PURPOSE: This study investigates SLC18A2 (vesicular monoamine transporter 2) expression in prostate adenocarcinoma and examines its potential as a predictive marker for prostate cancer patient outcome after radical prostatectomy. EXPERIMENTAL DESIGN: Expression and single nucleotide polymorphism microarray analyses identified SLC18A2 as both down-regulated and subject to common loss-of-heterozygosity in prostate cancer. Down-regulated SLC18A2 expression was validated on tissue microarrays containing benign and malignant prostate specimens from an independent patient group (n=738). Furthermore, SLC18A2 immunoreactivity in radical prostatectomy tumor specimens (n=506) was correlated to clinicopathologic characteristics and recurrence-free survival. The possibility of SLC18A2 silencing by aberrant DNA methylation in prostate cancer cells was investigated by bisulfite sequencing. RESULTS: Tissue microarray analysis revealed markedly lower cytoplasmic SLC18A2 staining in cancer compared with nonmalignant prostate tissue samples, confirming RNA expression profiling results. Furthermore, multivariate analysis identified cytoplasmic SLC18A2 immunoreactivity as a novel predictor of biochemical recurrence following prostatectomy (hazard ratio, 0.485; 95% confidence interval, 0.333-0.709; P<0.001) independent of prostate-specific antigen, Gleason score, tumor stage, and surgical margin status. SLC18A2 showed loss-of-heterozygosity in 23% of the tumors and was densely hypermethylated in 15 of 17 (88%) prostate cancer samples plus 6 of 6 prostate cancer cell lines. In contrast, SLC18A2 was unmethylated in 4 of 4 adjacent nonmalignant prostate and 3 of 5 benign prostatic hyperplasia tissue samples, whereas 2 of 5 benign prostatic hyperplasia samples had monoallelic hypermethylation. Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines. CONCLUSIONS: SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event in prostate cancer and a novel independent predictor of biochemical recurrence after prostatectomy.
PURPOSE: This study investigates SLC18A2 (vesicular monoamine transporter 2) expression in prostate adenocarcinoma and examines its potential as a predictive marker for prostate cancerpatient outcome after radical prostatectomy. EXPERIMENTAL DESIGN: Expression and single nucleotide polymorphism microarray analyses identified SLC18A2 as both down-regulated and subject to common loss-of-heterozygosity in prostate cancer. Down-regulated SLC18A2 expression was validated on tissue microarrays containing benign and malignant prostate specimens from an independent patient group (n=738). Furthermore, SLC18A2 immunoreactivity in radical prostatectomy tumor specimens (n=506) was correlated to clinicopathologic characteristics and recurrence-free survival. The possibility of SLC18A2 silencing by aberrant DNA methylation in prostate cancer cells was investigated by bisulfite sequencing. RESULTS: Tissue microarray analysis revealed markedly lower cytoplasmic SLC18A2 staining in cancer compared with nonmalignant prostate tissue samples, confirming RNA expression profiling results. Furthermore, multivariate analysis identified cytoplasmic SLC18A2 immunoreactivity as a novel predictor of biochemical recurrence following prostatectomy (hazard ratio, 0.485; 95% confidence interval, 0.333-0.709; P<0.001) independent of prostate-specific antigen, Gleason score, tumor stage, and surgical margin status. SLC18A2 showed loss-of-heterozygosity in 23% of the tumors and was densely hypermethylated in 15 of 17 (88%) prostate cancer samples plus 6 of 6 prostate cancer cell lines. In contrast, SLC18A2 was unmethylated in 4 of 4 adjacent nonmalignant prostate and 3 of 5 benign prostatic hyperplasia tissue samples, whereas 2 of 5 benign prostatic hyperplasia samples had monoallelic hypermethylation. Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines. CONCLUSIONS:SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event in prostate cancer and a novel independent predictor of biochemical recurrence after prostatectomy.
Authors: Nadia Solovieff; Andrea L Roberts; Andrew Ratanatharathorn; Michelle Haloosim; Immaculata De Vivo; Anthony P King; Israel Liberzon; Allison Aiello; Monica Uddin; Derek E Wildman; Sandro Galea; Jordan W Smoller; Shaun M Purcell; Karestan C Koenen Journal: Neuropsychopharmacology Date: 2014-02-14 Impact factor: 7.853
Authors: Joeri Van Liefferinge; Ann Massie; Jeanelle Portelli; Giuseppe Di Giovanni; Ilse Smolders Journal: Front Cell Neurosci Date: 2013-08-30 Impact factor: 5.505
Authors: Christa Haldrup; Anne-Sofie Lynnerup; Tine Maj Storebjerg; Søren Vang; Peter Wild; Tapio Visakorpi; Christian Arsov; Wolfgang A Schulz; Johan Lindberg; Henrik Grönberg; Lars Egevad; Michael Borre; Torben Falck Ørntoft; Søren Høyer; Karina Dalsgaard Sørensen Journal: Mol Oncol Date: 2016-02-09 Impact factor: 7.449
Authors: K D Sørensen; M O Abildgaard; C Haldrup; B P Ulhøi; H Kristensen; S Strand; C Parker; S Høyer; M Borre; T F Ørntoft Journal: Br J Cancer Date: 2013-01-15 Impact factor: 7.640