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Clinical Cancer Research 14, 3627, June 1, 2008. doi: 10.1158/1078-0432.CCR-07-4808
© 2008 American Association for Cancer Research
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Cancer Prevention and Susceptibility

Gly82Ser Polymorphism of the Receptor for Advanced Glycation End Products Is Associated with an Increased Risk of Gastric Cancer in a Chinese Population

Haijuan Gu1, Li Yang1,2, Qingmin Sun1, Bo Zhou1, Naping Tang1, Rihong Cong1, Ying Zeng1 and Bin Wang1

Authors' Affiliations: 1 Key Laboratory of Reproductive Medicine, Department of Pharmacology, Nanjing Medical University; and 2 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

Requests for reprints: Bin Wang, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, Jiangsu Province, China. Phone: 86-25-86862884; Fax: 86-25-86862884; E-mail: binwang{at}njmu.edu.cn.


   Abstract
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Purpose: It has been shown that the expression of the receptor for advanced glycation end products (RAGE) is closely associated with invasion and metastasis in gastric cancer. A Gly82Ser polymorphism in exon 3 of RAGE gene was identified and thought to have an effect on the functions of its protein. Therefore, the goal of the present study was to investigate whether the polymorphism is involved in the development or progression of gastric cancer.

Experimental Design: In the hospital-based case-control study, the RAGE genotypes were determined using PCR-RFLP in 566 individuals (283 gastric cancer patients and 283 age- and sex-matched controls).

Results: The distribution of genotype was significantly different between cases and controls (P = 0.038). Compared with the wild-type 82Gly/Gly carriers, subjects with the variant genotypes (82Gly/Ser and 82Ser/Ser) had a significantly higher risk of gastric cancer (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06). Moreover, the elevated gastric cancer risk was especially evident in younger individuals (ages ≤58 years), nonsmokers, and rural subjects. Further analyses revealed that the variant genotypes were associated with adjacent organ invasion in the subanalysis of gastric cancer patients.

Conclusions: Our findings indicate that the RAGE Gly82Ser polymorphism may confer not only an increased risk of gastric cancer but also with invasion of gastric cancer in the Chinese population.

Gastric cancer occurs with a high incidence in East Asia (1). Moreover, nearly 42% of the worldwide gastric cancer cases occur in China alone (1). Gastric carcinogenesis is a complex, multistep, and multifactorial process (2). Like many malignancies, gastric cancer is the result of interactions between environmental factors and genetic factors of the host (3). Moreover, our previous epidemiologic studies also provided the evidence that the risk of gastric cancer was associated with genetic polymorphisms (4–6).

The receptor for advanced glycation end products (RAGE), a cell surface molecule, is a multiligand member of the immunoglobulin superfamily (7). It has been shown to participate in several important pathologic responses, including Alzheimer's disease, diabetes, inflammation, and cancer (8–11). RAGE has previously been suggested to stimulate growth, survival, and metastatic spread of cancers (11). In addition, RAGE expression is closely associated with invasion and metastasis in gastric cancer (12). Furthermore, it was reported that blockade of the RAGE suppressed the invasive activity of gastric cancer cells (12).

The gene for RAGE is found on chromosome 6p21.3 in the MHC locus class II/III junction and is composed of a 1.7-kb 5' flanking region and 11 exons (13). To date, several genetic variants have been identified in RAGE gene, including T-429C, T-374A, G1704T, and A2184G (14). Several studies have suggested that polymorphisms within regulation elements and/or ligand-binding regions of RAGE gene may, alone or in combination, affect the expression or function of RAGE in a given milieu (14, 15). One of the most frequently studied and relatively high prevalence variants is the Gly82Ser (or G82S) polymorphism (15, 16). It is at codon 82 (GGC->AGC) in exon 3 of RAGE and leads to a change from glycine to serine within the putative ligand-binding domain of the protein (16). It has been proposed as a functional polymorphism and associated with enhanced RAGE signaling (15). Recent observations also indicated that the Gly82Ser polymorphism was associated with various diseases, including skin complications in type 2 diabetes, diabetic advanced nephropathy, coronary artery disease, and rheumatoid arthritis (15–20). However, to our knowledge, there has been no study that examined the influence of the polymorphism with risk of cancers.

