Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

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Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy. / Sørensen, Karina Dalsgaard; Wild, Peter Johannes; Mortezavi, Ashkan et al.

I: Clinical Cancer Research, Bind 15, Nr. 4, 2009, s. 1400-1410.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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Sørensen KD, Wild PJ, Mortezavi A, Adolf K, Tørring N, Heebøll S et al. Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy. Clinical Cancer Research. 2009;15(4):1400-1410. doi: 10.1158/1078-0432.CCR-08-2268

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Sørensen, Karina Dalsgaard ; Wild, Peter Johannes ; Mortezavi, Ashkan et al. / Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy. I: Clinical Cancer Research. 2009 ; Bind 15, Nr. 4. s. 1400-1410.

Bibtex

@article{d068c660024511dea987000ea68e967b,
title = "Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy",
abstract = "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.",
author = "S{\o}rensen, {Karina Dalsgaard} and Wild, {Peter Johannes} and Ashkan Mortezavi and Katja Adolf and Niels T{\o}rring and Sara Heeb{\o}ll and Ulh{\o}i, {Benedicte Parm} and Peter Ottosen and Tullio Sulser and Thomas Hermanns and Holger Moch and Michael Borre and {\O}rntoft, {Torben Falck} and Lars Dyrskj{\o}t",
year = "2009",
doi = "10.1158/1078-0432.CCR-08-2268",
language = "English",
volume = "15",
pages = "1400--1410",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "AMER ASSOC CANCER RESEARCH",
number = "4",

}

RIS

TY - JOUR

T1 - Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy

AU - Sørensen, Karina Dalsgaard

AU - Wild, Peter Johannes

AU - Mortezavi, Ashkan

AU - Adolf, Katja

AU - Tørring, Niels

AU - Heebøll, Sara

AU - Ulhøi, Benedicte Parm

AU - Ottosen, Peter

AU - Sulser, Tullio

AU - Hermanns, Thomas

AU - Moch, Holger

AU - Borre, Michael

AU - Ørntoft, Torben Falck

AU - Dyrskjøt, Lars

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-08-2268

DO - 10.1158/1078-0432.CCR-08-2268

M3 - Journal article

C2 - 19228741

VL - 15

SP - 1400

EP - 1410

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 4

ER -