2012
  2. Article first published online: 6 JUN 2012
  3. Accepted manuscript online: 3 MAY 2012 04:08AM EST
  4. Manuscript Revised: 24 APR 2012
  5. Manuscript Accepted: 24 APR 2012
  6. Manuscript Received: 27 FEB 2012

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Keywords:

  • molecular pathology;
  • massively parallel sequencing;
  • neuroendocrine prostate cancer;
  • REST repressor;
  • chromothripsis

Abstract

The current paradigm of cancer care relies on predictive nomograms which integrate detailed histopathology with clinical data. However, when predictions fail, the consequences for patients are often catastrophic, especially in prostate cancer where nomograms influence the decision to therapeutically intervene. We hypothesized that the high dimensional data afforded by massively parallel sequencing (MPS) is not only capable of providing biological insights, but may aid molecular pathology of prostate tumours. We assembled a cohort of six patients with high-risk disease, and performed deep RNA and shallow DNA sequencing in primary tumours and matched metastases where available. Our analysis identified copy number abnormalities, accurately profiled gene expression levels, and detected both differential splicing and expressed fusion genes. We revealed occult and potentially dormant metastases, unambiguously supporting the patients' clinical history, and implicated the REST transcriptional complex in the development of neuroendocrine prostate cancer, validating this finding in a large independent cohort. We massively expand on the number of novel fusion genes described in prostate cancer; provide fresh evidence for the growing link between fusion gene aetiology and gene expression profiles; and show the utility of fusion genes for molecular pathology. Finally, we identified chromothripsis in a patient with chronic prostatitis. Our results provide a strong foundation for further development of MPS-based molecular pathology. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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