title: Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression.
abstract: BACKGROUND
  There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples.
  
  
  METHODS
  About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold>3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample.
  
  
  RESULTS
  We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC).
  
  
  CONCLUSIONS
  We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression.
authors.affiliation: Department of Urology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Böttcher
authors.affiliation: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow G12 8TA, Scotland.
authors.forename: D J P
authors.initials: DJ
authors.lastname: Henderson
authors.affiliation: Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Dulla
authors.affiliation: Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van Strijp
authors.affiliation: Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.
authors.forename: L F
authors.initials: LF
authors.lastname: Waanders
authors.affiliation: Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.|Australian Prostate Cancer Research Centre-Institute of Health and Biomedical Innovation, University of Technology, and Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Tevz
authors.affiliation: Australian Prostate Cancer Research Centre-Institute of Health and Biomedical Innovation, University of Technology, and Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: M L
authors.initials: ML
authors.lastname: Lehman
authors.affiliation: Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Merkle
authors.affiliation: Department of Pathology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
authors.forename: G J L H
authors.initials: GJ
authors.lastname: van Leenders
authors.affiliation: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow G12 8TA, Scotland.
authors.forename: G S
authors.initials: GS
authors.lastname: Baillie
authors.affiliation: Department of Urology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Jenster
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London WC2R 2LS, UK.
authors.forename: M D
authors.initials: MD
authors.lastname: Houslay
authors.affiliation: Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow G12 8TA, Scotland.|Departments of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven 5656 AE, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Hoffmann
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D008297:Male; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human