title: PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity.
abstract: BACKGROUND
  Prostate cancer (PCa), a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3), is a negative regulator of the phosphatidylinositol 3-kinase (PIK3)/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR) signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up.
  
  
  METHODS
  Fluorescence In Situ Hybridization (FISH) was done on formalin fixed paraffin embedded (FFPE) PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC).
  
  
  RESULTS
  Using FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03). Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (P<0.05). To validate these observations we interrogated a copy number alteration and gene expression profiling dataset of 64 PCa samples, 17 of which were PTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03). PTEN deletion was also linked to diminished expression of PTEN (P<0.01) and AR (P=0.02). Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors.
  
  
  CONCLUSIONS
  Altogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.
authors.affiliation: Department of Surgery, Division of Urology, McGill University and the Research Institute of the McGill University Health Centre(RI-MUHC), Montreal H3G 1A4 QC, Canada.
authors.forename: Khalil
authors.initials: K
authors.lastname: Choucair
authors.forename: Joshua
authors.initials: J
authors.lastname: Ejdelman
authors.forename: Fadi
authors.initials: F
authors.lastname: Brimo
authors.forename: Armen
authors.initials: A
authors.lastname: Aprikian
authors.forename: Simone
authors.initials: S
authors.lastname: Chevalier
authors.forename: Jacques
authors.initials: J
authors.lastname: Lapointe
mesh_terms: D000368:Aged; D056915:DNA Copy Number Variations; D005500:Follow-Up Studies; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D011944:Receptors, Androgen; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human