Clinical Cancer Research Grants Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakamura, E.
Right arrow Articles by Ogawa, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakamura, E.
Right arrow Articles by Ogawa, O.
Clinical Cancer Research Vol. 8, 2620-2625, August 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Genetic Polymorphisms of the Interleukin-4 Receptor {alpha} Gene Are Associated with an Increasing Risk and a Poor Prognosis of Sporadic Renal Cell Carcinoma in a Japanese Population1

Eijiro Nakamura2, Yuzuru Megumi2, Takashi Kobayashi, Toshiyuki Kamoto, Satoshi Ishitoya, Toshiro Terachi, Mitsuhiro Tachibana, Hisanori Matsushiro, Tomonori Habuchi, Yoshiyuki Kakehi and Osamu Ogawa3

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan [E. N., Y. M., T. Ko., T. Ka., S. I., T. T., Y. K., O. O.]; Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto 606-8507 [M. T., H. M.]; and Department of Urology, Akita University School of Medicine, Akita 010-8543 [T. H.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: It has been suggested that the immune system of the host may be capable of modulating the clinical course of renal cell carcinoma (RCC) patients. In fact, the amount of Th2 cytokines such as interleukin (IL)-4 and IL-10 in the serum of patients has been found to be an important predictor of poor prognosis. Recently, it was reported that genetic polymorphisms of the IL-4 receptor {alpha} (IL-4R{alpha}) gene affect the strength of signaling through the receptor. In addition, these same polymorphisms were found to be associated with an increased risk of atopy by causing Th2-dominated responses of the host. The significance of the polymorphisms on the incidence and prognosis in sporadic RCC patients were examined to clarify the role of IL-4 as well as that of the Th1/Th2 immune system in this disease.

Experimental Design: A case-control study was performed with 143 sporadic RCCs in a Japanese population and 205 Japanese controls. Logistic regression models were also used to assess the genetic effects on prognosis.

Results: The frequencies of variant alleles that enhance signaling of IL-4 were significantly related to an increased risk of RCC. Furthermore, multivariate regression analysis showed that the genotype of the IL-4R gene was an independent prognostic factor for cause-specific survival (P = 0.018) together with M classification (P = 0.0002) and histopathological grade (P = 0.044).

Conclusions: The present findings show that the preferential Th2-type response to tumors was associated with a poorer prognosis and suggest that polymorphisms of the IL-4R{alpha} gene may serve as useful genetic markers for assessing the risk of the development and progression of RCC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
RCC4 has peculiar characteristics such as late relapses and spontaneous regressions of metastatic lesions after the resection of primary tumors. In addition, immunotherapy with IFN-{alpha}, IL-2, or a combination therapy of these biological response modifiers is the mainstay of management of metastatic RCC patients. These findings indicate a potential role for the host immune system in regulating tumor growth of RCC (1 , 2) . In support of this hypothesis, our previous study showed a significant association between HLA-DRB1 polymorphisms and the risk of RCC (3) .

Recently, considerable evidence has accumulated to suggest the existence of two types of responses in the human immune system: Th1 and Th2. Th1 cells produce IL-2, IFNs, and IL-12 and favor the development of a strong cellular immune response. Th2 cells produce IL-4, IL-10, and IL-13 and favor a strong humoral immune response (4 , 5) . The latter type of immune response appears to be associated with disease progression in RCC. It has been found that higher amounts of IL-4, IL-5, IL-6, and IL-10 are produced in the tumor tissues of patients with higher-stage tumors. In addition, an elevated pretreatment serum level of IL-10 was shown to be a significant independent predictor of poor prognosis in advanced patients (6 , 7) . Of these Th2 cytokines, IL-4 is intriguing in that high-affinity IL-4R is expressed on a variety of nonhematopoietic tumor cells such as melanoma, ovarian, breast, and renal carcinoma cells (8) . IL-4R is a heterodimeric comprising the IL-4R{alpha} and {gamma}c chains (9) . In fact, signaling through the receptors of IL-4 has also some direct biological effects on these nonhematopoietic tumor cells, such as the production of IL-6 (10 , 11) . Recently, it was reported that there exist two types of polymorphic sites on the IL-4R{alpha} gene, and both of them were associated with an increased risk of atopy (12 , 13) . These polymorphic sites result in the substitution of Ile for Val (Ile50Val) and Arg for Gln (Arg576Gln) in the extracellular and cytoplasmic domain, respectively. Functional assays have shown that substitution of Ile for Val enhances signal transduction via the IL-4R by augmenting the activation of STAT6, whereas the Arg variant strengthened them by impairing the binding of the negative regulatory molecule, protein tyrosine phosphatase SHP-1. Therefore, it is believed that both the Ile and Arg alleles, which strengthen signals through the IL-4R, were highly distributed in patients with atopy by their genetic effects of predisposing the host immune system to Th2 (12 , 13) .

