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Allele 2 of the Interleukin-1 Receptor Antagonist Gene Is Associated With Early Gastric Cancer

From the Medizinische Poliklinik, Chirurgische Klinik und Poliklinik, Klinikum der Universität München, Standort Innenstadt; Labor für Immungenetik, Kinderklinik und Kinderpoliklinik, Klinikum der Universität München, Standort Innenstadt; Chirurgische Klinik und Poliklinik, Klinikum der Universität München, Standort Großhadern, München; Institut für Pathologie, Klinikum Bayreuth, Bayreuth, Germany

Address reprint requests to Christian Folwaczny, MD, PhD, Medizinische Poliklinik, Chirurgische Klinik und Poliklinik, Klinikum der Universität München, Nußbaumstraße 20, D-80336 München, Germany; e-mail: Christian.Folwaczny{at}medinn.med.uni-muenchen.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: In advanced gastric cancer (tumor stages T2-T4), associations with polymorphisms of the interleukin-1 (IL-1) gene cluster have been made. In early-stage gastric cancer, which we defined as adenocarcinoma confined to the mucosa or submucosa (stage T1), the role of host genetic susceptibility remains to be determined.

PATIENTS AND METHODS: Eighty-eight patients with early-stage gastric cancer (stage T1, 77 positive for Helicobacter pylori) and 145 controls were genotyped for polymorphisms in the IL-1 gene cluster and the tumor necrosis factor alpha (TNF-A) gene. Statistical analysis was performed using the ² test and the Fisher's exact test, respectively.

RESULTS: The homozygous genotype IL-1RN*2/2 of the IL-RN gene was strongly associated with early-stage gastric cancer (P < .0001), whereas further associations with the IL-1 gene cluster were not observed. A weak association of the TNF-A–308A allele with the diffuse type of early-stage gastric cancer, and an association with a composite of two or three proinflammatory polymorphisms, which predispose to increased production of the proinflammatory cytokines IL-1ß and TNF-, could also be demonstrated.

CONCLUSION: The genotype IL-1RN*2/2 seems to be associated with early-stage gastric cancer. As opposed to advanced-stage gastric cancer, further proinflammatory cytokine polymorphisms were not associated independently, but might act in combination and mirror early steps of gastric carcinogenesis in hosts colonized by Helicobacter pylori. However, these findings await confirmation in future trials and should be underscored by gene expression studies.

	INTRODUCTION

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Worldwide gastric cancer is the second most common malignancy in both men and women.¹ Early-stage gastric cancer has been defined as an adenocarcinoma that is confined to the gastric mucosa (T1a) or submucosa (T1b), irrespective of lymph node invasion, which occurs in approximately 10% to 20%.^2-4 Early-stage gastric cancer accounts for 10% to 20% of all resected gastric carcinomas in the Western countries.⁴ As opposed to advanced stages (T2-4) early-stage gastric cancer has a comparably favorable prognosis with 5-year survival rates of 85% to 90% after resection.^3,4

For the development of gastric cancer environmental factors such as smoking, diet and in particular infection with Helicobacter pylori are of importance.^5-10 Decreased acid secretion with subsequent mucosal atrophy and intestinal metaplasia can result from infection with H pylori.^11-13 Also prerequisite for atrophy is autoimmunity against parietal cells, which can mimic classic autoimmune gastritis with presence of various autoantibodies in up to 40% of H pylori–infected individuals.¹⁴ Recent findings by Uemura et al¹⁵ sustain the importance of these histological findings as a precancerous condition in H pylori–associated gastritis. However, only a minority of H pylori–infected patients develops gastric cancer, which underscores the idea that the host genetic background might be of critical importance.