Given the roles of RAGE in the pathogenesis and progression of gastric cancer as well as the effect of the polymorphism in RAGE gene on the receptor function, we propose that RAGE Gly82Ser polymorphism may be associated with an increased risk of development or progression of gastric cancer. Therefore, to test the hypothesis, we assessed the association in a hospital-based case-control study in the Chinese population.


   Materials and Methods
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Subjects. Briefly, this was a hospital-based case-control study, which comprised 283 gastric cancer cases and 283 cancer-free controls. Cases were inpatients newly diagnosed with histologically confirmed gastric cancer, consecutively recruited at the Affiliated Hospital of Nanjing Medical University. Those with secondary, recurrent malignancies were excluded. Controls were selected from the inpatients admitted to the hospital during the same period, having no history or diagnosis of any cancer and genetic disease. They were matched with the cases on age (within 5 y) and sex. All of the subjects were unrelated Han nationality and from Jiangsu Province or its surrounding regions. Information on age, gender, smoking status, residence, body weight, and personal medical history was collected by questionnaire. Individuals who formerly or currently smoked ≥10 cigarettes per day on average were defined as smokers. Clinicopathologic variables were obtained from the medical records of the gastric cancer patients. All gastric carcinomas were classified according to the tumor-node-metastasis classification criteria of International Union Against Cancer (21). Differentiation grade was classified according to WHO classification. The study was approved by the Nanjing Medical University Affiliated Hospital Ethics Committee and informed consent was obtained from each participant.

RAGE genotyping. The protocol for genomic DNA extraction was described in our previous study (4). A PCR-RFLP assay was used to determine the RAGE Gly82Ser polymorphism. PCR was done in 20 µL reaction mixtures containing 1.625 mmol/L MgCl2, 0.14 mmol/L deoxynucleotide triphosphates, 1 unit of Taq polymerase (MBI Fermentas), 2 µL of 10x PCR buffer (MBI Fermentas), 200 ng genomic DNA, and 0.25 µmol/L of each primer (forward, 5'-GTAAGCGGGGCTCCTGTTGCA-3'; reverse, 5'-GGCCAAGGCTGGGGTTGAAGG-3'; ref. 15). After an initial denaturation at 95°C for 5 min, the DNA was amplified by 35 cycles of 94°C for 30s, 62°C for 40 s, and 72°C for 45s, with a final elongation at 72°C for 10 min. The 397-bp PCR products were digested by the restriction enzyme AluI (New England BioLabs), 5 units for 16 h at 37°C, followed by electrophoresis on a 2% agarose gel (15). The digestion revealed fragments of length 249, 123, and 26 bp for the wild-type Gly82 allele and 181, 123, 67, and 26 bp for the variant Ser82 allele. About 10% of the samples were randomly selected to do the repeated assays, and the results were 100% concordant. Two researchers, blinded to the clinical data, scored the genotypes independently.

Statistical analysis. All statistical analyses were done by using the Stata version 8.0 (STATA Corp.). All of the tests were two sided, and statistical significance was defined as P < 0.05. Quantitative variables departing from the normal distribution were summarized as median and analyzed by Mann-Whitney rank sum test. Pearson's {chi}2 test was used to test the difference in the distribution of categorical variables. The Hardy-Weinberg equilibrium of the RAGE genotypes was evaluated by a goodness-of-fit {chi}2 test. The association between the polymorphism and risk of gastric cancer was estimated by odds ratio (OR) and 95% confidence interval (95% CI). Carriers of the wild genotype 82Gly/Gly comprised reference group. The crude OR was computed using the Woolf approximation method and the adjusted OR was assessed by unconditional logistic regression method, with adjustment for age, sex, smoking status, residence, hypertension, and diabetes.


   Results
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Demographic characteristics of the study participants are summarized in Table 1 . Cases and controls were well matched in terms of sex and age (within 5 years). Moreover, the two groups were similar with respect to smoking status, residence, history of hypertension, and diabetes. Patients with cancer of the gastric cardia and noncardia were 83 and 200, respectively. Most of the cases were adenocarcinoma (97.88%). Among those 275 gastric cancers with available clinicopathologic data, 48, 31, 133, and 63 were T1, T2, T3, and T4, respectively; 38, 129, and 108 were reported well, moderate, and poor differentiation, respectively. Positive lymph nodes were identified in 177 cases.


