PTENgenomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity

Abstract

BackgroundProstate 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.MethodsFluorescence 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).ResultsUsing 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.ConclusionsAltogether, 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.

Genomic Gain of 16p13.3 in Prostate Cancer Predicts Poor Clinical Outcome after Surgical Intervention

“…Lapointe and colleagues have reported high frequency of DNA copy number alterations (CNA) in prostate cancer lymph node metastases (LN mets) including a gain of 16p13, 8q24 and deletion of 10q23 and 16q23 (11). These CNAs represent potential prognostic biomarkers that can be assessed in routine formalin-fixed paraffin-embedded (FFPE) tissue sections using specific DNA probes by FISH (14)(15)(16)(17)(18)(19). We recently mapped the previously uncharacterized focal 16p13.3 genomic gain in primary prostate tumors and identified PDPK1 encoding 3-phosphoinositide-dependent protein kinase-1 (PDK1) as a likely driver of the gain with functional impact on prostate cancer cell migration (20).…”

PTEN mRNA detection by chromogenic, RNA in situ technologies: a reliable alternative to PTEN immunohistochemistry

“…Loss of PTEN is directly correlated to disease stage and with increase in disease progression from benign to malignant there is significant increase in PTEN loss [17,18]. Data on a relatively small sample cohort of 43 prostate samples, suggest that PTEN deleted tumours expressing low levels of androgen receptor may represent a worse prognostic subset of prostate cancers establishing a challenge for therapeutic management [19]. Moreover, a recently published longitudinal molecular pathology analysis of a patient who died from prostate cancer demonstrated that the lethal clone arose from a small PTENdepleted focus in the primary tumour [20].…”

Reprint of: The prostate cancer genome: Perspectives and potential

“…A preponderance of evidence shows that deletion of PTEN is associated with advanced localized or metastatic disease, higher Gleason grade, and higher risk of progression, recurrence after therapy, and death from disease [57][58][59][60][61][62][63]. However, the clinical value in assessing PTEN is still unclear; studies have not demonstrated that it adds prognostic information when combined with standard clinicopathologic data.…”