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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2339-2345
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.02.345
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Prognostic Role of Interleukin-1ß Gene and Interleukin-1 Receptor Antagonist Gene Polymorphisms in Patients With Advanced Gastric Cancer

Francesco Graziano, Annamaria Ruzzo, Daniele Santini, Bostjan Humar, Giuseppe Tonini, Vincenzo Catalano, Rossana Berardi, Francesca Pizzagalli, Federica Arduini, Italo Bearzi, Mario Scartozzi, Stefano Cascinu, Enrica Testa, Rita Ficarelli, Mauro Magnani

From the Medical Oncology Unit, Hospital of Urbino; Institute of Biochemistry "G Fornaini", University of Urbino, Urbino; Medical Oncology Unit, University Campus Biomedico, Rome; Medical Oncology Unit, Hospital of Pesaro, Pesaro; Medical Oncology Unit and Department of Histopathology, University of Ancona, Ancona; Medical Oncology Unit, Hospital of Senigallia, Senigallia, Italy; and Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand

Address reprint requests to Francesco Graziano, MD, Medical Oncology Unit, Hospital of Urbino, via Bonconte da Montefeltro, 61029, Urbino, Italy; e-mail: frada{at}tin.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: A high interleukin-1ß (IL-1B) and interleukin-1 receptor antagonist (IL-RN) ratio underlies an unfavorable proinflammatory status. Also, it seems to be involved in the mechanisms of cancer cachexia and tumor angiogenesis and metastasis. Two single nucleotide polymorphisms in IL-1B gene (IL-1B-511C/T,IL-1B-31T/C) and a variable number of tandem repeat polymorphisms in IL-RN gene (IL-1RNlong/2) enhance the circulating levels of the two cytokines. The prognostic role of IL-1B/IL-1RN genotypes was investigated in patients with relapsed and metastatic gastric cancer treated with palliative chemotherapy.

PATIENTS AND METHODS: Before starting palliative chemotherapy, 123 prospectively enrolled patients supplied peripheral-blood samples for DNA extraction. Survival data were analyzed according to IL-1RN/IL-1B genotypes.

RESULTS: Forty-two patients showed wild-type genotypes (IL-1RNlong/long, IL-1B-511C/C, and IL-1B-31T/T; group A). Forty-five patients showed the IL-1RN2 polymorphism, with wild-type IL-1B genotypes in seven patients and with IL-1B-511C/T and/or IL-1B-31T/C polymorphisms in 38 patients (group B). The remaining 36 patients demonstrated wild-type IL-1RN, with IL-1B-511C/T and/or IL-1B-31T/C polymorphisms (group C). In group A and B patients, the median progression-free survival (PFS) was 25 and 26 weeks, respectively, and median overall survival (OS) was 42 and 43 weeks, respectively. Group C patients showed worse PFS (median, 16 weeks) and OS (median, 28 weeks) than group A (P = .006 for PFS; P = .0001 for OS) and group B patients (P = .01 for PFS; P = .0001 for OS). The long/T/C haplotype was overrepresented in patients with shortened PFS (P = .001) and OS (P = .0005).

CONCLUSION: In patients with advanced gastric cancer, IL-1B polymorphisms showed adverse prognostic influence when coupled with wild-type IL-1RN genotype. These findings deserve further investigation for potential anticancer activity of recombinant IL-RN.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Interleukin-1ß (IL-1B) is a member of the family of the proinflammatory cytokines, which modulate acute-phase response proteins.1,2 In vivo, the potentially injurious proinflammatory effects of IL-1B are counterbalanced by the action of the interleukin-1 receptor antagonist (IL-1RN).3 The IL-1RN gene produces the intracellular and the secreted isoforms of the cytokine. The secreted IL-1RN is found in monocytes, macrophages, neutrophils, and other cells, whereas the intracellular IL-1RN remains in the cytoplasm of keratinocytes and epithelial cells.3 Extensive evidence indicates that the biologic function of secreted IL-1RN is to competitively inhibit the binding of circulating IL-1B to cell-surface receptors.4,5 Typically, IL-1RN levels increase late during the course of an inflammatory event to terminate acute inflammation.3