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  		Table 1. Demographic information

 
Data for genotype frequency and the association between RAGE Gly82Ser polymorphism and the risk of gastric cancer are shown in Table 2 . The genotype distribution was in agreement with that predicted under Hardy-Weinberg equilibrium for both cases (P = 0.053) and controls (P = 0.081). The frequencies of the genotypes between the cases and controls were significantly different (Pearson {chi}2 = 6.552; P = 0.038). Furthermore, the Ser82 allele frequency was significantly higher (Pearson {chi}2 = 5.855; P = 0.016) in the case group (27.56%) than in the control group (21.38%). With the 82Gly/Gly genotype as reference, the OR for the variant genotypes (82Gly/Ser and 82Ser/Ser) was 1.47 (95% CI, 1.05-2.06; P = 0.024) after adjustment for age, sex, smoking status, residence, hypertension, and diabetes. Moreover, the 82Gly/Ser heterozygotes had a 41% increased risk of gastric cancer (adjusted OR, 1.41; 95% CI, 1.00-1.99), and the 82Ser/Ser homozygotes had a 150% increased risk (adjusted OR, 2.50; 95% CI, 1.01-6.17).


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  		Table 2. Distributions of the RAGE genotype in cases and controls and risk estimates

 
Table 3 presents the results of stratified analyses by the median age of controls (58 years), sex, smoking status, and residence with the RAGE variant genotypes. A significantly elevated risk associated with the variant genotypes was found for younger subjects (ages ≤58 years; adjusted OR, 2.49; 95% CI, 1.53-4.05) but not in older subjects (ages >58 years). Stratification by smoking status revealed a significant association of the polymorphism with an increased gastric cancer risk for nonsmokers (adjusted OR, 1.70; 95% CI, 1.16-2.49) but not in smokers. In rural subjects, possession of the variant genotypes was associated with a 75% increased risk of gastric cancer (adjusted OR, 1.75; 95% CI, 1.06-2.88), whereas the association was not statistically significant in urban subjects. However, the sex effect on the association between the polymorphism and susceptibility to gastric cancer was not observed.


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  		Table 3. Stratified analyses for variant RAGE genotypes in cases and controls

 
We also analyzed the correlations of the RAGE variant genotypes with clinicopathologic features of gastric cancer patients in this study (Table 4 ). A significant association between the variant genotypes and the risk of adjacent organ invasion was observed (adjusted OR, 3.20; 95% CI, 1.40-7.29). However, we did not note a statistically significant association between the polymorphism and tumor differentiation, lymph node status, or tumor location.


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  		Table 4. Associations between variant RAGE genotypes and clinicopathologic characteristics of gastric cancer

 

   Discussion
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Nowadays, genome-wide association study is encouraging and widely conducted to help in developing more accurate diagnostic and therapeutic strategies of various kinds of human diseases (22). However, as only a subset of human genetic variation has been identified, it is unknown what proportion of the total genetic variation can be captured in this way, and it is likely that additional technological approaches will be required to capture all common variation (22). In our candidate single nucleotide polymorphism investigation, we for the first time found that the functional RAGE Gly82Ser polymorphism conferred not only an increased risk of gastric cancer but also with invasion of gastric cancer in the Chinese population.

The RAGE Gly82Ser polymorphism occurs at a predicted N-linked glycosylation site and in the same immunoglobulin variable domain as the AGE-binding site (16). Ser82 has been reported to enhance ligand affinity and up-regulate receptor signaling through mitogen-activated protein kinases and nuclear factor-{kappa}B (15). Several epidemiologic studies have investigated the association between the polymorphism and various diseases (14–20). In a case-control study, Hofmann et al. (15) showed that the Ser82 allele exhibited an association with rheumatoid arthritis with relative risk of 2.6 (P < 0.001). There were reports on significant association between the polymorphism and type 2 diabetic complications (17, 18). Prevost et al. (19) suggested that the polymorphism was associated with progression to diabetic advanced nephropathy in Caucasian type 1 diabetic patients (adjusted OR, 3.17; 95% CI, 1.32-7.85). In a large population study in Korea, an association between the variant genotypes and a significantly decreased risk of coronary artery disease was shown (OR, 0.749; 95% CI, 0.579-0.969; ref. 20). Therefore, it has been indicated that the polymorphism within the ligand-binding domain of RAGE is a functional genetic variant association with activation of signal transduction pathways.

