Abstract
BackgroundExpression of Dkk-3, a secreted putative tumor suppressor, is altered in age-related proliferative disorders of the human prostate. We now investigated the suitability of Dkk-3 as a diagnostic biomarker for prostate cancer (PCa) in seminal plasma (SP).MethodsSP samples were obtained from 81 patients prior to TRUS-guided prostate biopsies on the basis of elevated serum prostate-specific antigen (PSA; > 4 ng/mL) levels and/or abnormal digital rectal examination. A sensitive indirect immunoenzymometric assay for Dkk-3 was developed and characterized in detail. SP Dkk-3 and PSA levels were determined and normalized to total SP protein. The diagnostic accuracies of single markers including serum PSA and multivariate models to discriminate patients with positive (N = 40) and negative (N = 41) biopsy findings were investigated.ResultsBiopsy-confirmed PCa showed significantly higher SP Dkk-3 levels (100.9 ± 12.3 vs. 69.2 ± 9.4 fmol/mg; p = 0.026). Diagnostic accuracy (AUC) of SP Dkk-3 levels (0.633) was enhanced in multivariate models by including serum PSA (model A; AUC 0.658) or both, serum and SP PSA levels (model B; AUC 0.710). In a subpopulation with clinical follow-up > 3 years post-biopsy to ensure veracity of negative biopsy status (positive biopsy N = 21; negative biopsy N = 25) AUCs for SP Dkk-3, model A and B increased to 0.667, 0.724 and 0.777, respectively.ConclusionsIn multivariate models to detect PCa, inclusion of SP Dkk-3 levels, which were significantly elevated in biopsy-confirmed PCa patients, improved the diagnostic performance compared with serum PSA only.
Highlights
Expression of Dickkopf-related protein 3 (Dkk-3), a secreted putative tumor suppressor, is altered in age-related proliferative disorders of the human prostate
Serum prostate-specific antigen (PSA) as well as seminal plasma (SP) Dkk-3 levels were found significantly higher in the prostate cancer (PCa) confirmed patients in both, the all patients cohort as well as the > 3 year follow-up subgroup
A multivariate logistic regression model based on serum PSA and SP Dkk-3 levels significantly discriminated negative from positive biopsies in both cohorts (Table 2; all patients: p = 0.007, predictive accuracy = 64.2%; follow-up > 3 years: p = 0.007, predictive accuracy = 73.9)
Summary
Expression of Dkk-3, a secreted putative tumor suppressor, is altered in age-related proliferative disorders of the human prostate. We investigated the suitability of Dkk-3 as a diagnostic biomarker for prostate cancer (PCa) in seminal plasma (SP). Our previous results indicated a possible link between Dkk-3 expression and age-associated processes in the human prostate. Serial analysis of gene expression (SAGE) of human prostate basal epithelial cells revealed specific induction of DKK3 gene during cellular. This study was intended to assess changes in Dkk-3 content in prostatic fluid in these two conditions and its potential as a diagnostic marker for PCa. Since prostatic secretions constitute approximately 30% of seminal fluid volume [14], of all readily obtainable body fluids, ejaculate supernatant (seminal plasma; SP) reflects the contemporary status of the prostate best. SP Dkk-3 and SP PSA levels were compared, alone and in combination with serum PSA, to the diagnostic performance of serum PSA alone to detect PCa in univariate and multivariate models
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