Although the production of IL-1B and IL-1RN seem to depend on several factors, there is increasing evidence that the genetic background plays a major role. The IL-1B and the IL-1RN genes are located on chromosome 2q14, within a 360-kb region. Two single nucleotide polymorphisms in the IL-1B promoter (IL-1B-511C/T and IL-1B-31T/C) and the short allele of a 86-base pair variable number of tandem repeats polymorphism in IL-1RN second intron (IL-1RN2) have been associated with gastric cancer risk.6–8 In recent years, in vitro and in vivo studies have indicated that these alleles enhance IL-1B and IL-1RN production and the circulating levels of the two cytokines in humans.9–19 Carriers of the IL-1B polymorphisms showed higher plasmatic concentrations of IL-1B than subjects with wild-type IL-1B genotypes.9–14 In vivo, the IL-1B-511T-IL-1B-31C haplotype was significantly associated with a two- to three-fold increase in IL-1B protein secretion.9 In vitro and in vivo studies have demonstrated that carriers of the IL-1RN2 polymorphism have higher IL-1RN circulating levels than carriers of the other alleles.14–18 In an experimental model, IL-1RN2 also seemed implicated in the enhanced production of IL-1B.19 However, this finding was not confirmed in subsequent in vivo studies, in which IL-1RN2 carriers showed similar or even significantly lower IL-1B levels than noncarriers.16–18

In cancer patients, a genetically determined high IL-1B and IL-1RN ratio may induce a number of detrimental effects, with potential adverse influence on the natural history of the disease.20–29 In vivo data suggest that functional IL-1B/IL-1RN polymorphisms determine the persistence of a systemic proinflammatory status.1,2,30 This effect has been recognized as a potential negative prognostic factor, mainly in patients with metastatic cancer.20 Also, IL-1B upregulation seems to be involved in the molecular mechanisms of the anorexia-cachexia syndrome.21 In experimental tumor models, IL-1B showed tumor-promoting effects like invasiveness, angiogenesis, and metastasis.22–25 Induction of vascular endothelial growth factor expression was observed in gastric and colorectal cancer cell lines.26,27 In previous studies, IL-1B polymorphisms were associated with shortened survival of patients with pancreatic cancer11 and the aggressiveness of cutaneous malignant melanoma.28 Patients with metastatic gastric cancer showed significantly higher serum levels of IL-1B than healthy controls.29 This background prompted us to investigate, in a prospective study, the prognostic role of IL-1RN/IL-1B polymorphisms in patients with relapsed or metastatic gastric cancer treated with palliative chemotherapy.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Study Population
Patients with histologically or cytologically confirmed, relapsed or metastatic gastric cancer were considered eligible for study entry. Patients were included if they had a Karnofsky performance score (KPS) ≥ 70 and were to receive cisplatin-fluorouracil–based palliative chemotherapy. Each patient underwent pathology review of the primary tumor for confirmation of diagnosis, grading, and histology, according to Lauren's classification. Blood samples for genotyping were taken before starting palliative chemotherapy. The study was performed in a blind fashion, so that patient characteristics and outcomes were unknown to the investigators performing the molecular analyses. The study was approved by local ethical committees, and patients provided signed informed consent.

Analysis of IL-1RN and IL-1B Polymorphisms
DNA was extracted from 200 µL of peripheral-blood samples by the use of GeneElute Mammalian Genomic DNA (Sigma-Aldrich, St. Louis, MO). Polymerase chain reaction amplification and IL-1B-511C/T, IL-1B-31T/C, and IL-1RN2 genotyping were performed as described previously.6,7 Primers and conditions are listed in Table 1. The PCR results were visualized by ethidium bromide staining on 2.5% agarose gels. The IL1-RN variable number of tandem repeat alleles were coded conventionally as follows: allele 1, four repeats; allele 2, two repeats; allele 3, five repeats; allele 4, three repeats; and allele 5, six repeats.6,7 The IL1-RN polymorphism consisted of the short allele 2 (IL1-RN2), and the remaining 1, 3, 4, and 5 alleles (three or more repeats) were grouped as IL1-RNlong.6,7


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  		Table 1. Primers and Conditions for the Analysis of the IL-1B and IL-1RN Polymorphisms

 
Statistical Analyses
The {chi}2 test was used to compare proportions in contingency tables. The survival time was calculated from the start of chemotherapy to death from any cause. The progression-free survival (PFS) was calculated from the start of chemotherapy to first evidence of disease progression. The Kaplan-Meier method was adopted to estimate survival curves, and the log-rank test was used to compare patients' survival time between genotype groups. Univariate and multivariate analyses using Cox regression were used to assess the prognostic importance of genotypes, with adjustment for clinical and histopathologic features (age, sex, KPS, tumor histology, and pattern of metastatic disease). All values were two-sided, and statistical significance was defined as P < .05.