RAGE has been reported to be one of the key factors accelerating tumor progression and metastasis in various types of cancers (10–12, 23–29). RAGE interacts with AGEs, amphoterin, β-amyloids, and S100 proteins (10). Engagement of RAGE by a ligand triggers activation of central cellular pathways, including mitogen-activated protein kinase, Cdc42/Rac, and nuclear factor-{kappa}B signaling pathways (11, 24, 28). Concordantly, additional evidence suggests that blockade of RAGE signaling inhibits the growth and metastasis of tumors (11, 25, 29).

Kuniyasu et al. (12) reported that mRNA expressions of RAGE were detected in gastric cancer cell lines. RAGE expression was also strongly associated with the invasive and metastatic activity of gastric cancer (12). Activation of RAGE is known to stimulate extracellular signal-regulated kinase and nuclear factor-{kappa}B activity and to increase cell proliferation, survival, and motility. RAGE activation also evokes cell growth through mitogen-activated protein kinase signaling (11, 12). Moreover, RAGE has been considered as a new indicator for malignant potential and as a potential therapeutic target in cases of gastric carcinoma (12). Therefore, increased ligand affinity of RAGE and up-regulation of intracellular signaling pathways may be associated with increased risk of gastric cancer.

Based on these previous observations, it would therefore be plausible to expect that the functional polymorphism of RAGE is a risk factor for gastric cancer. Our observation that the variant Ser82 allele is more frequent in patients with gastric cancer is therefore in accordance with the hypothesis. We found that the variant genotypes conferred a 47% increased risk of developing gastric cancer in this Chinese population. The frequency of the RAGE Ser82 allele in our control group was observed to be 21.38%. Although we found a higher prevalence of Ser82 allele in controls than in the Caucasian, Korean population, and Indians, the prevalence was similar to that observed in another study in the Chinese population (23.1%; refs. 14–20, 30). It is probably that the discrepancies in sample size, selection of cases and controls, study design, and ethnic background may partly explain the differences observed in this study and others (4, 6, 14–20, 30).

Moreover, blockade of RAGE using soluble RAGE suppresses local tumor growth and distant metastases (11). It was reported that soluble RAGE concentration was significantly higher in subjects with the 82Gly/Gly genotype (1,038 ± 33 pg/mL) than in those with the 82Gly/Ser (809 ± 19 pg/mL) or the 82Ser/Ser (428 ± 43 pg/mL) genotype (31). Therefore, the presence of the variant Ser82 allele, associated with enhanced ligand-binding affinity of RAGE and up-regulation of intracellular signaling pathways, as well as lower soluble RAGE concentration, could potentially explain, at least in part, the significantly elevated risk of gastric cancer in subjects carrying the variant genotypes.

Several recent data suggested that polymorphisms located in the MHC class II/III junction on chromosome 6p21.3, where the RAGE maps, substantially contributed to heritability of cancer (32, 33). Significant linkage disequilibria between class II and class III markers, such as RAGE, C4, NOTCH4, HSP70, TNFab, and HLA-DRB1, have been reported (34). It was indicated that the RAGE Ser82 allele was in linkage disequilibrium with HLA-DRB1*0401 in rheumatoid arthritis patients and diabetic individuals in Caucasian population (15, 34). The extent of linkage disequilibrium across the RAGE locus may vary in different populations. Further studies are necessary to understand the relationship between polymorphisms encoded in the MHC region and gastric cancer risk.

