STAT3 polymorphism predicts interferon-alfa response in patients with metastatic renal cell carcinoma

Purpose: To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-α) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN-α immunotherapy. Patients and Methods: We carried out an association study in which 463 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in 75 Japanese patients who had received IFN-α for MRCC. Results: After adjusting for lung metastasis, stepwise logistic regression analysis revealed that the SNPs in signal transducer and activator 3 (STAT3) were most significantly associated with better response to IFN-α. Linkage disequilibrium mapping revealed that the SNP in the 5′ region of STAT3, rs4796793, was the most significant predictor of IFN-α response (odds ratio [OR] = 2.73; 95% CI, 1.38 to 5.78). The highest OR was shown in the CC genotype at rs4796793 compared to the GG + GC genotypes (OR = 8.38, 95% CI, 1.63 to 42.96). Genotype-dependent expressions of STAT3 in B lymphocyte cell lines and the enhanced growth inhibitory effects of IFN-α by STAT3 suppression in an RCC cell line supported the results of the present association study. Conclusion: The present study suggested that the STAT3 polymorphism is a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. An efficient response marker for IFN-α needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.