SUMMARY
The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscape of this disease. We comprehensively characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes in mCRPC. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
Competing Interest Statement
A.D.C.: Honoraria: OncLive, Bayer, Targeted Oncology, Aptitude Health, Journal of Clinical Pathways, Cancer Network; Consulting: Blackstone; Advisory Board: Clovis, Dendreon, Bayer, Eli Lilly, AstraZeneca, Astellas, Blue Earth; Research Funding: Bayer E.M.V.: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; Travel reimbursement: Roche/Genentech; Patents: Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag M-E.T.: Advisory boards: Janssen, Pfizer, Astra Zeneca, Bayer M.L.F.: Served as a consultant to and has equity in Nuscan Diagnostics. This activity is outside of the scope of this manuscript. M.M.: Consultant for Bayer, Interline and Isobl; an inventor of patents licensed to LabCorp and Bayer; and receives research funding from Bayer, Janssen, and Ono Pharmaceuticals. P.S.N.: Served as a consultant to Bristol Myers Squibb, Janssen, and Pfizer in work unrelated to the present study. S.R.V.: Consulting (current or previous 3 years), MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors declare no competing interests.
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