title: Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer.
abstract: We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: G Steven
authors.initials: GS
authors.lastname: Bova
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Heini M L
authors.initials: HM
authors.lastname: Kallio
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Matti
authors.initials: M
authors.lastname: Annala
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Kati
authors.initials: K
authors.lastname: Kivinummi
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Gunilla
authors.initials: G
authors.lastname: Högnäs
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Sergei
authors.initials: S
authors.lastname: Häyrynen
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Tommi
authors.initials: T
authors.lastname: Rantapero
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Virpi
authors.initials: V
authors.lastname: Kivinen
authors.affiliation: The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Teemu
authors.initials: T
authors.lastname: Tolonen
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, BioMediTech, University of Tampere and Fimlab Laboratories, Tampere University Hospital, FI-33014 Tampere, Finland;
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
keywords: malignant genitourinary tract tumor; neoplasm of the genitourinary tract