Subclassification, survival prediction and drug target analyses of chemotherapy-naïve muscle-invasive bladder cancer with a molecular screening
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Sebastien Rinaldetti1, Eugen Rempel2,3, Thomas Stefan Worst3,4, Markus Eckstein5, Annette Steidler4, Cleo Aaron Weiss6, Christian Bolenz7, Arndt Hartmann5 and Philipp Erben4,*
1Department of Hematology and Oncology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
2German Cancer Research Center (DKFZ), Division of Signalling and Functional Genomics, 69120 Heidelberg, Germany
3Department of Stem Cell Biology, Centre of Organismal Studies, University Heidelberg, 69120 Heidelberg, Germany
4Department of Urology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
5Institute of Pathology, University Erlangen-Nuremberg, 91054 Erlangen, Germany
6Institute of Pathology, University Medical Centre Mannheim, 68167 Mannheim, Germany
7Department of Urology, University of Ulm, 89075 Ulm, Germany
*On behalf of the BRIDGE Consortium
Sebastien Rinaldetti email: [email protected]
Keywords: bladder cancer subtypes; survival prediction; drug targets; gene expression; biomarkers
Received: September 19, 2017 Accepted: April 27, 2018 Published: May 25, 2018
Background: Transcriptome expression studies identified distinct muscle invasive bladder cancer (MIBC) subtypes closely related with breast cancer subclasses. Here we developed a sensitive quantification method for MIBC subclassification (luminal, basal, p53-like). In addition, the subtype specific expression of drug targets has been investigated.
Methods: Absolute quantification (nCounter) of a 64-gene panel was performed on MIBC patients (n=47) treated exclusively with radical cystectomy (RC). In conjunction of 170 MIBCs from 3 independent cohorts, a minimal set of consensus genes has been established. Survival of the consensus subtypes has been assessed by multivariate analysis. Relevant drug targets were tested for their subtype specificity in a clustering independent assessment.
Results: A reduced 36-gene panel stably clustered into 3 subtypes throughout the cohorts (luminal, basal, infiltrated). Patients treated by RC only, showed worst 8-year disease specific survival (DSS) for the luminal subtype in contrast to the infiltrated subtype (17% vs. 73%, p=0.011). In multivariate analyses, the risk stratification based on luminal versus not-luminal MIBC proved to be an independent predictor for DSS superior to the TNM system in patients with RC. Drug targets (e.g. ERBB2, FGFR, AR, PDGFRB) showed a distinct subtype attribution. The subtypes based on this nCounter screening could further be validated by the TCGA cohort.
Conclusion: This MIBC subtype screening predicted survival and allowed an analysis of subtype specific drug targets, thus being a powerful tool for the translation of personalized MIBC treatment concepts.
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