MP44-07 A CRITICAL ANALYSIS AND VALIDATION OF THE RENAL CELL CARCINOMA BIOMARKER LITERATURE USING THE CANCER GENOME ATLAS (TCGA)

Abstract

You have accessJournal of UrologyKidney Cancer: Evaluation and Staging II1 Apr 2015MP44-07 A CRITICAL ANALYSIS AND VALIDATION OF THE RENAL CELL CARCINOMA BIOMARKER LITERATURE USING THE CANCER GENOME ATLAS (TCGA) Samuel Kaffenberger, Irina Ostrovnaya, Andrew Winer, Victor Reuter, Jonathan Coleman, Paul Russo, James Hsieh, and Ari Hakimi Samuel KaffenbergerSamuel Kaffenberger More articles by this author , Irina OstrovnayaIrina Ostrovnaya More articles by this author , Andrew WinerAndrew Winer More articles by this author , Victor ReuterVictor Reuter More articles by this author , Jonathan ColemanJonathan Coleman More articles by this author , Paul RussoPaul Russo More articles by this author , James HsiehJames Hsieh More articles by this author , and Ari HakimiAri Hakimi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1549AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES A tremendous number of biomarker studies have been published for prognostication in clear cell renal cell carcinoma (ccRCC). Unfortunately, most have not been validated in independent patient cohorts and even fewer have supporting biological studies for mechanistic corroboration. We therefore sought to systematically appraise the ccRCC biomarker literature and to validate putative biomarkers in a large cohort with clinical and comprehensive molecular information—the Cancer Genome Atlas (TCGA). METHODS A comprehensive literature search using Pubmed was performed to identify mRNA and protein tissue-based biomarker studies in ccRCC which were prognostic for overall (OS) and disease-specific survival (DSS). mRNA expression and reverse phase protein array (RPPA) normalized data from the ccRCC TCGA along with clinical information were collected and biomarkers from the literature were matched to the cohort. Univariable and multivariable analyses for OS and DSS were performed using log-rank tests and Cox proportional hazards models and p-values were adjusted for multiple comparisons (q<0.1 set as threshold for statistical significance). The stage, size, grade, and necrosis (SSIGN) score, a validated ccRCC prognostic instrument, was utilized to account for pathologic data in the multivariable model. RESULTS 12 studies evaluating 16 mRNA biomarkers and 123 studies evaluating 103 protein biomarkers (109 genes in total) met inclusion criteria of which only 36.2% presented any sort of validation and only 14.8% presented any mechanistic corroboration. Within the clinical TCGA cohort of 424 patients with median follow-up of 39 months, RPPA data on 19 biomarkers and mRNA expression data on 108 biomarkers were evaluated. After adjusting for multiple comparisons, 79 total biomarkers (66%)—12 from the RPPA dataset and 67 from the mRNA expression dataset were significantly associated with DSS in the univariate analyses. After controlling for SSIGN score, only 6 biomarkers--AR from the RPPA dataset, and AR, CLDN4, CD274 (B7-H1), HAVCR2 (TIM-3), and VEGFA from mRNA expression dataset remained independently associated with DSS. CONCLUSIONS We were able to validate 66% of the tissue-based biomarkers using the TCGA, of which 6 were independently prognostic after accounting for SSIGN score. Given the importance of novel therapeutic target discovery and rising availability of public, large-scale genomic datasets, future biomarker research should increasingly utilize external and/or mechanistic validation where possible. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e528-e529 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Samuel Kaffenberger More articles by this author Irina Ostrovnaya More articles by this author Andrew Winer More articles by this author Victor Reuter More articles by this author Jonathan Coleman More articles by this author Paul Russo More articles by this author James Hsieh More articles by this author Ari Hakimi More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...