|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 845-851 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.8154 Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma
From the Central Institute for Blood Transfusion and Immunological Department, Department of Neurology, and Department of Urology, Innsbruck Medical University, Innsbruck, Austria Address reprint requests to Reinhold Ramoner, PhD, Department of Urology, Innsbruck Medical University, Anichstr 35, Innsbruck, Ty, Austria; e-mail: reinhold.ramoner{at}i-med.ac.at; cc: martin.thurnher{at}i-med.ac.at
Purpose Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. Patients and Methods A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Results Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype –589T–33T/–589C–33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype –589T–33T and –589C–33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype –589T–33T (P < .01) and an increase of IL4 haplotype –589C–33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype –589T–33T and –589C–33C (3.78 months) compared with patients homozygote for IL4 haplotype –589C–33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Conclusion Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.
Renal cell carcinoma (RCC) is resistant to conventional therapies such as radiation, hormone therapy, and chemotherapy. At diagnosis, 20% to 30% of patients with RCC already have metastatic disease and 20% to 40% of patients with organ-confined tumors at nephrectomy will develop metastatic disease.1 Metastatic disease is characterized by a poor prognosis, with a median survival of 13 months.2 RCC tissue frequently is infiltrated by lymphocytes,3 macrophages,4 and dendritic cells,5 reflecting the immunogenicity of RCC.
RCC has also been shown in vitro to respond to various cytokines including tumor necrosis factor alpha (TNF- Cytokines and their receptors are known to be highly conserved within their coding region.19,20 However, several examples of amino acid sequence variations have been described in healthy individuals.21 Although polymorphisms outside of the coding region do not influence the amino acid sequence, they may affect protein expression by influencing alternative mRNA splicing, mRNA stability, or transcription levels.22,23 Especially polymorphisms within the 5'- and 3'-regulatory regions of cytokines are of crucial impact, given that they can determine transcription factor binding sites within the cytokine gene promoters as well as the structure of enhancers and silencers.21 In part, human diversity in immune responses may be explained by such polymorphisms because they lead to interindividual differences in cytokine-producing capacity, which results in a variety of biologic consequences. For example, findings of different studies showed that the IL4 promoter variants IL4/–589T and IL4/–33T lead up to a three-fold higher transcriptional activity in vitro, which was subsequently confirmed in vivo.24-26 IL4/–589, IL4/–33, and other noncoding variations of IL4 were also shown to influence the risk of Th2-mediated diseases such as asthma and atopy, and to be involved in the regulation of serum immunoglobulin E levels, which is one of the major clinical characteristics of these diseases.25,27,28 To elucidate further a potential role of endogenous cytokines in the course of metastatic RCC, a representative selection of interindividual cytokine and cytokine receptor gene promoter polymorphisms were investigated in 80 RCC patients.
Study Population Eighty-nine white patients were selected in a single-center study. Nine patients were excluded from analysis because of low DNA quality or poor DNA yield. All patients had RCC with clear-cell histology and had already developed bidimensionally measurable metastatic lesions. Furthermore, all patients were participants in the local dendritic cell vaccine program (1998 to the end of 2004).29,30 The primary tumor was removed in all patients and the start of follow-up was defined by the beginning of immunotherapy. Patients with solitary brain metastasis, other malignancies than RCC within the last 5 years, treatment with immunosuppressive drugs, other immunotherapies or chemotherapies within 4 weeks before treatment start, pregnancy or lactation, presence of acute or chronic infections, HIV or viral hepatitis, or a Karnofsky performance score less than 60 were excluded from the study. Furthermore, a computed tomography of brain, chest, and abdomen and a bone scan were performed. All patients were informed about the investigative character of the study and provided their written informed consent.
