MP47-06 BRCA1 ASSOCIATED PROTEIN-1 (BAP-1) LOSS IN CCRCC: MOLECULAR CORRELATIONS AND VALIDATION AS A PROGNOSTIC FACTOR.

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research II1 Apr 2015MP47-06 BRCA1 ASSOCIATED PROTEIN-1 (BAP-1) LOSS IN CCRCC: MOLECULAR CORRELATIONS AND VALIDATION AS A PROGNOSTIC FACTOR. Nils Kroeger, Payal Kapur, Jiaoti Huang, Arie Belldegrun, James Brugarolas, and Allan Pantuck Nils KroegerNils Kroeger More articles by this author , Payal KapurPayal Kapur More articles by this author , Jiaoti HuangJiaoti Huang More articles by this author , Arie BelldegrunArie Belldegrun More articles by this author , James BrugarolasJames Brugarolas More articles by this author , and Allan PantuckAllan Pantuck More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1526AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES BAP1 is a classical two-hit tumor suppressor gene. It has been shown that BAP-1 is the only significantly mutated gene that is associated with poor prognosis in ccRCC. Yet, the reasons for this finding and interactions with central ccRCC pathways like the mTOR or VEGF pathways are largely unknown. Validation of existing prognostic and prediction molecular markers is one of the most important issues of biomarker research in ccRCC. Therefore, the current study sought to correlate BAP-1 loss with biologically relevant ccRCC pathways and to validate BAP-1 loss as prognostic factor in ccRCC. METHODS The study cohort was comprised of 321 ccRCC patients of whom 294 had evaluable tissue micro array (TMA) data. Patients with vs. without loss of BAP-1 expression were compared for differences in clinicopathological features, survival outcome and correlations with molecular markers of the mTOR, VEGF pathways as well as cell cycle markers. RESULTS Loss of BAP1 was found in 64 (21.8%) patients. Patients with vs. without BAP1 loss had significantly higher T stages (p<0.001), more often presented with distant metastases (p=0.017), and had larger tumors sizes (p=0.003) and more frequently sarcomatoid features (p=0.018). BAP1 loss was associated with worse survival outcome for both cancer specific (p <0.001) and recurrence free survival (p<0.001) in univariate analyses. However, when adjusted with parameters of the UISS, multivariable Cox regression analyses failed to retain BAP-1 loss as an independent predictor of either CSS (p=0.183) or RFS (p=0.233). Correlations with ccRCC biomarkers revealed lower expression of nuclear p27 (p=0.009) while phosphorylated-S6 was significantly higher (p<0.001) expressed in ccRCC with vs. without BAP-1 loss. Additionally, tumors without BAP-1 had greater VEGF-A (p=0.018), VEGF-R1 (p=0.001), and VEGF-R2 (p=0.016) expression. CONCLUSIONS The current investigation has validated an association of BAP-1 loss and poor prognosis in ccRCC. Immunohistochemistry can be used to rapidly and cost-effectively detect evidence of inactivating mutations in the BAP1 gene in paraffin-embedded ccRCC tissues. The interaction between BAP-1 and crucial mTOR and VEGF pathway members in BAP-1 negative ccRCC warrant further molecular investigation. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e554 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nils Kroeger More articles by this author Payal Kapur More articles by this author Jiaoti Huang More articles by this author Arie Belldegrun More articles by this author James Brugarolas More articles by this author Allan Pantuck More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...