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In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene- signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa arecharacterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for theirassociation with event-free survival in a validation cohort (n=272), we identifiedfive genes (ASPN,BGN,COL1A1,RRM2andTYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantlyassociated with worse outcome exclusively in T2E-negative PCa. Among these genes,RRM2andTYMSwere validated byimmunohistochemistry in another validation cohort (n=135), and several of them proved to add prognostic information tocurrent clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkerswere identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which ispersenot astrong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that themolecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa. What’s new? Genetic rearrangements involving androgen-regulated transmembrane protease serine 2

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene- signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa arecharacterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for theirassociation with event-free survival in a validation cohort (n=272), we identifiedfive genes (ASPN,BGN,COL1A1,RRM2andTYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantlyassociated with worse outcome exclusively in T2E-negative PCa. Among these genes,RRM2andTYMSwere validated byimmunohistochemistry in another validation cohort (n=135), and several of them proved to add prognostic information tocurrent clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkerswere identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which ispersenot astrong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that themolecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa. What’s new? Genetic rearrangements involving androgen-regulated transmembrane protease serine 2

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene- signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa arecharacterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for theirassociation with event-free survival in a validation cohort (n=272), we identifiedfive genes (ASPN,BGN,COL1A1,RRM2andTYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantlyassociated with worse outcome exclusively in T2E-negative PCa. Among these genes,RRM2andTYMSwere validated byimmunohistochemistry in another validation cohort (n=135), and several of them proved to add prognostic information tocurrent clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkerswere identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which ispersenot astrong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that themolecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa. What’s new? Genetic rearrangements involving androgen-regulated transmembrane protease serine 2