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


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.


CONCLUSIONS
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.
Ito
Noriyuki
N
Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Eto
Masatoshi
M
Nakamura
Eijiro
E
Takahashi
Atsushi
A
Tsukamoto
Taiji
T
Toma
Hiroshi
H
Nakazawa
Hayakazu
H
Hirao
Yoshihiko
Y
Uemura
Hirotsugu
H
Kagawa
Susumu
S
Kanayama
Hiroomi
H
Nose
Yoshiaki
Y
Kinukawa
Naoko
N
Nakamura
Tsuyoshi
T
Jinnai
Nobuyoshi
N
Seki
Toyokazu
T
Takamatsu
Masanobu
M
Masui
Yoshihiro
Y
Naito
Seiji
S
Ogawa
Osamu
O
D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016898:Interferon-alpha / Q000627:therapeutic use*; D007564:Japan; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D009362:Neoplasm Metastasis; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000502:physiology*; D016896:Treatment Outcome
D016898:Interferon-alpha; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human