To clarify the significance of IL-4 and polymorphisms of the IL-4R{alpha} gene in RCC patients, we have examined how this polymorphism influenced the incidence and prognosis in a series of 143 sporadic RCCs in a Japanese population.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects.
The institutional review board of the Kyoto University Graduate School of Medicine approved this study. A total of 348 subjects, consisting of 143 sporadic RCC patients and 205 controls were enrolled after receiving appropriate informed consent. All of the RCC patients were diagnosed histologically with specimens obtained from primary tumors or metastatic lesions, or by autopsy at Kyoto University Hospital or a related community hospital during the 10-year period between 1990 and 1999. Tumors were staged using the TNM system for RCC and graded using the three-grade system (14 , 15) . Their operations consisted of radical nephrectomy in 115 cases, partial nephrectomy in 22 cases, and metastatectomy in 2 cases. Two patients were treated by trans-arterial embolization of primary lesions. After surgery or embolization, patients with metastatic disease, including those who developed recurrence after surgery on the primary lesion, received systemic immunotherapy. IFN-{alpha} was administered alone to 21 patients, IFN-{gamma} alone to 4 patients, IFN-{alpha}+IFN-{gamma} to 4 patients, IFN-{alpha}+5-fluorouracil to 5 patients, and IFN-{alpha}+IL-2 to 4 patients (16 , 17) . Treatment was continued until apparent disease progression. Twenty-five patients died of cause-specific disease and 15 patients were alive with disease. No systemic immunotherapy was given to two patients because of poor performance status.

Genotyping of Two IL-4R{alpha} Gene Polymorphisms.
Genomic DNA was obtained from a blood sample or the normal kidney of each patient, as described previously (3) . The IL-4R{alpha} gene polymorphisms were examined by a mismatch PCR-RFLP method using the primers and enzymes described below. All of the DNA samples were analyzed twice, and samples homozygous for the restriction site were used as a positive control in each digestion to avoid false results by incomplete enzyme digestion.

Ile50Val (Ile for Val Substitution).
The Ile50Val polymorphism was genotyped by a mismatch PCR-RFLP method. The 273-bp fragment in which the RsaI restriction site was introduced by a single-basepair mismatched antisense primer was amplified using primers and PCR conditions described previously by Noguchi et al. (18) . PCR products were digested with RsaI and electrophoresed in 1.5% agarose + 3.0% NuSieve agarose gel (FMC BioProducts, Rockland, ME; Fig. 1ACitation ).



View larger version (47K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Genotyping of the polymorphisms of IL-4R{alpha} by a mismatch PCR-RFLP method. A, Lane M, {phi}X174-HaeIII marker, Lane 1, Ile/Ile; Lane 2, Ile/Val; Lane 3, Val/Val. B, Lane M, {phi}X174-HaeIII marker, Lane 4, Gln/Gln; Lane 5, Arg/Gln; Lane 6, Arg/Arg.

 
Arg576Gln (Arg for Gln Substitution).
The Arg576Gln polymorphism was genotyped by a mismatch PCR-RFLP method described previously by Noguchi et al. (19) . Briefly, a single basepair mismatch was introduced in the sense primer to obtain the MspI restriction site, and digested PCR fragments were analyzed using agarose gel electrophoresis (Fig. 1B)Citation .

