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

Anna V. Lapuk, Chunxiao Wu, Alexander W. Wyatt, Andrew McPherson, Brian J. McConeghy, Sonal Brahmbhatt, Fan Mo, Amina Zoubeidi, Shawn Anderson, Robert H. Bell, Anne Haegert, Robert Shukin, Yuzhuo Wang, Ladan Fazli, Antonio Hurtado-Coll, Edward C. Jones, Faraz Hach, Fereydoun Hormozdiari, Iman Hajirasouliha, Paul C. BoutrosRobert G. Bristow, Yongjun Zhao, Marco A. Marra, Andrea Fanjul, Christopher A. Maher, Arul M. Chinnaiyan, Mark A. Rubin, Himisha Beltran, S. Cenk Sahinalp, Martin E. Gleave, Stanislav V. Volik, Colin C. Collins

Research output: Contribution to journalArticle

115 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)286-297
Number of pages12
JournalJournal of Pathology
Volume227
Issue number3
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

Keywords

  • Chromothripsis
  • Massively parallel sequencing
  • Molecular pathology
  • Neuroendocrine prostate cancer
  • REST repressor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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  • Cite this

    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., ... Collins, C. C. (2012). From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. Journal of Pathology, 227(3), 286-297. https://doi.org/10.1002/path.4047