The Proteogenomic Landscape of Curable Prostate Cancer

Ankit Sinha; Vincent Huang; Julie Livingstone; Jenny Wang; Natalie S Fox; Natalie Kurganovs; Vladimir Ignatchenko; Katharina Fritsch; Nilgun Donmez; Lawrence E Heisler; Yu-Jia Shiah; Cindy Q Yao; Javier A Alfaro; Stas Volik; Anna Lapuk; Michael Fraser; Ken Kron; Alex Murison; Mathieu Lupien; Cenk Sahinalp; Colin C Collins; Bernard Tetu; Mehdi Masoomian; David M Berman; Theodorus van der Kwast; Robert G Bristow; Thomas Kislinger; Paul C Boutros

doi:10.1016/j.ccell.2019.02.005

The Proteogenomic Landscape of Curable Prostate Cancer

Cancer Cell. 2019 Mar 18;35(3):414-427.e6. doi: 10.1016/j.ccell.2019.02.005.

Authors

Ankit Sinha¹, Vincent Huang², Julie Livingstone², Jenny Wang³, Natalie S Fox⁴, Natalie Kurganovs⁵, Vladimir Ignatchenko⁶, Katharina Fritsch⁷, Nilgun Donmez⁸, Lawrence E Heisler², Yu-Jia Shiah², Cindy Q Yao², Javier A Alfaro⁴, Stas Volik⁸, Anna Lapuk⁸, Michael Fraser², Ken Kron⁶, Alex Murison⁶, Mathieu Lupien⁹, Cenk Sahinalp⁸, Colin C Collins¹⁰, Bernard Tetu¹¹, Mehdi Masoomian¹², David M Berman¹³, Theodorus van der Kwast¹⁴, Robert G Bristow¹⁵, Thomas Kislinger¹⁶, Paul C Boutros¹⁷

Affiliations

¹ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
² Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
³ Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada; Queen's Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
⁴ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
⁵ Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
⁸ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
¹⁰ Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada; Department of Urologic Sciences, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
¹¹ Department of Pathology and Research Centre of CHU de Québec-Université Laval, Québec City, QC G1V 4G2, Canada.
¹² Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.
¹³ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada; Queen's Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
¹⁴ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.
¹⁵ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada.
¹⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: thomas.kislinger@utoronto.ca.
¹⁷ Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Human Genetics, University of California, 12-109 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; Department of Urology, University of California, Los Angeles, CA 90024, USA; Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA 90024, USA; Institute for Precision Health, University of California, Los Angeles, CA 90024, USA. Electronic address: pboutros@mednet.ucla.edu.

Abstract

DNA sequencing has identified recurrent mutations that drive the aggressiveness of prostate cancers. Surprisingly, the influence of genomic, epigenomic, and transcriptomic dysregulation on the tumor proteome remains poorly understood. We profiled the genomes, epigenomes, transcriptomes, and proteomes of 76 localized, intermediate-risk prostate cancers. We discovered that the genomic subtypes of prostate cancer converge on five proteomic subtypes, with distinct clinical trajectories. ETS fusions, the most common alteration in prostate tumors, affect different genes and pathways in the proteome and transcriptome. Globally, mRNA abundance changes explain only ∼10% of protein abundance variability. As a result, prognostic biomarkers combining genomic or epigenomic features with proteomic ones significantly outperform biomarkers comprised of a single data type.

Keywords: biomarker; epigenome; genome; multi-omic features; prostate cancer; proteome; transcriptome.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Cell Line, Tumor
Epigenomics
Gene Expression Profiling
Humans
Male
Middle Aged
Prognosis
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology*
Proteogenomics / methods*
Proto-Oncogene Proteins c-ets / genetics*
Proto-Oncogene Proteins c-ets / metabolism*
Translocation, Genetic
Whole Genome Sequencing

Substances

Biomarkers, Tumor
Proto-Oncogene Proteins c-ets

Abstract

Publication types

MeSH terms

Substances

Grants and funding