e15523 Background: Bone metastasis is a frequent complication of ccRCC and predictors of this type of progression are scanty. The aim of this study was to analyse HIF and HIF regulated gene expressions in bone metastatic ccRCC. Methods: A pre-target therapy era cohort of 125 ccRCC patients with <100 month follow-up period have been collected with paraffin embedded primary tumors. 65 patients developed bone metastasis where 45 metastases were available for analysis. RNA was isolated from FFPE tissues and gene expression of HIF1A, HIF2A as well as HIF-regulated genes GLUT1, LDH5, GAPDH, CAIX, VEGF, VEGFR2 and EPOR were measured by RT-PCR using B2M as control. Protein product of these genes was measured on TMA arrays using standardized immunohistochemistry and an image analysis program (Mirax Viewer, 3DHistech). Results: Expression of HIF1A and HIF2A was significantly increased in bone metastatic primary ccRCC tumor tissues both at mRNA and protein levels. Significant upregulation of 3 out of 7 HIF-regulated genes (VEGFR2, EPOR and LDH5) in the primary tumor tissues of bone metastatic ccRCC was proved at mRNA levels and confirmed at protein level for VEGFR2 as well. In bone metastatic tissues a significant overexpression of HIF2A and VEGF mRNA was also detected compared to the primary site. Prognostic power of the protein expression in primary tumor was found for HIF1A (p= .001), HIF2A (p = .041), and VEGFR2 (p = .001) (confirmed at mRNA levels as well) for overall survival at time of surgical removal of primary renal tumor using Kaplan-Meier method and log-rank statistics. To further test the power of HIF1A and HIF2A as prognostic factors we have performed multivariate analysis considering available clinicopathological variables (gender, Fuhrman grade, stage) and found that HIF2A protein level outperformed all other factors in the model. Conclusions: These data indicate that HIF genes are overexpressed in bone metastatic ccRCC among which HIF2A expression at mRNA and protein levels can be used as a strong independent prognostic marker.