Background: Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. Methods: Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naïve PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. Results: AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. Conclusions: The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting.

The identification of appropriate biomarkers is essential to support important clinical decisions in patients with prostate cancer. The aim of our study was a systematic bioinformatical analysis of the mRNA expression of all genes available for the prostate adenocarcinoma cohort of The Cancer Genome Atlas (TCGA), regarding their potential prognostic and diagnostic role. The study cohort comprises 499 patients (TCGA prostate cancer cohort). mRNA expression data were available for approx. 20,000 genes. The bioinformatical statistical pipeline addressed gene expression differences in tumor vs. benign prostate tissue (including gene set enrichment analysis, GSEA) in samples from tumors with different aggressivenesses (Gleason score), as well as prognostic values in multistep survival analyses. Among all genes analyzed, 1754 were significantly downregulated and 1553 genes were significantly upregulated in tumor tissue. In GSEA, 16 of 30 top enriched biological processes were alterations of epigenetic regulation at different levels. Significant correlation with Gleason Score was evident for 8724 genes (range of Pearson r-values 0.09–0.43; all p < 0.05). In univariate Cox regression analyses, mRNA expression of 3571 genes showed statistically significant association with biochemical recurrence-free survival with a range of hazard ratios 0.3–3.8 (p-value 7.4e− 07 to 0.05). Among these, 571 genes were independently associated with biochemical recurrence in multivariate analysis. Access to the full database including results is provided as supplement. In our systematic analysis we found a big number of genes of potential diagnostic and prognostic value, many of which have not been studied in prostate cancer to date. Due to the comprehensive nature of this analysis and free access to the results, this study represents a reference database for prostate cancer researchers which can be used as a powerful tool for validation purposes and planning of new studies.