Recent data strongly suggest that the suceptibility toward an infection with H pylori is mainly conferred by genes involved in inflammatory processes following colonization with H pylori.¹⁶ Chronic gastritis is characterized by the release of proinflammatory cytokines^5,7 such as interleukin-1ß (IL-1ß) or tumor-necrosis factor alpha (TNF-), which are potent inhibitors of gastric acid secretion.^17-20 Advanced-stage gastric cancer was repeatedly associated with polymorphisms of the IL-1 gene cluster on chromosome 2q, which contains three related genes within a 430-kb region, IL-1A, IL-1B, and IL-1RN, encoding for IL-1, IL-1ß, and the endogenous receptor antagonist IL-1ra, respectively. It was hypothesized that genetic differences within these genes could influence the immune response against pathogens such as H pylori and the development of premalignant histological alterations in the gastric mucosa.^21,22 In patients with advanced-stage gastric cancer, an increased frequency of the IL-1B–31C and IL-1B–511T alleles and the uncommon IL-1B–31C/IL-1B–511T haplotype were demonstrated. In addition, the IL-1RN*2 allele and the homozygous genotype IL-1RN*2/2 were found in increased prevalence in gastric cancer.²¹ Furthermore a possible functional relevance of the IL-1B–31 polymorphism has been demonstrated by electrophoretic mobility shift assay.²¹ Three subsequent studies confirmed these genetic associations.^24-26 Recently, El-Omar et al²⁵ genotyped patients with gastric cancer according to tumor localization (cardia v noncardia) and esophageal cancers (adenocarcinomas v squamous cell carcinomas) for various polymorphisms of genes encoding for pro- and anti-inflammatory cytokines. An increased risk for noncardia gastric cancer in carriers of the IL-1B–511T allele, IL-1RN*2 homozygotes, carriers of the TNF-A–308A allele and the haplotype IL-10–1082A/–819T/–592A was described and the cumulative risk was dependent on the number of high-risk alleles or genotypes per patient.²⁵ The risk increase for development of gastric carcinoma in carriers of multiple proinflammatory genotypes has been confirmed in a previous study.²⁶ The alleles IL-1RN*2 and IL-1B–511T are associated with increased synthesis of the proinflammatory cytokine IL-1ß,^22,27-29 and the allele TNFA–308A results in an increased production of the proinflammatory cytokine TNF-.^30,31

The aim of the present study was to determine the role of polymorphisms within the genes of the IL-1 gene cluster and the TNF-A gene in early-stage gastric cancer after stratification according to histologic subtype (intestinal-, diffuse-, and mixed-type). Based on the available published data, the polymorphisms at positions –31, –511, and +3954 of the IL-1B gene; at position –889 of the IL-1A gene; the intron 2 variable number of tandem repeats (VNTR) polymorphism of the IL-1RN gene; and the polymorphisms at positions –238 and –308 of the TNF-A gene were genotyped.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Study Population
The study population comprised a control group of 145 ethnically matched, healthy, unrelated blood donors and 88 patients with early-stage noncardia gastric cancers. Forty-one tumors (47%) were confined to the mucosa (pT1a), and 47 (53%) involved the submucosa (pT1b). In five cases, regional lymph node invasion had been diagnosed, but all cases were devoid of distant metastases. The tumors were histopathologically classified according to the Laurén classification³²: 46 intestinal-, 23 diffuse-, and 19 mixed-type. In 88% (77 of 88 patients), the presence of H pylori was diagnosed histologically. All study participants were white. The baseline characteristics of the study population are presented in Table 1.

Genotyping
Genotyping was performed by restriction fragment length polymorphism analysis, as described previously for IL-1A–889, IL-1B+3954, IL-1B–511, TNF-A–238 and TNF-A–308.^35-39 The IL-1B–31 polymorphism was assessed by polymerase chain reaction (PCR) using the primers 5'-GCTTCCACCAATACTCTTTTCC-3' and 5'-GAATATGCATACACACAAAGAGGC-3', and restriction analysis with Alu I. Confirmation was obtained by sequencing one control sample for each possible genotype. The IL-1RN VNTR polymorphism was genotyped by PCR and electrophoresis on 2% agarose gels according to El-Omar et al.²¹ In every patient genotyping was performed twice in two independent assays to confirm reproducibility. Efficacy of PCR was comparable between patients and controls.