Haplotypes are combinations of specific genetic variants (alleles), which are inherited together on the same chromosome. When specific variants are inherited together nonrandomly and more often than expected, they are considered to be in linkage disequilibrium (LD). In such a case, the association of a variant with disease may be only a result of LD with a neighboring etiologic variant. Haplotype and LD analyses were included in the study plan because they may contribute to the prognostic evaluation of the IL-1RN2, IL-1B-511T, and IL-1B-31C alleles.31–33 Haplotypes and LD between loci were assessed via the GLUE interface (www.hgmp.mrc.ac.uk) using the Unphased software package (United Kingdom Medical Research Council Human Genome Mapping Project, Cambridge, United Kingdom). LD was estimated by r2, which can range from 0 (random coinheritance of alleles) to 1 (complete LD). Values less than 0.33 suggest absence of strong LD.34 Because it is not possible to unambiguously assign the individual haplotype in a population of unrelated subjects (eg, a patient with IL-1RN2/L, IL-1BT/T, and IL-1BT/C genotypes may have two of four possible haplotypes, 2-T-C and L-T-T or 2-T-T and L-T-C), the study population was dichotomized into good and bad survivors on the basis of the observed median PFS and overall survival (OS) times, and haplotype frequencies were estimated and compared between the two groups.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
This study was conducted over a 2-year period as a prospective investigation of 123 consecutively accrued patients. The median follow-up was 14 months (range, 3 to 24 months), and at the time of the writing of this report, all patients except one have died with progressing disease. The characteristics and the genotypes of enrolled patients are listed in Table 2. In the whole group, the median PFS time was 22 weeks (range, 4 to 50 weeks), and the median OS time was 36 weeks (range, 10 to 68+ weeks).


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  		Table 2. Characteristics of the 123 Patients and Distribution of IL-1RN and IL-1B Genotypes

 
IL-1RN/IL-1B Genotypes and Prognosis
As shown in Table 3, the wild-type pattern (IL-1RNlong/long, IL-1B-511C/C, and IL-1B-31T/T) was found in 42 patients (group A). The IL-1RN2 polymorphism, with either wild-type IL-1B genotypes or IL-1B-511C/T and/or IL-1B-31T/C polymorphisms, was found in 45 patients (group B). The genotypes of the remaining 36 patients were wild-type IL-1RN with IL-1B-511C/T and/or IL-1B-31T/C polymorphisms (group C).


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  		Table 3. Distribution of the 123 Patients According to the Combined Analysis of IL-1RN/IL-1B Genotypes

 
The activity of chemotherapy was similar in the three groups, without significant differences in the distribution of responsive and unresponsive patients according to IL-1B/IL-1RN combined genotypes (Table 4). Median PFS time was 25 weeks in group A patients, 26 weeks in group B patients, and 16 weeks in group C patients. As shown in Figure 1A, the difference in PFS between group A and group C patients (P = .006) and between group B and group C patients (P = .01) was statistically significant. Median OS time was 42 weeks in group A patients, 43 weeks in group B patients, and 28 weeks in group C patients. As shown in Figure 1B, the difference in OS between group A and group C patients (P = .0001) and between group B and groups C patients (P = .0001) was statistically significant.


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  		Table 4. Activity of Chemotherapy in the Three Groups of Combined IL-1B/IL-1RN Genotypes

 


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  		Fig 1. (A) Progression-free survival curves of the three groups. The results of the log-rank comparisons were as follows: P = .9 in A versus B; P = .006 in A versus C; and P = .01 in B versus C. (B) Overall survival curves of the three groups. The results of the log-rank comparisons were as follows: P = .6 in A versus B; P = .0001 in A versus C; and P = .0001 in B versus C.

 
The genetic pattern of group C patients, KPS of 70 to 80, the number of metastatic sites, liver involvement, and peritoneal metastases were the variables with statistical significance in the univariate analysis, which were included in the multivariate model (Table 5). The genetic pattern of group C patients retained an independent prognostic role.


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  		Table 5. Results of Cox Multivariate Analysis for Progression-Free and Overall Survival in the 123 Patients

 
IL-1RN/IL-1B Haplotypes and Prognosis
Allelic segregation from the IL-1RN and IL-1B genotypes in the 123 patients determined eight haplotypes (Table 6). There was LD between alleles of the three loci with the following r2 values: -511/-31 = 0.84; RN/-511 = 0.53; and RN/-31 = 0.38. Haplotype frequencies were estimated and compared between patients with a PFS time ≤ 22 weeks versus patients with a PFS time of more than 22 weeks and between patients with an OS time ≤ 36 weeks versus patients with an OS time of more than 36 weeks.


