Diagnostic value and prognostic significance of plasmatic proteasome level in patients with melanoma

Abstract

Plasmatic proteasome (p-proteasome) also called circulating proteasome has recently been described as a tumor marker. We investigated the diagnostic and prognostic accuracies of p-proteasome levels in a melanoma population classified according to the American Joint Committee on Cancer staging system. Using an ELISA test, we measured p-proteasome levels in 90 patients and 40 controls between March 2003 and March 2008. The subunit composition of p-proteasomes was determined in metastatic melanoma by proteomic analysis. The mean p-proteasome levels were correlated with stages (P < 0.0001; r(S) = 0.664). They were significantly higher in patients with stage IV and stage III with lymph node metastasis (9187 ± 1294 and 5091 ± 454 ng/ml, respectively) compared to controls (2535 ± 187 ng/ml; P < 0.001), to stage I/II (2864 ± 166 ng/ml; P < 0.001) and to stage III after curative lymphadenectomy (2859 ± 271 ng/ml; P < 0.001). The diagnostic accuracy of p-proteasome was evaluated by receiver operating characteristic analysis. With a cut-off of 4300 ng/ml, diagnostic specificity and sensitivity of p-proteasome for regional or visceral metastases were respectively 96.3% and 72.2%. In univariate analysis, high p-proteasome levels (>4300 ng/ml) were significantly correlated with an increased risk of progression [hazard ratio (HR) = 7.34; 95% CI 3.54-15.21, P < 0.0001] and a risk of death (HR = 5.92; 95% CI 2.84-12.33, P < 0.0001). In multivariate analysis, high p-proteasome levels were correlated with a poorer clinical outcome in the subgroup analysis limited to patients with disease stages I, II and III. Proteomic analysis confirmed the presence of all proteasome and immunoproteasome subunits. Taken together, these results indicate that p-proteasomes are a new marker for metastatic dissemination in patients with melanoma.