Cytokine Genotyping and DNA Preparation A selection of 21 single nucleotide polymorphisms (SNPs) within 13 genes (IFNG, IL1A, IL1B, IL1R1, IL1RN, IL2, IL4, IL4R, IL6, IL10, IL12B, TGFB1, and TNF) was typed using the Cytokine CTS-PCR-SSP Tray Kit as described by the manufacturer (Department of Transplantation Immunology, University of Heidelberg, Heidelberg, Germany) according to procedures recommended by the 13th International Histocompatibility Workshop Cytokine Polymorphisms Component.31 Details on specificities, primer sequences, and reaction conditions of the Cytokine CTS-PCR-SSP Tray Kit are available for IL10, TGFB1, TNF, IL4R, IL1B, IL1RN, IL1R1, IL1A, IL4, and IL6.32-34 Typing results for SNP rs2243248 did not meet quality requirements for interpretation and were therefore excluded from additional analysis. Many different aliases for the same polymorphism are found in the literature. Some authors refer to the position relative to the transcriptional start site, whereas others use the position relative to the "A" of the start codon ATG, the position according to the GenBank-sequence used, or simply refer to a restriction enzyme used.27,35-37 We followed the recommendations of the Human Genome Variation Society38 by giving detailed data on all detectable SNPs of the Cytokine CTS-PCR-SSP Tray Kit including the corresponding database SNP (dbSNP) identifications (reference SNP [rs] numbers), the positions relative to the "A" of the start codon ATG, and commonly used SNP aliases (Table 1). 27,35,37,39-55
Eighty patients were typed for all SNPs described above. For six of these genes (IL2, IL4, IL6, IL10, TGFB1, and TNF), a typing method also known as double amplification refractory mutation system–polymerase chain reaction56 was chosen, which allowed the detection of haplotypes instead of simply the analysis of SNPs. Hence, for each of the above-mentioned genes, four haplotypes could be defined.
Linkage Disequilibrium Analysis
Statistical Analysis
This study was conducted during a 6-year period in 80 patients with metastatic RCC. All patients had clear cell histology. Median age of patients was 56 years at the beginning of the study, with a median overall survival of 12.6 months. Sixty-one patients (76%) already had lung metastases and seven patients (9%) developed brain metastases during follow-up (Table 2). The median follow-up was 19.7 months. Sixty-four percent of the study population was male and 36% was female. All patients were enrolled for dendritic cell vaccination protocols.29,30
Multivariate Analysis First, a multivariate analysis of the effects of genotype on survival was conducted using Cox proportional hazards models to adjust for confounding factors. Using a significance level of .05 for entering and .10 for removing a variable in a stepwise cox regression, four variables were selected: tumor grading, IL4, IL10, and transforming growth factor beta (TGFß1). However, when fitting the final model with these four variables, as well as sex and age as independent predictors, TGFß1 and IL10 showed a P value of more than .05. Therefore, TGFß1 and IL10 were not included in the final model. To confirm this decision, a bootstrapping technique was applied. The percentage of inclusion among the 1,000 samples created by the bootstrapping technique for tumor grading and IL4 were 99.9% and 93.4%, respectively. In contrast, the percentage of inclusion for TGFß1 and IL10 was lower than 60%. The results of the bootstrap procedure confirmed the variables chosen for the final model. Among these 13 promoter variations, the IL4 promoter polymorphisms –589/–33 turned out to be the best independent risk factor predicting survival. The IL4 genotype 1,4 was found in 11 patients, showing a 3.1-fold increased risk ratio (P < .01) adjusted for age, sex, and grading (Table 3).
