Genomic hallmarks of localized, non-indolent prostate cancer

Michael Fraser, Veronica Y. Sabelnykova, Takafumi N. Yamaguchi, Lawrence E. Heisler, Julie Livingstone, Vincent Huang, Yu Jia Shiah, Fouad Yousif, Xihui Lin, Andre P. Masella, Natalie S. Fox, Michael Xie, Stephenie D. Prokopec, Alejandro Berlin, Emilie Lalonde, Musaddeque Ahmed, Dominique Trudel, Xuemei Luo, Timothy A. Beck, Alice MengJunyan Zhang, Alister D'Costa, Robert E. Denroche, Haiying Kong, Shadrielle Melijah G. Espiritu, Melvin L.K. Chua, Ada Wong, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas B. Buchner, Michèle Orain, Valérie Picard, Helène Hovington, Alexander Murison, Ken Kron, Nicholas J. Harding, Christine P'ng, Kathleen E. Houlahan, Kenneth C. Chu, Bryan Lo, Francis Nguyen, Constance H. Li, Ren X. Sun, Richard de Borja, Christopher I. Cooper, Julia F. Hopkins, Shaylan K. Govind, Clement Fung, Daryl Waggott, Jeffrey Green, Syed Haider, Michelle A. Chan-Seng-Yue, Esther Jung, Zhiyuan Wang, Alain Bergeron, Alan Dal Pra, Louis Lacombe, Colin C. Collins, Cenk Sahinalp, Mathieu Lupien, Neil E. Fleshner, Housheng H. He, Yves Fradet, Bernard Tetu, Theodorus van der Kwast, John Douglas Mcpherson, Robert G. Bristow, Paul C. Boutros

Research output: Contribution to journalArticle

202 Scopus citations

Abstract

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Original languageEnglish (US)
Pages (from-to)359-364
Number of pages6
JournalNature
Volume541
Issue number7637
DOIs
StatePublished - Jan 19 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • General

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    Fraser, M., Sabelnykova, V. Y., Yamaguchi, T. N., Heisler, L. E., Livingstone, J., Huang, V., Shiah, Y. J., Yousif, F., Lin, X., Masella, A. P., Fox, N. S., Xie, M., Prokopec, S. D., Berlin, A., Lalonde, E., Ahmed, M., Trudel, D., Luo, X., Beck, T. A., ... Boutros, P. C. (2017). Genomic hallmarks of localized, non-indolent prostate cancer. Nature, 541(7637), 359-364. https://doi.org/10.1038/nature20788