Stromal Gene Expression is Predictive for Metastatic Primary Prostate Cancer.
Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for identification of biomarkers that can more accurately stratify patients with primary PCa.



To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa).



To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes. Multiple independent clinical cohorts including an intermediate-risk cohort were used to validate the biomarkers.



The outcome measurement defining aggressive PCa was metastasis following radical prostatectomy. A generalized linear model with lasso regularization was used to build a 93-gene stroma-derived metastasis signature (SDMS). The SDMS association with metastasis was assessed using a Wilcoxon rank-sum test. Performance was evaluated using the area under the curve (AUC) for the receiver operating characteristic, and Kaplan-Meier curves. Univariable and multivariable regression models were used to compare the SDMS alongside clinicopathological variables and reported signatures. AUC was assessed to determine if SDMS is additive or synergistic to previously reported signatures.



A close association between stromal gene expression and metastatic phenotype was observed. Accordingly, the SDMS was modeled and validated in multiple independent clinical cohorts. Patients with higher SDMS scores were found to have worse prognosis. Furthermore, SDMS was an independent prognostic factor, can stratify risk in intermediate-risk PCa, and can improve the performance of other previously reported signatures.



Profiling of stromal gene expression led to development of an SDMS that was validated as independently prognostic for the metastatic potential of prostate tumors.



Our stroma-derived metastasis signature can predict the metastatic potential of early stage disease and will strengthen decisions regarding selection of active surveillance versus surgery and/or radiation therapy for prostate cancer patients. Furthermore, profiling of stroma cells should be more consistent than profiling of diverse cellular populations of heterogeneous tumors.
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Fan
F
Mo
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Dong
D
Lin
Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
Mandeep
M
Takhar
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Varune Rohan
VR
Ramnarine
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Xin
X
Dong
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Robert H
RH
Bell
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Stanislav V
SV
Volik
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Kendric
K
Wang
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Hui
H
Xue
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Yuwei
Y
Wang
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Anne
A
Haegert
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Shawn
S
Anderson
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Sonal
S
Brahmbhatt
Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
Nicholas
N
Erho
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Xinya
X
Wang
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
Peter W
PW
Gout
Department of Radiation Oncology, BC Cancer Agency, Vancouver, BC, Canada.
James
J
Morris
Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, USA.
R Jeffrey
RJ
Karnes
Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
Robert B
RB
Den
Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.
Eric A
EA
Klein
Department of Urology, James Buchanan Brady Urological Institute, Department of Oncology, Johns Hopkins Hospital, Baltimore, MD, USA; Department of Urology, Northwestern University School of Medicine, Chicago, IL, USA.
Edward M
EM
Schaeffer
Department of Urology, James Buchanan Brady Urological Institute, Department of Oncology, Johns Hopkins Hospital, Baltimore, MD, USA.
Ashley
A
Ross
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
Shancheng
S
Ren
School of Computing Sciences, Simon Fraser University, Burnaby, BC, Canada; School of Informatics and Computing, Indiana University, Bloomington, IN, USA.
S Cenk
SC
Sahinalp
BGI-Shenzhen, Shenzhen, China.
Yingrui
Y
Li
BGI-Shenzhen, Shenzhen, China.
Xun
X
Xu
BGI-Shenzhen, Shenzhen, China.
Jun
J
Wang
BGI-Shenzhen, Shenzhen, China.
Jian
J
Wang
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Martin E
ME
Gleave
Research and Development, GenomeDx Biosciences, Vancouver, BC, Canada.
Elai
E
Davicioni
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
Yinghao
Y
Sun
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada. Electronic address: ywang@bccrc.ca.
Yuzhuo
Y
Wang
Vancouver Prostate Centre & Laboratory for Advanced Genome Analysis, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada; School of Computing Sciences, Simon Fraser University, Burnaby, BC, Canada. Electronic address: ccollins@prostatecentre.com.
Colin C
CC
Collins
D000368:Aged; D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000175:diagnosis / Q000235:genetics; D009367:Neoplasm Staging; D017063:Outcome Assessment, Health Care; D011237:Predictive Value of Tests; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000032:analysis; D011468:Prostatectomy / Q000009:adverse effects / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000601:surgery; D018570:Risk Assessment / Q000379:methods; D017154:Stromal Cells / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D017430:Prostate-Specific Antigen
Genomic profiling; Prognostic biomarkers; Prostate cancer metastasis; RNA sequencing; Stromal gene