Frequencies of IL4 Haplotypes 1 and 4 in Metastatic RCC In white control populations, which include a locally matched control group, IL4 haplotypes 1 and 4 were found with frequencies ranging from 0.108 to 0.144 and 0.877 to 0.852, respectively.60,61 In our RCC patient cohort, the frequency of IL4 haplotype 1 was decreased significantly (0.069; P < .01), and at the same time, IL4 haplotype 4 was increased significantly (0.925; P < .05). In line with the study by Beghé et al,60 a trend for a decreased IL4 haplotype 4 frequency was also found in the locally matched control population analyzed with the same cytokine genotyping kit for IL4 haplotype 4 (P = .095). Data are summarized in Table 4. 24-26,60
Univariate Survival Analysis In the next step, the influence of IL4 haplotypes on patient survival was examined. Using the Kaplan-Meier method and log-rank test, the only significant association with survival was found for the IL4 promotor polymorphism. Median overall survival was 3.5-fold increased (P = .027) in patients homozygote for IL4 haplotype 4 (13.44 months) compared with heterozygote patients carrying IL4 haplotypes 1 and 4 (3.78 months; Fig 1 and Table 5). Thus, patients expressing the IL4 genotype 1,4 showed a significantly decreased survival. Given the haplotype frequencies observed, the rare IL4 genotype 1,1 was not encountered in our study group (Table 5).
IL4 haplotypes 1 and 2 both carrying the IL4/–589T allele represent two high IL4-expressing haplotypes, whereas low-expressing haplotypes 3 and 4 exhibit an IL4/–589C allele.24-26 Hence, the predicted functional phenotypes for the homozygous genotype IL4 4,4, the heterozygous genotype IL4 1,4, and the homozygous genotype IL4 1,1 are low (low/low), intermediate (high/low), and high (high/high) IL-4 producers, respectively (Tables 4 and 5). Thus, patients with an expected low IL-4–producing phenotype have a 9.7 median months survival benefit compared with patients with an intermediate IL-4–producing phenotype (Fig 1).
LD Analysis of the IL4 region
In this study, we demonstrate for the first time the prognostic role of IL4 promoter polymorphisms in patients with metastatic RCC. Median overall survival was 3.5-fold decreased in heterozygote patients carrying haplotypes 1 and 4 compared with patients homozygote for haplotype 4 (3.78 v 13.44 months; P = .027; Fig 1). The heterozygous IL4 genotype 1,4 (intermediate IL-4 producer) is thus associated with an approximately three-fold increased risk of an unfavorable clinical course of RCC compared with genotype 4,4 (low IL-4 producer). Given that the rare IL4 genotype 1,1 (high IL-4 producer) was not encountered in our study group, no actual data on the outcome for these patients can be presented. However, it seems plausible that survival of such patients might even be shorter, compared with IL4 genotype 1,4 heterozygotes (intermediate IL-4 producers). Another finding of this study was the reduced frequency of the IL4 haplotype 1, which is associated with decreased survival, and the concomitantly increased frequency of the IL4 haplotype 4 in metastatic RCC patients compared with other white study populations (Table 4). One possible interpretation of this finding is that rapid disease progression in patients with the IL4 haplotype 1 may prevent patient enrollment into study protocols due to insufficient performance status, and thus results in a relative paucity of IL4 haplotype 1 in RCC study populations. However, the issue is complicated further by the observation that the frequency of IL4 haplotype 1 is increased 5.4-fold in Asians (0.789)61 compared with whites (0.144).60 Intriguingly, the substantially increased frequency of the IL4 haplotype 1 in Asians is associated with a lower incidence of kidney cancer.62 These data, which may appear contradictory at first glance, can be interpreted to suggest that different mechanisms underlie the early development of RCC and the subsequent progression of the disease, and that genetically determined IL-4 may affect these two mechanisms differentially. Thus, a distinct capacity to produce IL-4 may be protective and prevent RCC development, for instance through anti-inflammatory activity, but may be detrimental once the disease is established, for instance by hampering tumor immune surveillance. For additional exploration of the biologic effects of IL4 polymorphisms, an LD map (data not shown) was created to detect possible nearby functional variants in strong linkage with our investigated haplotypes. Analysis revealed a high LD throughout the genes IL4 and KIF3A, but no linkage to the nearby locus of IL13. Therefore, no linkage of IL4 haplotypes 1 to 4 to potentially functional IL13 variants may be expected. KIF3A is coding for a subunit of kinesin II, a microtubule-based motility protein.63 Because of its biologic function, a correlation of KIF3A with RCC may not be expected, but should not be excluded either, given that KIF3A expression levels are known to play a role in the metastatic ability of tumor cells; its genetic inactivation in mice inhibits renal ciliogenesis and produces polycystic kidney disease.64,65 To date, there are no reports of association studies of KIF3A polymorphisms. In contrast to KIF3A, however, association of specific polymorphisms of IL4 with biologic functions (eg, its transcriptional activity and circulating immunoglobulin E levels) have been shown.24,25,27,28 Additional detailed genetic investigations inside the LD block harboring IL4 and KIF3A will be needed to reveal and prove the causative polymorphisms correlated with survival in RCC.
