Abstract 4957: Gene expression signature of Gleason score is associated with prostate cancer outcomes in a radical prostatectomy cohort
Authors: Jhun Min A , Geybels Milan S. , Wright Jonathan L. , Kolb Suzanne , April Craig , Bibikova Marina , Ostrander Elaine A. , Fan Jian-Bing , Feng Ziding , Stanford Janet L. 
Published: July 2017

Abstract
Background: Prostate cancer (PCa) is a leading cause of cancer-related mortality worldwide. Many men treated for clinically localized PCa will be cured, however, 20 to 30% of men will relapse and some will experience metastatic-lethal (ML) progression. Gleason score (GS) is one of the best predictors of PCa aggressiveness, but additional tumor biomarkers may improve its prognostic accuracy. We developed a gene expression signature of GS to enhance prediction of PCa outcomes.
Methods: Elastic Net regularization was used to construct a gene expression signature by contrasting tumors with GS 8-10 (high) vs. ≤6 (low) in The Cancer Genome Atlas (TCGA). Tumor tissue samples obtained at radical prostatectomy for a Fred Hutchinson (FH) patient cohort of men with localized PCa were used to generate genome-wide gene expression data. The gene expression signature was then evaluated for its ability to predict recurrence and ML progression in the FH patient cohort (N=503; NRecurrence=106; NML progression=27; mean follow-up for recurrence=8 years).
Results: The expression signature includes transcripts representing 49 genes. In the FH cohort, the signature was associated with recurrence and ML progression with hazard ratios (HRs) for a 25% increase in the signature of 1.51 (95% CI: 1.24-1.82; P=2.7×10-5) and 2.41 (95% CI: 1.51-3.85; P=0.0002), respectively. Among patients with GS 7 tumors, the signature was also significantly associated with PCa recurrence (HR=1.38, 95% CI: 1.09-1.76; P=0.008) and ML progression (HR=2.42, 95% CI: 1.30-4.52; P=0.006). The signature’s area under the curve (AUC) for predicting recurrence and ML progression was 0.68 and 0.76, respectively. Compared to a model with pathological stage and GS only, the gene expression signature significantly improved the AUC for overall recurrence (3%, P=0.0003) and ML progression (7%, P=0.0004), particularly among patients with GS 7 tumors (recurrence: 5%, P=0.01; ML progression: 13%,
P=0.009). Higher levels of the signature were associated with increased expression of genes in cell cycle-related pathways including G2M checkpoint, epithelial mesenchymal transition, and E2F targets pathways, and decreased expression of genes in several pathways including androgen response, estrogen response, oxidative phosphorylation, and apoptosis.
Conclusion: The gene expression signature based on GS may improve the prediction of overall recurrence as well as ML progression in PCa patients after radical prostatectomy, in particular among men with GS 7 tumors.
Citation Format: Min A Jhun, Milan S. Geybels, Jonathan L. Wright, Suzanne Kolb, Craig April, Marina Bibikova, Elaine A. Ostrander, Jian-Bing Fan, Ziding Feng, Janet L. Stanford. Gene expression signature of Gleason score is associated with prostate cancer outcomes in a radical prostatectomy cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4957. doi:10.1158/1538-7445.AM2017-4957