title: Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer.
abstract: Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.
authors.affiliation: Minnesota Supercomputing Institute, University of Minnesota, 117 Pleasant Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Henzler
authors.affiliation: Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Li
authors.affiliation: Minnesota Supercomputing Institute, University of Minnesota, 117 Pleasant Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Rendong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.|Medical Scientist Training Program, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Terri
authors.identifier: http://orcid.org/0000-0002-9305-8038
authors.initials: T
authors.lastname: McBride
authors.affiliation: Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Yeung
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington 98104, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sprenger
authors.affiliation: Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington 98104, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, Washington 98195, USA.
authors.forename: Bryce
authors.initials: B
authors.lastname: Lakely
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Shihong
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, 200 Union Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Landman
authors.affiliation: Department of Computer Science and Engineering, University of Minnesota, 200 Union Street Southeast, Minneapolis, Minnesota 55455, USA.
authors.forename: Vipin
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, Texas 75390, USA.
authors.forename: Tae Hyun
authors.identifier: http://orcid.org/0000-0002-0389-5597
authors.initials: TH
authors.lastname: Hwang
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.|Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, Washington 98195, USA.|Department of Medicine, University of Washington, 825 Eastlake Avenue East, Seattle, Washington 98109, USA.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, Washington 98195, USA.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington 98104, USA.|Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, Washington 98195, USA.|Geriatric Research Education and Clinical Centers, VA Puget Sound Health Care System, 325 9th Avenue, Box 359625, Seattle, Washington 98104, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Plymate
authors.affiliation: Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.|Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Scott M
authors.identifier: http://orcid.org/0000-0002-7827-5579
authors.initials: SM
authors.lastname: Dehm
mesh_terms: D000483:Alleles; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002999:Clone Cells; D005091:Exons / Q000235:genetics; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics*; D015894:Genome, Human; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen