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Gerke, J.S.* ; Orth, M.F.* ; Tolkach, Y.* ; Romero-Pérez, L.* ; Wehweck, F.S.* ; Stein, S.* ; Musa, J.* ; Knott, M.M.L.* ; Hölting, T.L.B.* ; Li, J.* ; Sannino, G.* ; Marchetto, A.* ; Ohmura, S.* ; Cidre-Aranaz, F.* ; Müller-Nurasyid, M. ; Strauch, K.* ; Stief, C.* ; Kristiansen, G.* ; Kirchner, T.* ; Buchner, A.* ; Grunewald, T.G.P.*

Integrative clinical transcriptome analysis reveals TMPRSS2-ERG dependency of prognostic biomarkers in prostate adenocarcinoma.

Int. J. Cancer 146, 2036-2046 (2020)
Publ. Version/Full Text Postprint Research data DOI PMC
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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 are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)—three of which are included in commercially available prognostic tests—whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Metastasis ; Personalized Medicine ; Prognostic Biomarker ; Prostate Adenocarcinoma ; Tmprss2-erg; Population-based Cohort; Genomic Classifier; Gleason Score; Cancer; Men; Validation; Expression; Overexpression; Mortality; Features
Language english
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0020-7136
e-ISSN 1097-0215
Journal International Journal of Cancer
Quellenangaben Volume: 146, Issue: , Pages: 2036-2046 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504100-001
DOI 10.1002/ijc.32792
WOS ID WOS:000499277000001
Scopus ID 85076040904
PubMed ID 31732966
Erfassungsdatum 2019-11-26
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