Interferon-induced gene expression profiles and clinical response in renal cell carcinoma.

B116

Renal Cell Carcinoma (RCC) accounts for 12,000 deaths each year. Although surgery can be curative for patients with localized RCC, treatment options for the roughly one third of patients with disseminated disease are limited. Resistance to traditional chemotherapeutics, as well as a history of spontaneous immune based tumor regression, led to implementation of immunotherapy with Interferon alpha (IFNα) for RCC. Despite partial response rates of only 15-20%, a small percentage of patients experience complete disease regression in response to IFN therapy. To determine contributing factors and potential markers of IFN response, gene expression profiles of RCC tumor and normal adjacent kidney tissue (NAK) explants from 59 patients obtained following nephrectomy and treated with IFNα in vitro were analyzed for IFN-stimulated gene induction using a custom cDNA microarray of Interferon Stimulated Genes (ISGs). Tumor ISG expression profiles in the absence of IFN treatment were first compared to those of the patient matched NAK. The only significant changes were for genes with higher expression in the tumor relative to the normal, confirming previous findings that ISG expression increases in RCC. IFN-induced changes in gene expression following IFN treatment were also analyzed, and gene induction profiles in tumor samples were not significantly different from patient matched NAK tissue, indicating ISG response is not significantly affected in the tumors. Gene clustering coupled with functional bioinformatics shows genes with similar expression patterns across the various samples share functional similarities, irrespective of tumor status. Significant changes in ISG expression profiles according to clinical characteristics of stage, nuclear grade and relapse status were investigated using Significance Analysis of Microarrays (SAM). Although no significant correlation between ISG expression profiles and stage or nuclear grade was found, ISG induction was significantly reduced in tumors fated to relapse. Taken together, these analyses suggest that subtle differences in ISG expression profiles likely impact clinical outcome. ISG profiling may therefore be useful as a prognostic tool, and aid in determining clinical therapeutic strategies.