Statistical Analysis.
We used the {chi}2 test to evaluate whether the distribution of genotypes varied significantly between RCC and controls. The linkage disequilibrium between the two polymorphisms was evaluated by a {chi}2 test. Cause-specific survival was defined as the time from surgery to death if the patient died from RCC, or to last contact. Survival curves were generated by the Kaplan-Meier method, and differences between groups defined by genotypes of the IL-4R{alpha} gene were compared by the log-rank test. To produce multivariant models of cause-specific survival, variables including clinicopathological parameters, previously described as predictors of prognosis of RCC (20) and revealed to be significant by univariate analysis including genotypes of IL-4R{alpha}, were assessed for relative risk, 95% CI, and Ps using the Cox proportional hazards model (21) . Clinicopathological parameters and genotypes of the IL-4R{alpha} gene were dichotomized as follows: T stage (T1–2 versus T3–4), nodal status (>1 versus no positive lymph nodes), tumor grade (1–2 versus 3), genotypes of the IL-4R{alpha} gene (Ile/Ile versus others, Gln/Gln versus others). All of the statistical analyses were performed using statistical software (StatView version 5.0, SAS Institute, Inc. NC). Statistical significance in this study was set at P < 0.05. All of the reported Ps are two-sided.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients and Clinicopathological Parameters.
Table 1Citation shows the clinicopathological characteristics of the 143 sporadic RCC patients. The mean age of the patients at initial presentation was 60.5 years (range, 31–84). A total of 25 patients showed nodal involvement or distant metastasis at initial presentation. The distribution of the clinical findings was in good agreement with previously reported data of RCC in Japanese populations (22 , 23) , which indicated that the present population was representative of RCC patients in the Japanese population.


View this table:
[in this window]
[in a new window]

  		Table 1 Clinicopathological characteristics of the 143 RCC patients

 
Allele Frequencies.
Table 2Citation shows the distribution of both alleles in the references from previous studies (13 , 18 , 19 , 24 , 25) , present controls, and the 143 sporadic RCC patients. The allele frequencies in control individuals were consistent with those of previous studies. Similar to the atopic population, the frequencies of both Ile and Arg alleles among RCC patients were significantly higher than controls with OR of 2.0 [(Ile/Ile+Ile/Val versus Val/Val), 95% CI, 1.38–2.90; P = 0.026] and 1.68 [(Arg/Arg+Arg/Gln versus Gln/Gln), 95% CI, 1.03–2.73; P = 0.036]. Thus, these findings indicate that alleles associated with enhanced signaling of the IL-4 were correlated with increasing risks of RCC. We then further examined whether the linkage disequilibrium was present between the two polymorphisms by analyzing their distribution in the controls (Table 3)Citation . Assuming that Ile and Val alleles in Ile50Val are in disequilibrium with Arg and Gln alleles in Arg576Gln, respectively (i.e., an excess of Ile/Arg and Val/Gln haplotypes), the observed agreement was 61.0%. This was significantly higher than the expected agreement (52.7%; P < 0.01), which indicated that linkage disequilibrium existed between these polymorphic sites. Thus, it remains unclear whether both or one of the alleles are responsible for the genetic effects on the incidence of RCC.


View this table:
[in this window]
[in a new window]

  		Table 2 The distribution of polymorphisms in the IL-4R{alpha} gene in RCC patients and controls

 

View this table:
[in this window]
[in a new window]

  		Table 3 Linkage disequilibrium between the Ile50Val and Arg576Gln polymorphisms in controlsa

 
Association of Polymorphisms of the IL-4R{alpha} Gene with Clinicopathological Stage and Patients Survival.
Next, we examined their association with clinicopathological stage. No significant association was observed between the Arg576Gln polymorphism and the clinicopathological stage at initial presentation (Table 4)Citation . However, patients with the Ile/Ile genotype showed a trend toward exhibiting higher tumor stages than the Ile/Val or Val/Val. As many as 32% (8 of 25) of patients had distant or lymph-node metastasis in the Ile homozygotes, whereas 14.4% (17 of 118) of patients in other genotypes did so. These findings suggest that polymorphisms of the IL-4R{alpha} gene may influence disease progression and prognosis of RCC patients. To clarify this, cause-specific survival curves were generated by the Kaplan-Meier method. Differences in survival between genotypes of the IL-4R{alpha} gene were compared by the log-rank test. As expected, patients with the Ile/Ile genotype had a significantly lower cause-specific survival compared with those with other genotypes (Ile/Ile versus Ile/Val: P = 0.0011; Ile/Ile versus Val/Val: P = 0.015; Fig. 2ACitation ). These findings indicate that the Ile allele has a recessive genetic effect on the poor prognosis of RCC patients and is similar to that of the atopic population in that the genetic effect turned out to be most apparent in homozygotes (13) . As for the Arg576Gln polymorphism, no association was observed between genotype and prognosis of RCC patients (Arg/Arg versus Arg/Gln: P = 0.42; Arg/Arg versus Gln/Gln: P = 0.79; Fig. 2BCitation ).


