Identification and validation of TGFBI as a promising prognosis marker of clear cell renal cell carcinoma

Objective: To identify prognostic biomarkers in clear cell renal cell carcinoma (ccRCC) using a proteomic approach. Material and methods: We performed a comparative proteomic profiling of ccRCC and normal renal tissues from 9 different human specimens. We assessed differential protein expression by iTRAQ (isobaric tagging reagent for absolute quantity) labeling with regard to tumor aggressiveness according to the stage, size, grade, and necrosis (SSIGN) score and continued our results using Western blot (9 patients) and immunohistochemistry (135 patients) analysis. Results: After proteomic analysis, 928 constitutive proteins were identified. Among these proteins, 346 had a modified expression in tumor compared with that of normal tissue. Pathway and integrated analyses indicated the presence of an up-regulation of the pentose phosphate pathway in aggressive tumors. In total, 14 proteins were excreted and could potentially become biomarkers. Overexpression of transforming growth factor, beta-induced (TGFBI) in ccRCC was confirmed using Western blot and immunohistochemistry analysis. A significant association was found between the presence of TGFBI expression with tumor category T3-4 (P < 0.0001), Fuhrman grades III and IV (P < 0.00011, tumor size >4 cm (P < 0.0001), presence of tumor necrosis (P < 0.0001), nodal involvement (n = 0.009), metastasis (P = 0.012), SSIGN score >= 5 (P < 0.0001), cancer progression (P < 0.0001), and cancer-specific death (P < 0.0001). Cancer-specific survival was significantly better for patients with no cytoplasmic TGFBI expression (1-, 3-, 5-y cancer-specific survival of 94.7%, 87.8%, and 73.4% vs. 92.9%, 71.2%, and 49.8%, respectively; P < 0.0001). Conclusion: We identified 346 proteins involved in renal carcinogenesis and continued the presence of a metabolic shift in aggressive tumors. TGFBI was overexpressed in tumors with high SSIGN scores and was significantly associated with oncologic outcomes. (C) 2014 Elsevier Inc. All rights reserved.