In the present study, we found that the polymorphism was associated with the increased risk of gastric cancer among subgroups of younger subjects (ages ≤58 years) but not among older subjects. Weak immune system and overwhelming accumulated exposure to environmental carcinogens in older individuals may account for the age difference we observed (4). Our results seem consistent with the notion in our previous studies (4, 6). The older individuals are at a higher risk of gastric cancer, which is more likely due to the aging effect rather than direct genetic effects. Therefore, the variation in the RAGE gene may be more influential in early-onset gastric cancer, although this result needs confirmation.

Similarly, subjects with the variant genotypes were susceptible to developing gastric cancer in nonsmokers, whereas not in smokers. Cigarette smoking has been unequivocally established as the main causative factor for gastric cancer (1). The association between the polymorphism and gastric cancer risk could be masked by the overwhelming accumulated exposure to tobacco carcinogens in smokers so that the association is more evident in nonsmokers.

In statistical analyses stratified by residence, a significant association was observed in rural subjects. It has been suggested that the genetic differences have their strongest effects under conditions of low environmental pollution (4, 35). Our results plausibly agree with the hypothesis that the genetic effects might be more prominent in the better environments of rural areas (4). However, it is possible that the finding is due to chance and further replication is needed.

We observed the significant correlation of the RAGE variant genotypes with adjacent organ invasion in the subanalysis of gastric cancer patients. Several lines of evidence have suggested that matrix metalloproteinases 2 and 9 and mitogen-activated protein kinase, which are important for cancer cell invasion and metastasis, are controlled by RAGE signals (11, 12). It has also been shown that blockade of the RAGE signal inhibited the metastasis of cancer (11). Kuniyasu et al. (12) reported that RAGE provided a system for accelerating in vitro migration and invasion of gastric cancer cells and that this system was associated with metastasis in patients with gastric cancer. Therefore, the high ligand-binding affinity of RAGE and enhanced RAGE signaling in the presence of variant Ser82 allele were associated with invasion in gastric cancer. However, our results did not support the correlation between the polymorphism and lymph node status, tumor differentiation, or location of gastric cancer. Because of the limited number of gastric cancer patients in the subgroups and the clinicopathologic variables obtained at the time of diagnosis, we could not exclude the possibility that these factors might affect the association between them. Therefore, larger studies with prospectively followed-up clinical outcome, especially the survival rate, may be required to elucidate the association between the polymorphism and gastric cancer progression.

Our study has several limitations. First, the design was a case-control study. A hospital-based control group recruited among patients with noncancer diseases was used. We could not rule out the possibility of selection and recall bias. However, the genotype distribution of controls was in Hardy-Weinberg equilibrium and the Ser82 allele frequency was in the range of those in previous reports (14–20, 30). Second, no linkage disequilibrium analysis has been conducted in the present study. It is possible that the polymorphism is in linkage disequilibrium with other functional polymorphisms that may affect gastric cancer risk. Third, Helicobacter pylori infection is one of independent risk factors of gastric cancer. We did not have enough information on Helicobacter pylori status in cases and controls because it was unethical to do Helicobacter pylori tests in every subject, especially in controls. Finally, the sample size was relatively small, particularly for stratified analyses, to evaluate the gene-environment interactions. Nevertheless, our initial data provided interesting information and valuable guidance to future studies in this area.

In summary, the present study suggests that the RAGE Gly82Ser polymorphism is associated with an increased risk of gastric cancer in the Chinese population. Especially in younger individuals, nonsmokers, and rural subjects, the polymorphism may modulate gastric cancer risk. Moreover, the RAGE variant genotypes may also play a role in the invasion of gastric cancer. Further studies with larger sample size are needed to verify these initial observations in diverse ethnic populations and with other types of tumors.


   Disclosure of Potential Conflicts of Interest
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No potential conflicts of interest were disclosed.


   Footnotes
 
Grant support: National Natural Science Foundation of China (No. 30672486), Natural Science Foundation of Jiangsu Province (No. BK2006525), and "333 Project" and "Qinglan Project" Funding for the Young Academic Leader of Jiangsu Province (B. Wang).

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.

Note: H. Gu, L. Yang, and Q. Sun contributed equally to this work.

Received 11/ 3/07; revised 12/30/07; accepted 1/17/08.


   References
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