title: Large-scale evaluation of SLC18A2 in prostate cancer reveals diagnostic and prognostic biomarker potential at three molecular levels.
abstract: Limitations of current diagnostic and prognostic tools for prostate cancer (PC) have led to over-diagnosis and over-treatment. Here, we investigate the biomarker potential of the SLC18A2 (VMAT2) gene for PC at three molecular levels. Thus, SLC18A2 promoter methylation was analyzed in 767 malignant and 78 benign radical prostatectomy (RP) samples using methylation-specific qPCR and Illumina 450K methylation microarray data. SLC18A2 transcript levels were assessed in 412 malignant and 45 benign RP samples using RNAseq data. SLC18A2 protein was evaluated by immunohistochemistry in 502 malignant and 305 benign RP samples. Cancer-specificity of molecular changes was tested using Mann-Whitney U tests and/or receiver operating characteristic (ROC) analyses. Log rank, uni- and multivariate Cox regression tests were used for survival analyses. We found that SLC18A2 promoter hypermethylation was highly cancer-specific (area under the curve (AUC): 0.923-0.976) and associated with biochemical recurrence (BCR) after RP in univariate analyses. SLC18A2 transcript levels were reduced in PC and had independent prognostic value for BCR after RP (multivariate HR 0.13, P < 0.05). Likewise, SLC18A2 protein was down-regulated in PC (AUC 0.898) and had independent prognostic value for BCR (multivariate HR 0.51, P < 0.05). Reduced SLC18A2 protein expression was also associated with poor overall survival in univariate analysis (HR 0.29, P < 0.05). Our results highlight SLC18A2 as a new promising methylation marker candidate for PC diagnosis. Furthermore, SLC18A2 expression (RNA and protein) showed promising prognostic potential beyond routine clinicopathological variables. Thus, novel SLC18A2-based molecular tests could have useful future applications for PC detection and identification of high-risk patients.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Christa
authors.initials: C
authors.lastname: Haldrup
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Anne-Sofie
authors.initials: AS
authors.lastname: Lynnerup
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Tine Maj
authors.initials: TM
authors.lastname: Storebjerg
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.affiliation: Prostate Cancer Research Center, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, and Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Arsov
authors.affiliation: Department of Urology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schulz
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.affiliation: Department of Oncolocy and Pathology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: kdso@clin.au.dk.
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørensen
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000601:surgery; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D016019:Survival Analysis; D050493:Vesicular Monoamine Transport Proteins / Q000032:analysis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins
keywords: Biomarkers; Diagnosis; Prognosis; Prostate cancer; SLC18A2