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

J Clin Oncol. 2007 Jul 1;25(19):2785-91. doi: 10.1200/JCO.2006.09.8897.

Abstract

Purpose: To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-alpha) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN-alpha 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-alpha 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-alpha. Linkage disequilibrium mapping revealed that the SNP in the 5' region of STAT3, rs4796793, was the most significant predictor of IFN-alpha 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- 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-alpha therapy in patients with MRCC. An efficient response marker for IFN-alpha needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics*
  • Female
  • Humans
  • Immunotherapy / methods
  • Interferon-alpha / therapeutic use*
  • Japan
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics
  • Linkage Disequilibrium
  • Male
  • Neoplasm Metastasis
  • Odds Ratio
  • Polymorphism, Genetic*
  • Polymorphism, Single Nucleotide
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / physiology*
  • Treatment Outcome

Substances

  • Interferon-alpha
  • STAT3 Transcription Factor
  • STAT3 protein, human