IL-4 is a pleiotropic cytokine mainly produced by a subset of CD4+ T cells, designated T helper (TH) 2 cells, but also by basophils, mast cells, natural killer T cells, and Reliable prognostic factors in human RCC are Karnofsky performance score68 and the Eastern Cooperative Oncology Group performance status,69 which include histopathology of TNM staging and Fuhrman nuclear grading. Less specific and selective prognostic factors are high corrected level of serum calcium, high level of the serum lactate dehydrogenase, and low hemoglobin level.70,71 Moreover, increased serum IL-6 or serum vascular endothelial growth factor have been reported to influence negatively the prognosis of metastatic RCC.72 On the basis of the current study, we recommend IL4 promoter polymorphisms –589/–33 as an additional independent and routine-relevant genetic predictor for survival in metastatic RCC.
The authors indicated no potential conflicts of interest.
Conception and design: Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner Financial support: Martin Thurnher, Christoph Gassner Administrative support: Christoph Gassner, Reinhold Ramoner Provision of study materials or patients: Martin Thurnher, Reinhold Ramoner Collection and assembly of data: Thomas Kleinrath, Christoph Gassner, Martin Thurnher, Reinhold Ramoner Data analysis and interpretation: Thomas Kleinrath, Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner Manuscript writing: Thomas Kleinrath, Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner Final approval of manuscript: Thomas Kleinrath, Christoph Gassner, Peter Lackner, Martin Thurnher, Reinhold Ramoner
We thank Hubert Gander and Andrea Rahm for their efforts in sample collection. We also thank G. Bartsch, head of the Department of Urology, as well as D. Schönitzer, former head of the Central Institute for Blood Transfusion, for their continuous support.
Supported by Grant No. 03a of the Kompetenzzentrum Medizin Tirol (to M.T., work was performed in the Department of Urology). All institutions are certified according to International Standards Organization 9001:2000. Both T.K. and C.G. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Janzen NK, Kim HL, Figlin RA, et al: Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30:843-852, 2003[CrossRef][Medline] 2. Cohen HT, McGovern FJ: Renal-cell carcinoma. N Engl J Med 353:2477-2490, 2005 3. Thurnher M, Radmayr C, Hobisch A, et al: Tumor-infiltrating T lymphocytes from renal-cell carcinoma express B7-1 (CD80): T-cell expansion by T-T cell co-stimulation. Int J Cancer 62:559-564, 1995[Medline] 4. Ikemoto S, Yoshida N, Narita K, et al: Role of tumor-associated macrophages in renal cell carcinoma. Oncol Rep 10:1843-1849, 2003[Medline] 5. Thurnher M, Radmayr C, Ramoner R, et al: Human renal-cell carcinoma tissue contains dendritic cells. Int J Cancer 68:1-7, 1996[CrossRef][Medline] 6. Ikemoto S, Narita K, Yoshida N, et al: Effects of tumor necrosis factor alpha in renal cell carcinoma. Oncol Rep 10:1947-1955, 2003[Medline] 7. Alberti L, Thomachot MC, Bachelot T, et al: IL-6 as an intracrine growth factor for renal carcinoma cell lines. Int J Cancer 111:653-661, 2004[CrossRef][Medline] 8. Nanus DM, Pfeffer LM, Bander NH, et al: Antiproliferative and antitumor effects of alpha-interferon in renal cell carcinomas: Correlation with the expression of a kidney-associated differentiation glycoprotein. Cancer Res 50:4190-4194, 1990 9. Kuebler JP, Oberley TD, Meisner LF, et al: Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells. Invest New Drugs 5:21-29, 1987[Medline] 10. Cheon J, Chung DJ, Kim JJ, et al: Inhibitory effects of