Statistical Analysis
Statistical analysis was performed using the ² test and the Fisher's exact test, respectively. P values less than .05 were considered significant. Hardy-Weinberg equilibrium was assessed in the control group by the ² test. The Hardy-Weinberg law is a simple relationship between gene frequencies and genotype frequencies that is found in a population under certain conditions. The most important assumption for Hardy-Weinberg equilibrium is random mating. Disequilibrium is mainly caused by assortive mating and inbreeding.

	RESULTS

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Associations With Polymorphisms in the IL-1 Gene Cluster
The IL-1RN*2 allele was significantly increased in early-stage gastric cancer (62% v 29%; P < .0001), while the frequency of the IL-1RN*1 allele was decreased (36% v 68%). The genotype IL-1RN*2/2 was strongly associated with early-stage gastric cancer (58% v 8%; P < .0001). This was paralleled by a significant decrease in the frequency of the genotype IL-1RN*1/2 (9% v 41%; P < .0001) and a decreased frequency of the IL-1RN*1/1 genotype (31% v 45%). The extent of these differences was comparable in the different histological subtypes. No significant differences were observed with respect to the rare alleles IL-1RN*3 and IL-1RN*4 (Tables 2 and 3). In the control group, the alleles of the IL-1RN polymorphism were in complete Hardy-Weinberg equilibrium.

Associations With Polymorphisms in the TNF-A Gene
Allele and genotype frequencies of the TNF-A–238 and the TNF-A–308 polymorphisms were similar in patients and controls. Subgroup analyses revealed an impaired frequency of the TNF-A–308A allele (7% v 15%; P < .03) and carriers (11 v 28%; P < .03) in the intestinal type, whereas in diffuse-type gastric cancers, the frequency of the TNF-A–308A allele (30% v 15%; P < .02) and carriers (44% v 28%; P < .03) were significantly increased (P < .02; Tables 2 and 3).

Association With a Composite of Proinflammatory Cytokine Polymorphisms
According to published literature, carrier status of IL-1B–31C or IL-1B–511T, TNF-A–308A, and the homozygous genotype IL-RN*2/2 were defined as high-risk genotypes. Due to the linkage disequilibrium, IL-1B–31C and IL-1B–511T were defined as one risk factor.²¹ In early-stage gastric cancer, 48% of patients (P < .0001) had two high-risk genotypes, and 9% (P < .01) had three high-risk genotypes, while in the controls, 21% had two and 1% had three of these genotypes. Thirty-one percent of patients (P < .05) displayed one, and 12% (P < .001) of patients exhibited no proinflammatory genotype. In the intestinal and diffuse subtypes, comparable associations were observed. In intestinal type, early-stage gastric cancer, 50% of patients (P < .001) had two, and 7% (P < .05) had three high-risk genotypes for development of gastric cancer.^25,26 In the diffuse type, 53% of patients (P < .01) were carriers of two, and 17% were carries of three high-risk genotypes (Table 4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Herein, a novel association of the homozygous genotype IL-1RN*2/2 with early-stage gastric cancer was observed. The IL-1RN VNTR intron contains three potential protein-binding sites: an interferon alfa silencer A, an interferon beta silencer B, and an acute phase response element, and, thus, may be of functional relevance.⁴⁰ Mucosal concentrations of IL-1ra seem to depend on the number of IL-1RN*2 alleles, because in different forms of colitis, carriers of the homozygous genotype IL-1RN*2/2 display impaired mucosal IL-1ra levels.^41,42 Moreover, associations of the allele IL-1RN*2 with diverse inflammatory and autoimmune conditions have been detailed recently^43,44 and are compatible with a role of IL-1RN*2 as a proinflammatory allele. The homozygous genotype IL-1RN*2/2 was also identified as a risk factor in esophageal squamous cell carcinoma.²⁵ Furthermore, in cervical cancer, the frequency of the heterozygous genotype IL-1RN*1/2 is increased, whereas in ovarian cancer, the homozygous genotype IL-1RN*2/2 seems to be extremely rare.⁴⁵

In noncardia gastric cancer, the A allele at position –308 within the promotor region of the TNF-A gene was identified as a risk factor compared with the healthy unrelated controls.^25,26 The latter is associated with higher constitutive and inducible levels of TNF-,^30,31 and results in impaired gastric acid secretion.²⁰ Herein, we observed a weak association between the TNF-A-308A carrier status and diffuse-type gastric cancer, while the frequency was moderately reduced in intestinal type. It should be noted that these associations were only observed after stratification of patients according to the histological subtype.

