Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

Objective: To determine the expression patterns of NF-kappa B regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods: Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-kappa B regulators and targets to determine the nature and extent of NF-kappa B deregulation in ccRCC. Results: A highly-disproportionate fraction (similar to 40%; p < 0.001) of NF-kappa B regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-kappa B activity in this cancer. A subset of these genes, comprising a key NF-kappa B regulator (IKBKB) and established mediators of the NF-kappa B cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an 'interferon signature' may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-kappa B- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-kappa B controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-kappa B activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions: These findings identify NF-kappa B and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-kappa B inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-kappa B targets for potential therapeutic intervention in this currently-incurable malignancy.