interleukin-4 on human renal cell carcinoma cells in vitro: In combination with interferon-alpha, tumor necrosis factor-alpha or interleukin-2. Int J Urol 3:196-201, 1996[Medline] 11. Obiri NI, Hillman GG, Haas GP, et al: 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 Invest 91:88-93, 1993[Medline] 12. Yu SJ, Kim HS, Cho SW, et al: IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 and IRF-1. Exp Mol Med 36:372-379, 2004[Medline] 13. Falkensammer C, Johrer K, Gander H, et al: IL-4 inhibits the TNF-alpha induced proliferation of renal cell carcinoma (RCC) and cooperates with TNF-alpha to induce apoptotic and cytokine responses by RCC: Implications for antitumor immune responses. Cancer Immunol Immunother 55:1228-1237, 2006[CrossRef][Medline] 14. Obiri NI, Husain SR, Debinski W, et al: Interleukin 13 inhibits growth of human renal cell carcinoma cells independently of the p140 interleukin 4 receptor chain. Clin Cancer Res 2:1743-1749, 1996[Abstract] 15. Margolin K, Aronson FR, Sznol M, et al: Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma. J Immunother Emphasis Tumor Immunol 15:147-153, 1994[Medline] 16. Whitehead RP, Unger JM, Goodwin JW, et al: Phase II trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: A Southwest Oncology Group study. J Immunother 21:440-446, 1998[Medline] 17. Whitehead RP, Lew D, Flanigan RC, et al: Phase II trial of recombinant human interleukin-4 in patients with advanced renal cell carcinoma: A southwest oncology group study. J Immunother 25:352-358, 2002[Medline] 18. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335:865-875, 1996 19. Bidwell JL, Wood NA, Morse HR, et al: Human cytokine gene nucleotide sequence alignments, 1998. Eur J Immunogenet 25:83-265, 1998[CrossRef][Medline] 20. Bidwell JL, Wood NA, Morse HR, et al: Human cytokine gene nucleotide sequence alignments: Supplement 1. Eur J Immunogenet 26:135-223, 1999[CrossRef][Medline] 21. Bidwell J, Keen L, Gallagher G, et al: Cytokine gene polymorphism in human disease: On-line databases. Genes Immun 1:3-19, 1999[CrossRef][Medline] 22. Rao N, Nguyen S, Ngo K, et al: A novel splice variant of interleukin-1 receptor (IL-1R)-associated kinase 1 plays a negative regulatory role in Toll/IL-1R-induced inflammatory signaling. Mol Cell Biol 25:6521-6532, 2005 23. Linker-Israeli M, Wallace DJ, Prehn J, et al: Association of IL-6 gene alleles with systemic lupus erythematosus (SLE) and with elevated IL-6 expression. Genes Immun 1:45-52, 1999[CrossRef][Medline] 24. Vandenbroeck K, Goris A: Cytokine gene polymorphisms in multifactorial diseases: Gateways to novel targets for immunotherapy? Trends Pharmacol Sci 24:284-289, 2003[CrossRef][Medline] 25. Rosenwasser LJ, Klemm DJ, Dresback JK, et al: Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 25 Suppl 2:74-78, 1995; discussion 95-96[CrossRef] 26. Nakashima H, Miyake K, Inoue Y, et al: Association between IL-4 genotype and IL-4 production in the Japanese population. Genes Immun 3:107-109, 2002[CrossRef][Medline] 27. Kabesch M, Tzotcheva I, Carr D, et al: A complete screening of the IL4 gene: Novel polymorphisms and their association with asthma and IgE in childhood. J Allergy Clin Immunol 112:893-898, 2003[CrossRef][Medline] 28. Basehore MJ, Howard TD, Lange LA, et al: A comprehensive evaluation of IL4 variants in ethnically diverse populations: Association of total serum IgE levels and asthma in white subjects. J Allergy Clin Immunol 114:80-87, 2004[CrossRef][Medline] 29. Holtl L, Ramoner R, Zelle-Rieser C, et al: Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother 54:663-670, 2005[CrossRef][Medline] 30. Holtl L, Zelle-Rieser