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  		Table 6. Haplotype Frequencies in Patients With Disease Progression Within and After 22 Weeks and Death Within and After 36 Weeks

 
The long-T-C haplotype (wild-type IL-1RN with both IL-1B-511T and IL-1B-31C alleles) was significantly more frequent in patients with a PFS time ≤ 22 weeks than in patients with a longer PFS time. Conversely, haplotypes containing both IL-1B-511C and IL-1B-31T wild-type alleles (long-C-T and 2-C-T) were more frequent in patients with a PFS time of more than 22 weeks, and a statistically significant difference was achieved for the 2-C-T haplotype (Table 6). The frequency of the long-T-C haplotype was significantly higher in patients with an OS time ≤ 36 weeks than in patients with an OS time of more than 36 weeks. Both the long-C-T and 2-C-T haplotypes were more prevalent in patients with an OS time of more than 36 weeks; this different distribution achieved a borderline P value for the long-C-T.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
The present findings support the hypothesis that IL-1RNlong/2, IL-1B-511C/T, and IL-1B-31T/C polymorphisms influence the prognosis of patients with advanced gastric cancer. Patients with wild-type genotypes (group A) and patients whose genotypes included the IL-1RN2 allele (group B) showed better prognosis than patients who were IL-1B-511T/IL-1B-31C carriers with wild-type IL-1RN (group C). Interestingly, 38 (84%) of 45 group B patients were also IL-1B-511T/IL-1B-31C carriers, and this genetic pattern suggests a favorable effect of the IL-1RN2 allele in counterbalancing the adverse influence of the IL-1B-511T and IL-1B-31C risk alleles. It is noteworthy that group C patients did not show lower chemotherapy response rates than group A and group B patients. Despite recent experimental data, which indicate a potential role of IL-1B in chemoresistance,35 this effect does not seem to be the leading mechanism for the poor outcome of group C patients. An unfavorable proinflammatory status with pronounced tendency to cancer cachexia and enhanced tumor aggressiveness in IL-1RNlong/IL-1B-511T/IL-1B-31C carriers are the likely factors that underlie their shortened survival times.

In the present investigation, we focused on IL-1B/IL-1RN genotypes, and we did not plan measurements of serum levels of the two cytokines. Interestingly, in the course of the study, we started to measure the baseline C-reactive protein (CRP) serum level in patients without concomitant clinical conditions and medical therapies (infection, jaundice, recent surgery, corticosteroids, and nonsteroidal anti-inflammatory drugs), which could influence CRP analysis. Sixty-one patients met these criteria. Among them, 26 group C patients showed significantly higher mean CRP serum levels than the remaining 35 patients with group A and group B genotypes (data not shown). Previous studies have shown high and low CRP serum levels in carriers of IL-1B1,2,11,36 and IL-1RN236 polymorphisms, respectively. However, additional investigations are needed to evaluate CRP as a potential surrogate marker for IL-1B upregulation.

Current knowledge on the fine interplay between IL-1B and its antagonist and the detrimental effects of the system dysregulation in the development and the clinical progression of human diseases has opened new windows for the treatment of rheumatoid arthritis, septic shock, inflammatory bowel disease, and graft-versus-host disease.37,38 Recently, a recombinant human IL-1RN was approved as the new first biologic agent to block the proinflammatory effects of IL-1B in patients with rheumatoid arthritis.39 Experimental data support the rationale for testing this novel therapeutic approach in patients with human solid neoplasms,40,41 in which recombinant IL-1RN could antagonize IL-1B and display antiangiogenic activity.41 These findings suggest that recombinant IL-1RN may represent a new therapy that targets not only tumor cells but also the homeostatic factors that are favorable to the spread and growth of metastatic cells.42 In this perspective, our findings not only indicate a new prognostic tool, but they also suggest the possibility of an innovative anticancer treatment strategy to be tested in patients with metastatic cancer and, possibly, in the adjuvant setting. It probably would be wise to evaluate the activity of this treatment with stratification of patients on the basis of IL-1B/IL-1RN genotypes.

In the present study, a sufficiently large population of prospectively and homogeneously accrued patients should support the reliability of conclusions. Interestingly, a novel alternative approach was also used to evaluate the prognostic influence of the IL-1RN/IL-1B alleles, by calculating haplotype frequencies in patients with short and long duration of survival outcomes. The long-T-C haplotype was significantly overrepresented in patients with shortened PFS and OS times, whereas haplotypes containing the IL-1B-511C allele and the IL-1B-31T allele were more frequent in patients with longer duration of PFS time (2-C-T haplotype) and OS time (long-C-T haplotype). These distributions of haplotypes parallel the results of the log-rank survival comparisons from individual IL-1RN/IL-1B genotypes and corroborate our hypothesis.

In conclusion, functional IL-1B/IL-1RN polymorphisms showed prognostic influence in advanced gastric cancer patients, and this finding supports potential therapeutic implications. Therefore, additional studies in other solid tumors and in patients undergoing palliative care are warranted.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   NOTES
 
Supported by grant No. FIRB2001 RBNE01T8C8_008 from the Italian Ministry for Scientific and Technology Research.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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Submitted October 15, 2004; accepted December 30, 2004.




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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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