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Gene expression signature of Gleason score is associated with prostate cancer outcomes in a radical prostatectomy cohort.

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.

SUBMITTER: Jhun MA

PROVIDER: S-EPMC5522125 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Project description:The time and speed of biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) is highly variable. Stratification methods based on TNM staging and Gleason score (GS) do not allow the identification of patients at risk of BCR following RP. Therefore, the aim of the present study was to identify molecular signatures that can predict BCR risk effectively and facilitate treatment-related decisions for patients with PCa. RNA sequencing data and corresponding clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Oncomine databases. Bioinformatics analysis was performed to identify differentially expressed genes in patients with GS=6 and GS ?7. Cox regression models were used to determine the PCa signature (PCasig) and a clinical nomogram for the prediction of BCR. The performance of nomograms was assessed using time-dependent receiver operating characteristic curves and the concordance index (C-index). A PCasig comprising 10 genes, including SEMG2, KCNJ16, TFAP2B, SYCE1, KCNU1, AFP, GUCY1B2, GRIA4, NXPH1 and SOX11, was significantly associated with BCR, which was identified in TCGA cohort [hazard ratio (HR), 5.18; 95% CI, 3.241-8.272; C-index, 0.777] and validated in the Oncomine cohort (HR, 2.78; 95% CI, 1.39-5.54; C-index, 0.66). The expression levels of SEMG2, KCNJ16 and TFAP2B were downregulated in patients with GS ?7. The expression levels of SYCE1, KCNU1, AFP, GUCY1B2, GRIA4, NXPH1 and SOX11 were upregulated in patients with GS ?7. The clinical nomogram was constructed based on the GS and pathologic T stage (HR, 4.15; 95% CI, 1.39-5.54; C-index, 0.713). The addition of the PCasig to the clinical nomogram significantly improved prognostic value (HR, 7.25; 95% CI, 4.54-11.56; C-index, 0.782) with an net reclassification improvement of 75.3% (95% CI, 46.8-104.6%). Furthermore, the endogenous expression of each gene in the PCasig was measured in five PCa cell lines and in normal prostate cells, and these genes exhibited different expression levels relative to one another. In conclusion, an PCasig was identified by mining TCGA and successfully validated in an Oncomine cohort. This PCasig was an independent prognostic factor with a greater prognostic value for all patients regardless of GS than traditional clinical variables, which can improve the performance of clinical nomograms in predicting BCR of patients with GS ?7.

Project description:PURPOSE:Very high-risk prostate cancer (PC) is associated with poor response to local and systemic treatments; however, few cases have been molecularly profiled. We studied clinical outcomes and molecular profiles of patients with clinically localized primary Gleason pattern 5 PC. PATIENTS AND METHODS:Clinicopathologic features, targeted somatic and germline sequencing, and PTEN, TP53, and ERG status by immunohistochemistry were assessed in patients undergoing surgery from 2005 to 2015; 60 consecutive patients were identified with Gleason score 5 + 4 = 9 or 5 + 5 = 10 PC after radical prostatectomy with available tissue and clinical follow-up. Clinicopathologic and genomic parameters were correlated with biochemical relapse, metastasis-free survival, time to castration resistance, and overall survival using Cox proportional hazards models. RESULTS:Of patients with somatic sequencing data and clinical follow-up, 34% had DNA repair gene mutations, including 22% (11 of 49) with homologous recombination and 12% (six of 49) with mismatch repair gene alterations. Homologous recombination mutations were germline in 82% (nine of 11) of patients. In addition, 33% (16 of 49) had TP53 mutation, and 51% (29 of 57) had PTEN loss. Overall, 43% developed metastasis, with a time to castration resistance of 12 months. On multivariable analysis of clinicopathologic variables, only ductal/intraductal histology (hazard ratio, 4.43; 95% CI, 1.76 to 11.15; P = .002) and seminal vesicle invasion (hazard ratio, 5.14; 95% CI, 1.83 to 14.47; P = .002) were associated with metastasis. Among genomic alterations, only TP53 mutation and PTEN loss were associated with metastasis on univariable analysis, and neither remained significant in multivariable analyses. These data are retrospective and hypothesis generating. CONCLUSION:Potentially actionable homologous recombination and mismatch repair alterations are observed in a significant proportion of patients with very high-risk PC at the time of radical prostatectomy. These findings could inform the design of prospective trials in this patient population.

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Gene expression signature of Gleason score is associated with prostate cancer outcomes in a radical prostatectomy cohort.

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