C, Gander H, et al: Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin Cancer Res 8:3369-3376, 2002 31. Louie LG, Hartogensis WE, Jackman RP, et al: Mycobacterium tuberculosis/HIV-1 coinfection and disease: Role of human leukocyte antigen variation. J Infect Dis 189:1084-1090, 2004[CrossRef][Medline] 32. Mytilineos J, Laux G, Opelz G: Relevance of IL10, TGFbeta1, TNFalpha, and IL4Ralpha gene polymorphisms in kidney transplantation: A collaborative transplant study report. Am J Transplant 4:1684-1690, 2004[CrossRef][Medline] 33. Hunt PJ, Marshall SE, Weetman AP, et al: Cytokine gene polymorphisms in autoimmune thyroid disease. J Clin Endocrinol Metab 85:1984-1988, 2000 34. Mullighan CG, Marshall SE, Bunce M, et al: Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1:137-148, 1999[CrossRef][Medline] 35. Hoffmann SC, Stanley EM, Darrin Cox E, et al: Association of cytokine polymorphic inheritance and in vitro cytokine production in anti-CD3/CD28-stimulated peripheral blood lymphocytes. Transplantation 72:1444-1450, 2001[CrossRef][Medline] 36. Solovieva S, Leino-Arjas P, Saarela J, et al: Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain 109:8-19, 2004[CrossRef][Medline] 37. Bergholdt R, Karlsen AE, Johannesen J, et al: Characterization of polymorphisms of an interleukin 1 receptor type 1 gene (IL1RI) promotor region (P2) and their relation to insulin-dependent diabetes mellitus (IDDM): The Danish Study Group of Diabetes in Childhood. Cytokine 7:727-733, 1995[CrossRef][Medline] 38. den Dunnen JT, Antonarakis E: Human Genome Variation Society: Nomenclature for the description of sequence variations. http://www.hgvs.org/mutnomen/index.html 39. Hefler LA, Ludwig E, Lebrecht A, et al: Polymorphisms of the interleukin-1 gene cluster and ovarian cancer. J Soc Gynecol Investig 9:386-390, 2002[CrossRef][Medline] 40. El-Omar EM, Carrington M, Chow WH, et al: Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404:398-402, 2000[CrossRef][Medline] 41. Hall SK, Perregaux DG, Gabel CA, et al: Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum 50:1976-1983, 2004[CrossRef][Medline] 42. Maksymowych WP, Reeve JP, Reveille JD, et al: High-throughput single-nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum 48:2011-2018, 2003[CrossRef][Medline] 43. Matesanz F, Fedetz M, Leyva L, et al: Effects of the multiple sclerosis associated -330 promoter polymorphism in IL2 allelic expression. J Neuroimmunol 148:212-217, 2004[CrossRef][Medline] 44. Rockman MV, Hahn MW, Soranzo N, et al: Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr Biol 13:2118-2123, 2003[CrossRef][Medline] 45. Caggana M, Walker K, Reilly AA, et al: Population-based studies reveal differences in the allelic frequencies of two functionally significant human interleukin-4 receptor polymorphisms in several ethnic groups. Genet Med 1:267-271, 1999[Medline] 46. Fishman D, Faulds G, Jeffery R, et al: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369-1376, 1998[Medline] 47. Terry CF, Loukaci V, Green FR: Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J Biol Chem 275:18138-18144, 2000 48. Shin HD, Winkler C, Stephens JC, et al: Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. Proc Natl Acad Sci U S A 97:14467-14472, 2000 49. Alamartine E, Berthoux P, Mariat C, et al: Interleukin-10 promoter polymorphisms and susceptibility to skin squamous cell carcinoma after renal transplantation. J Invest Dermatol 120:99-103, 2003[CrossRef][Medline] 50. Hall MA, McGlinn E, Coakley G, et al: Genetic polymorphism of IL-12 p40 gene in immune-mediated disease. Genes Immun 1:219-224, 2000[CrossRef][Medline] 51. Pravica V, Perrey