View this table:
[in this window]
[in a new window]

  		Table 4 Relationship between the IL-4R{alpha} gene polymorphisms and clinicopathological stage of patients

 


View larger version (28K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Cause-specific survival for 143 patients with RCC according to the genotype of the IL-4R{alpha} gene. A, a significant difference in survival was obtained between groups categorized by the Ile50Val genotype. B, the Arg576Gln genotype did not significantly influence cause-specific survival of patients. Cause-specific survival was analyzed using the Kaplan-Meier method, and comparison of groups was performed with the log-rank test.

 
Prognostic Significance of Polymorphisms of the IL-4R{alpha} Gene.
To further examine the correlation between polymorphisms of the IL-4R{alpha} gene and the prognosis of RCC patients, the clinicopathological stage and genotypes of the IL-4R{alpha} gene were examined by a multivariate regression analysis using a Cox proportional hazard model. Univariate analyses using the log-rank test identified tumor (T) classification (P < 0.0001), n classification (P < 0.0001), metastasis (M) classification (P < 0.0001), histopathological grade (P < 0.0001), and Ile variants of the IL-4R{alpha} gene (Ile/Ile versus Ile/Val+Val/Val: P = 0.0014) as significant prognostic predictors for cause-specific survival. Then, multivariate analyses were performed for polymorphisms of the IL-4R{alpha} gene together with independent prognostic variables with univariate statistical significance. Homozygosity of the Ile allele of the IL-4R{alpha} gene was an independent prognostic factor for cause-specific survival (Ile/Ile versus Ile/Val+Val/Val: relative risk = 3.4; P = 0.018). Metastasis classification and histopathological grade also had prognostic value with a relative risk of 6.8 (P = 0.0002) and 2.8 (P = 0.044), respectively (Table 5)Citation . These findings were compatible with those of a previous study of RCC in a Japanese population examined by multivariate analyses (23) .


View this table:
[in this window]
[in a new window]

  		Table 5 Univariate and multivariate analysis of clinicopathological stage and the IL-4R{alpha} gene polymorphisms for cause-specific survival

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we show that genetic polymorphisms of the IL-4R{alpha} gene are associated with the incidence and prognosis of sporadic RCC in a Japanese population. In comparison to healthy controls, it was shown that both Arg and Ile alleles, which in lymphoid cells enhance signaling through the IL-4R (9 , 12 , 13) , had dominant genetic effects on increasing risks of sporadic RCC. Because this receptor is also expressed on freshly isolated RCC cells (10 , 26) , it is possible that signals through the receptor are responsible for this genetic effect. At present, the effect of IL-4 and signals through IL-4R for RCC cells still remains controversial. It has been shown in primary cultures of RCC tumor cells that IL-4 had inhibitory effects for the growth of the tumor cells in a dose-dependent manner (10) . However, in response to IL-4, the RCC cell line Caki-1 produces IL-6, one of the representative growth factors that lead renal tumor cells to further transformation and proliferation (11 , 27) . Although, the exact roles of IL-4 and its signaling pathway on RCC are still unknown and require further examination, it is possible that the dominant genetic effects of the polymorphisms on increasing risks of RCC are attributable to the direct effects of signals through the IL-4R. In addition, patients homozygous for the Ile allele exhibited unfavorable prognosis compared with those with other genotypes (Fig. 2)Citation . Moreover, this genotype was identified as an independent prognostic factor for cause-specific survival by multivariate analyses using representative prognostic variables (Table 5)Citation . Because patients carrying the same genotype are at higher risk of atopy by the predisposition of their immune system to Th2 (13 , 25) , this may also cause the unfavorable prognosis of these patients. This assumption is further supported by some important clinical aspects of RCC patients in that higher amounts of Th2 cytokines are produced in advanced-stage disease of patients, and the serum level of IL-10 was identified as a significant independent prognostic factor for patients (6 , 7) . In fact, it is also the case with other kinds of malignancies in that the polarization of the host immune system to Th2 is associated with the disease progression (28, 29, 30) . Although it is suggested from the murine tumor model that Th1-dominant immunity plays a critical role in the induction of antitumor immunity in vivo, the precise mechanisms are still undefined (31) . Further clarifications of roles of the Th1/2 immune system in antitumor immunity are required for the improvement of the prognosis of not only the RCC but also other types of cancer patients.

