The Association of the Long Prostate Cancer Expressed PDE4D Transcripts to Poor Patient Outcome Depends on the Tumour’s TMPRSS2-ERG Fusion Status

Objectives. To investigate the added value of assessing transcripts for the long cAMP phosphodiesterase-4D (PDE4D) isoforms, PDE4D5 and PDE4D9, regarding the prognostic power of the ‘CAPRA & PDE4D7’ combination risk model to predict longitudinal postsurgical biological outcomes in prostate cancer. Patients and Methods. RNA was extracted from both biopsy punches of resected tumours (606 patients; RP cohort) and diagnostic needle biopsies (168 patients; DB cohort). RT-qPCR was performed in order to determine PDE4D5, PDE4D7, and PDE4D9 transcript scores in both study cohorts. By RNA sequencing, we determined the TMPRSS2-ERG fusion status of each tumour sample in the RP cohort. Kaplan-Meier survival analyses were then applied to correlate the PDE4D5, PDE4D7 and PDE4D9 scores with postsurgical patient outcomes. Logistic regression was then used to combine the clinical CAPRA score with PDE4D5, PDE4D7, and PDE4D9 scores in order to build a ‘CAPRA & PDE4D5/7/9’ regression model. ROC and decision curve analysis was used to estimate the net benefit of the ‘CAPRA & PDE4D5/7/9’ risk model. Results. Kaplan-Meier survival analysis, on the RP cohort, revealed a significant association of the PDE4D7 score with postsurgical biochemical recurrence (BCR) in the presence of the TMPRSS2-ERG gene rearrangement (logrank p<0.0001), compared to the absence of this gene fusion event (logrank p=0.08). In contrast, the PDE4D5 score was only significantly associated with BCR in TMPRSS2-ERG fusion negative tumours (logrank p<0.0001 vs. logrank p=0.4 for TMPRSS2-ERG