C, Stevens A, et al: A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: Absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production. Hum Immunol 61:863-866, 2000[CrossRef][Medline] 52. Tzakas P, Wong BY, Logan AG, et al: Transforming growth factor beta-1 (TGFB1) and peak bone mass: Association between intragenic polymorphisms and quantitative ultrasound of the heel. BMC Musculoskelet Disord 6:29-39, 2005[CrossRef][Medline] 53. Kim YJ, Lee HS, Yoon JH, et al: Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection. Hum Mol Genet 12:2541-2546, 2003 54. Lu CC, Sheu BS, Chen TW, et al: Host TNF-alpha-1031 and -863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection. Am J Gastroenterol 100:1274-1282, 2005[CrossRef][Medline] 55. The International HapMap Project: http://www.hapmap.org. Nature 426:789-796, 2003[CrossRef][Medline] 56. Lo YM, Patel P, Newton CR, et al: Direct haplotype determination by double ARMS: Specificity, sensitivity and genetic applications. Nucleic Acids Res 19:3561-3567, 1991 57. Hardy G: Mendelian proportions in a mixed population. Science 28:49-50, 1908 58. Benjamini Y, Drai D, Elmer G, et al: Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279-284, 2001[CrossRef][Medline] 59. Sauerbrei W, Schumacher M: A bootstrap resampling procedure for model building: Application to the Cox regression model. Stat Med 11:2093-2109, 1992[Medline] 60. Beghé B, Barton S, Rorke S, et al: Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 33:1111-1117, 2003[CrossRef][Medline] 61. Modi WS, O'Brien TR, Vlahov D, et al: Haplotype diversity in the interleukin-4 gene is not associated with HIV-1 transmission and AIDS progression. Immunogenetics 55:157-164, 2003[CrossRef][Medline] 62. Ries LAG, Eisner MP, Kosary CL, et al: National Cancer Institute: SEER Cancer Statistics Review, 1975-2002. http://seer.cancer.gov/csr/1975_2002/ 63. Vale RD: The molecular motor toolbox for intracellular transport. Cell 112:467-480, 2003[CrossRef][Medline] 64. Yanagawa T, Watanabe H, Takeuchi T, et al: Overexpression of autocrine motility factor in metastatic tumor cells: Possible association with augmented expression of KIF3A and GDI-beta. Lab Invest 84:513-522, 2004[CrossRef] 65. Lin F, Hiesberger T, Cordes K, et al: Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A 100:5286-5291, 2003 66. Nelms K, Keegan AD, Zamorano J, et al: The IL-4 receptor: Signaling mechanisms and biologic functions. Annu Rev Immunol 17:701-738, 1999[CrossRef][Medline] 67. Banchereau J, Briere F, Galizzi JP, et al: Human interleukin 4. J Lipid Mediat Cell Signal 9:43-53, 1994[Medline] 68. Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 19:1649-1657, 2001 69. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 70. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530-2540, 1999 71. Motzer RJ, Bacik J, Schwartz LH, et al: Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22:454-463, 2004 72. Negrier S, Perol D, Menetrier-Caux C, et al: Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: Prognostic value of interleukin-6–from the Groupe Francais d'Immunotherapie. J Clin Oncol 22:2371-2378, 2004 Submitted June 9, 2006; accepted December 6, 2006.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
),
),
2 test (two-tailed, significance level = .05). The IL4 heterozygote genotype 2/4 was observed in only one of the 80 patients and was therefore excluded from the survival analysis. The Kaplan-Meier method and log-rank test were used to assess the prognostic significance of the respective cytokine genotypes for overall survival. 
T cells in response to receptor-mediated activation events.