One of the unresolved issues raised by the present study is whether or not both polymorphic sites of the IL-4R{alpha} gene are associated with the increasing risks of RCC. Although the presence of the linkage disequilibrium should be confirmed by haplotype analyses with a greater number of subjects, our present results suggested the possibility that the linkage disequilibrium between the two markers caused the positive association of both polymorphisms with those risks. To resolve this, further examination is required, e.g., how the polymorphisms affect the production of IL-6 or cell proliferation in RCC cell lines. However, the effect of the Arg576Gln variant in the signal transduction pathways via IL-4R was not replicated in several recent functional assays (13 , 25 , 32 , 33) . So, it is probable that the Arg allele might appear to exhibit its association with increasing risks of RCC merely in linkage with the Ile allele.

Because various environmental factors such as cigarette smoking, obesity, and hypertension are known to increase the risk of RCC (1 , 2) , it remains possible that genetic variants of the IL-4R{alpha} gene are merely in linkage with another important RCC-susceptible gene. In addition, because the IL-4R{alpha} chain is also an essential component of the receptor for IL-13 (34) , another representative Th2 cytokine, we cannot exclude the possibility that the effects of these polymorphisms are also caused by signaling through that receptor. However, the present preliminary findings suggest that polymorphisms of the IL-4R{alpha} gene may serve as useful genetic markers for assessing the increasing risks of RCC and also the probability that the polarization of the host immune system to Th2 causes the unfavorable prognosis of patients with RCC. Additional studies in other and larger populations are necessary to confirm the present observation, and it is also necessary to examine the influences of these polymorphisms on the Th1/Th2 profiles of cytokines produced locally in the tumors or in the serum of RCC patients.


   ACKNOWLEDGMENTS
 
We thank Drs. William Kim and Chikuma Hamada for useful suggestions and comments on the manuscripts.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by grants from the Public Trust Haraguchi Memorial Cancer Research Fund and the Shimizu Foundation for the Promotion of Immunology Research, and by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Back

2 E. N. and Y. M. contributed equally to this work. Back

3 To whom requests for reprints should be addressed, at Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. Phone: 81-75-751-3325 or 3326; Fax: 81-75-761-3441; E-mail: ogawao{at}kuhp.kyoto-u.ac.jp Back

4 The abbreviations used are: RCC, renal cell carcinoma; IL, interleukin; IL-4R, IL-4 receptor; OR, odds ratio; CI confidence interval; TNM, tumor-node-metastasis; STAT, signal transducer and activator of transcription. Back

