Abstract
Prostate cancer (PCa) is a leading cause of cancer-related mortality worldwide. 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 the prediction of PCa outcomes. Elastic net was used to construct a gene expression signature by contrasting GS 8-10 vs. ≤6 tumors in The Cancer Genome Atlas (TCGA) dataset. The constructed signature was then evaluated for its ability to predict recurrence and metastatic-lethal (ML) progression in a Fred Hutchinson (FH) patient cohort (N=408; NRecurrence=109; NMLprogression=27). The expression signature included transcripts representing 49 genes. In the FH cohort, a 25% increase in the signature was associated with a hazard ratio (HR) of 1.51 (P=2.7×10−5) for recurrence. 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 age at diagnosis, pathological stage and GS, the gene expression signature improved the AUC for recurrence (3%) and ML progression (6%). Higher levels of the signature were associated with increased expression of genes in cell cycle-related pathways and decreased expression of genes in androgen response, estrogen response, oxidative phosphorylation, and apoptosis. This gene expression signature based on GS may improve the prediction of recurrence as well as ML progression in PCa patients after radical prostatectomy.
Highlights
Prostate cancer (PCa) is the most common noncutaneous cancer and a leading cause of cancer-related deaths among men in the U.S Following primary curative treatment, PCa recurrence rates vary depending on stage, Gleason score (GS), and prostate-specific antigen (PSA)level [1]
A 25% increase in the gene expression signature was associated with a hazard ratio (HR) for recurrence of 1.65, which remained significant after adjusting for age at diagnosis and pathological stage (HR = 1.51; 95% CI: 1.24, 1.82; P = 2.7×10-5) (Table 3; Figure 2)
When the analysis was restricted to patients with GS 7 tumors, a 25% increase in the gene expression signature was associated with a HR of 1.44, which remained significant after adjusting for age at diagnosis and pathological stage (HR = 1.38; 95% CI: 1.09, 1.76; P = 0.008)
Summary
Prostate cancer (PCa) is the most common noncutaneous cancer and a leading cause of cancer-related deaths among men in the U.S Following primary curative treatment, PCa recurrence rates vary depending on stage, Gleason score (GS), and prostate-specific antigen (PSA). 20 to 30% of patients with clinically localized disease will relapse within 5 years after initial therapy [2], predicting an individual patient’s risk of recurrence or metastatic progression remains challenging. Several previous studies have constructed prognostic gene expression signatures based on cell cycle proliferation genes [3], prostate tumorigenesis related www.impactjournals.com/oncotarget genes [4], and PCa recurrence [5,6,7]. GS has been utilized to construct gene expression signatures [8,9,10], which have been associated with relapse [8] and prostate cancer mortality [9, 10]. The constructed signature was evaluated for its ability to predict recurrence and metastatic-lethal (ML) progression after radical prostatectomy in a PCa patient cohort (N=408, mean follow-up for biochemical recurrence=8 years)
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