title: Identification and validation of TGFBI as a promising prognosis marker of clear cell renal cell carcinoma.
abstract: OBJECTIVE
  To identify prognostic biomarkers in clear cell renal cell carcinoma (ccRCC) using a proteomic approach.
  
  
  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 quantify) labeling with regard to tumor aggressiveness according to the stage, size, grade, and necrosis (SSIGN) score and confirmed 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<0.0001), tumor size>4cm (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).
  
  
  CONCLUSIONS
  We identified 346 proteins involved in renal carcinogenesis and confirmed 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.
authors.affiliation: Department of Urology, Angers University Hospital, Angers, France.
authors.forename: Souhil
authors.initials: S
authors.lastname: Lebdai
authors.affiliation: Department of Urology, Pontchaillou University Hospital, Rennes, France.
authors.forename: Gregory
authors.initials: G
authors.lastname: Verhoest
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.affiliation: Department of Pathology, Pontchaillou University Hospital, Rennes, France.
authors.forename: Solène Florence
authors.initials: SF
authors.lastname: Jacquet
authors.affiliation: Department of Urology, Pontchaillou University Hospital, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.affiliation: Department of Urology, Angers University Hospital, Angers, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Chautard
authors.affiliation: Department of Pathology, Pontchaillou University Hospital, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rioux Leclercq
authors.affiliation: Department of Urology, Angers University Hospital, Angers, France.
authors.forename: Abdel Rahmène
authors.initials: AR
authors.lastname: Azzouzi
authors.affiliation: Department of Urology, Angers University Hospital, Angers, France; Université Pierre et Marie Currie, Paris, France. Electronic address: pibigot@chu-angers.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bigot
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D011379:Prognosis; D040901:Proteomics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: Mass spectrometry; Prognosis; Proteomics; Renal cancer; SSIGN score; Transforming growth factor beta-induced protein ig-h3