Received 3/ 7/02; revised 5/13/02; accepted 5/15/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Motzer R. J., Bander N. H., Nanus D. M. Renal cell carcinoma. N. Engl. J. Med., 335: 865-875, 1996.[Free Full Text]
  2. Godley P. A., Stinchcombe T. E. Renal cell carcinoma. Curr. Opin. Oncol., 11: 213-217, 1999.[CrossRef][Medline]
  3. Ozdemir E., Kakehi Y., Nakamura E., Kinoshita H., Terachi T., Okada Y., Yoshida O. HLA-DRB1*0101 and *0405 as protective alleles in Japanese patients with renal cell carcinoma. Cancer Res., 57: 742-746, 1997.[Abstract/Free Full Text]
  4. Romagnani S. The Th1/Th2 paradigm. Immunol. Today, 18: 263-266, 1997.[Medline]
  5. Lucey D. R., Clerici M., Shearer G. M. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin. Microbiol. Rev., 9: 532-562, 1996.[Abstract]
  6. Onishi T., Ohishi Y., Imagawa K., Ohmoto Y., Murata K. An assessment of the immunological environment based on intratumoral cytokine production in renal cell carcinoma. BJU Int., 83: 488-492, 1999.[CrossRef][Medline]
  7. Wittke F., Hoffmann R., Buer J., Dallmann I., Oevermann K., Sel S., Wandert T., Ganser A., Atzpodien J. Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma. Br. J. Cancer, 79: 1182-1184, 1999.[CrossRef][Medline]
  8. Obiri N. I., Siegel J. P., Varricchio F., Puri R. K. Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells. Clin. Exp. Immunol., 95: 148-155, 1994.[Medline]
  9. Nelms K., Keegan A. D., Zamorano J., Ryan J. J., Paul W. E. The IL-4 receptor: signaling mechanisms and biologic functions. Annu. Rev. Immunol., 17: 701-738, 1999.[CrossRef][Medline]
  10. Obiri N. I., Hillman G. G., Haas G. P., Sud S., Puri R. K. Expression of high affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4. J. Clin. Investig., 91: 88-93, 1993.
  11. Caput D., Laurent P., Kaghad M., Lelias J. M., Lefort S., Vita N., Ferrara P. Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor {alpha} chain. J. Biol. Chem., 271: 16921-16926, 1996.[Abstract/Free Full Text]
  12. Hershey G. K., Friedrich M. F., Esswein L. A., Thomas M. L., Chatila T. A. The association of atopy with a gain-of-function mutation in the {alpha} subunit of the interleukin-4 receptor. N. Engl. J. Med., 337: 1720-1725, 1997.[Abstract/Free Full Text]
  13. Mitsuyasu H., Izuhara K., Mao X. Q., Gao P. S., Arinobu Y., Enomoto T., Kawai M., Sasaki S., Dake Y., Hamasaki N., Shirakawa T., Hopkin J. M. Ile50Val variant of IL4R {alpha} upregulates IgE synthesis and associates with atopic asthma. Nat. Genet., 19: 119-120, 1998.[CrossRef][Medline]
  14. Guinan P., Sobin L. H., Algaba F., Badellino F., Kameyama S., MacLennan G., Novick A. TNM staging of renal cell carcinoma: Workgroup No. 3. Union International Contrele Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer (Phila.), 80: 992-993, 1997.[CrossRef][Medline]
  15. Medeiros L. J., Jones E. C., Aizawa S., Aldape H. C., Cheville J. C., Goldstein N. S., Lubensky I. A., Ro J., Shanks J., Pacelli A., Jung S. H. Grading of renal cell carcinoma: Workgroup No. 2. Union Internationale Contre le Cancer and the American Joint Committee on Cancer (AJCC). Cancer (Phila.), 80: 990-991, 1997.[CrossRef][Medline]
  16. Terachi T., Yoshida O. Anti-tumor effect of combination therapy with IFN{alpha} and low dose IFN{gamma} against metastatic renal cell carcinoma. Biotherapy, 7: 278-279, 1993.
  17. Igarashi T., Marumo K., Onishi T., Kobayashi M., Aiba K., Tsushima T., Ozono S., Tomita Y., Terachi T., Satomi Y., Kawamura J. Interferon-{alpha} and 5-fluorouracil therapy in patients with metastatic renal cell cancer: an open multicenter trial. The Japanese Study Group Against Renal Cancer. Urology, 53: 53-59, 1999.[CrossRef][Medline]
  18. Noguchi E., Shibasaki M., Arinami T., Takeda K., Yokouchi Y., Kobayashi K., Imoto N., Nakahara S., Matsui A., Hamaguchi H. No association between atopy/asthma and the ILe50Val polymorphism of IL-4 receptor. Am. J. Respir. Crit. Care Med., 160: 342-345, 1999.[Abstract/Free Full Text]
  19. Noguchi E., Shibasaki M., Arinami T., Takeda K., Yokouchi Y., Kobayashi K., Imoto N., Nakahara S., Matsui A., Hamaguchi H. Lack of association of atopy/asthma and the interleukin-4 receptor {alpha} gene in Japanese. Clin. Exp. Allergy, 29: 228-233, 1999.[CrossRef][Medline]