In contrast to observations in advanced-stage gastric cancer, in which associations with proinflammatory polymorphisms within the of the IL-1B and the TNF-A gene were noted, we were unable to demonstrate further significant associations with alleles or genotypes of the IL-1B gene such as the IL-1B–31C or IL-1B–511T polymorphisms. However, regarding the balance between IL-1ß and its endogenous antagonist IL-1ra, which is of critical importance for the mucosal inflammatory response, recent observations suggest a synergistic functional relation of polymorphisms of both genes in gastric disorders. Increased IL-1ß levels in the gastric mucosa of composite carriers of the IL-1B–511T/T genotype and the IL-RN*2 allele were observed and exceeded those associated with either the IL-1B–511T/T genotype or the IL-RN*2 allele.^22,27-29 In addition, the TNF-A–308A allele is associated with increased transcriptional activation of the TNF-A gene.^30,31 In line with these observations, the risk of gastric carcinoma seems to increase with the individual number of distinct proinflammatory polymorphisms.^25,26 According to previous studies^21-31 we defined carrier status of IL-1B–31C or IL-1B–511T, the homozygous genotype IL-1RN*2/2, and the TNF-A–308A allele, as proinflammatory polymorphisms and observed a cumulative risk increase, with the highest level of significance observed in carriers of two proinflammatory polymorphisms. In view of the current literature and the findings presented herein, it seems possible that a selection concerning the polymorphisms IL-1B–31C/IL-1B–511T and TNF-A–308A might occur during progression of early-stage gastric cancer to advanced stages, whereas the frequency of the homozygous genotype IL-1RN*2/2 seems to decrease later on.

In the current study, three additional polymorphisms were tested. Similar to advanced-stage gastric cancer, the IL-1B+3954 polymorphism, which is a silent polymorphism within the coding region of the IL-1B gene, was not associated with early-stage gastric cancer. Recently, the rare A allele of the polymorphism at position –238 of the TNF-A gene promotor was reported to be protective in various cancers.⁴⁶ In the current study, such an association was not observed. The biallelic polymorphism at position –889 of the promotor region of the IL-1A gene has been investigated herein for the first time, but was also not associated with early-stage gastric cancer. However, it has to be kept in mind that for some of the polymorphisms that we assessed, data concerning the expression of cytokines are not yet available. Furthermore, we compared DNA from peripheral blood samples with DNA from paraffin-embedded tissue samples. Although tumor-free resection margins were used in order to avoid allelic imbalance in neoplastic tissue, future prospective trials might either use normal gastric biopsy specimens or blood samples in both study groups.

In summary, the current study demonstrates a striking association between the homozygous genotype IL-1RN*2/2 of the IL-1 receptor antagonist gene and early-stage gastric cancer, regardless of histological type, depth of tumor invasion (mucosal or submucosal), and presence of regional lymph node metastasis. Furthermore, we found a weak association of the proinflammatory A allele of the TNF-A gene with the diffuse subtype of early-stage gastric cancer. Further significant associations were not observed, in particular not with polymorphisms of the gene encoding for IL-1ß, which contrasts observations in advanced-stage gastric cancer. However, a significant association of early-stage gastric cancer with an increasing number of proinflammatory cytokine polymorphisms was demonstrated, and parallels observations in advanced-stage noncardia gastric cancer. Taken together, these observations are compatible with a different genetic background of early-stage, as opposed to advanced-stage gastric cancer.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

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

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Submitted March 3, 2004; accepted September 13, 2004.

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