  20. Srigley J. R., Hutter R. V., Gelb A. B., Henson D. E., Kenney G., King B. F., Raziuddin S., Pisansky T. M. Current prognostic factors-renal cell carcinoma: Workgroup No. 4. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer (Phila.), 80: 994-996, 1997.[CrossRef][Medline]
  21. Cox D. R., McCullagh P. Some aspects of analysis of covariance. Biometrics, 38: 541-561, 1982.[CrossRef][Medline]
  22. Masuda H., Kurita Y., Suzuki A., Kanbayashi T., Suzuki K., Fujita K. Prognostic factors for renal cell carcinoma: a multivariate analysis of 320 cases. Int. J. Urol., 4: 247-253, 1997.[Medline]
  23. Onodera Y., Matsuda N., Ohta M., Goto R., Fujii N., Yamada Y., Ikeuchi T., Kai Y. Prognostic significance of tumor grade for renal cell carcinoma. Int. J. Urol., 7: 4-9, 2000.[CrossRef][Medline]
  24. Kanemitsu S., Takabayashi A., Sasaki Y., Kuromaru R., Ihara K., Kaku Y., Sakai K., Hara T. Association of interleukin-4 receptor and interleukin-4 promoter gene polymorphisms with systemic lupus erythematosus. Arthritis Rheum., 42: 1298-1300, 1999.[CrossRef][Medline]
  25. Mitsuyasu H., Yanagihara Y., Mao X. Q., Gao P. S., Arinobu Y., Ihara K., Takabayashi A., Hara T., Enomoto T., Sasaki S., Kawai M., Hamasaki N., Shirakawa T., Hopkin J. M., Izuhara K. Dominant effect of Ile50Val variant of the human IL-4 receptor {alpha}-chain in IgE synthesis. J. Immunol., 162: 1227-1231, 1999.[Abstract/Free Full Text]
  26. Varricchio F., Obiri N. I., Haas G. P., Puri R. K. Immunostaining of interleukin-4 receptor on human renal cell carcinoma. Lymphokine Cytokine Res., 12: 465-469, 1993.[Medline]
  27. Takenawa J., Kaneko Y., Fukumoto M., Fukatsu A., Hirano T., Fukuyama H., Nakayama H., Fujita J., Yoshida O. Enhanced expression of interleukin-6 in primary human renal cell carcinomas. J. Natl. Cancer Inst. (Bethesda), 83: 1668-1672, 1991.[Abstract/Free Full Text]
  28. Ito N., Nakamura H., Tanaka Y., Ohgi S. Lung carcinoma: analysis of T helper type 1 and 2 cells and T cytotoxic type 1 and 2 cells by intracellular cytokine detection with flow cytometry. Cancer (Phila.), 85: 2359-2367, 1999.[CrossRef][Medline]
  29. Goto S., Sato M., Kaneko R., Itoh M., Sato S., Takeuchi S. Analysis of Th1 and Th2 cytokine production by peripheral blood mononuclear cells as a parameter of immunological dysfunction in advanced cancer patients. Cancer Immunol. Immunother., 48: 435-442, 1999.[CrossRef][Medline]
  30. Shurin M. R., Lu L., Kalinski P., Stewart-Akers A. M., Lotze M. T. Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin. Immunopathol., 21: 339-359, 1999.[Medline]
  31. Nishimura T., Nakui M., Sato M., Iwakabe K., Kitamura H., Sekimoto M., Ohta A., Koda T., Nishimura S. The critical role of Th1-dominant immunity in tumor immunology. Cancer Chemother. Pharmacol., 46: 52-61, 2000.[CrossRef]
  32. Shirakawa T., Deichmann K. A., Izuhara I., Mao I., Adra C. N., Hopkin J. M. Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol. Today, 21: 60-64, 2000.[CrossRef][Medline]
  33. Wang H. Y., Shelburne C. P., Zamorano J., Kelly A. E., Ryan J. J., Keegan A. D. Cutting edge: effects of an allergy-associated mutation in the human IL-4R{alpha} (Q576R) on human IL-4-induced signal transduction. J. Immunol., 162: 4385-4389, 1999.[Abstract/Free Full Text]
  34. Obiri N. I., Debinski W., Leonard W. J., Puri R. K. Receptor for interleukin 13. Interaction with interleukin 4 by a mechanism that does not involve the common {gamma} chain shared by receptors for interleukins 2, 4, 7, 9, and 15. J. Biol. Chem., 270: 8797-8804, 1995.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Ann OncolHome page
N. Schoof, F. von Bonin, S. Zeynalova, M. Ziepert, W. Jung, M. Loeffler, M. Pfreundschuh, L. Trumper, and D. Kube
Favorable impact of the interleukin-4 receptor allelic variant I75 on the survival of diffuse large B-cell lymphoma patients demonstrated in a large prospective clinical trial
Ann. Onc., June 10, 2009; (2009) mdp110v1.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
N. Ito, M. Eto, E. Nakamura, A. Takahashi, T. Tsukamoto, H. Toma, H. Nakazawa, Y. Hirao, H. Uemura, S. Kagawa, et al.
STAT3 Polymorphism Predicts Interferon-Alfa Response in Patients With Metastatic Renal Cell Carcinoma
J. Clin. Oncol., July 1, 2007; 25(19): 2785 - 2791.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nakamura, E.
Right arrow Articles by Ogawa, O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nakamura, E.
Right arrow Articles by Ogawa, O.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online