Japanese Journal of Clinical Oncology Advance Access originally published online on October 19, 2008
Japanese Journal of Clinical Oncology 2008 38(12):861-866; doi:10.1093/jjco/hyn111
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© The Author (2008). Published by Oxford University Press. All rights reserved
Association of Transforming Growth Factor-beta 1 Polymorphisms with Genetic Susceptibility to TNM Stage I or II Gastric Cancer
1 Department of General Surgery, The Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai
2 Department of Pathology, No. 113 Hospital of People’s Liberation Army, Ningbo
3 Department of General Surgery, Tongji hospital, Tongji University, Shanghai
4 Shanghai GeneCore Biotechnologies Co., Ltd, Shanghai, China
5 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
For reprints and all correspondence: Yu Wang, Department of General Surgery, The Sixth People's Hospital, Shanghai Jiaotong University, No. 600 Yishan Road, 200233 Shanghai, China. E-mail: wangyudjz{at}126.com
Received August 24, 2008; accepted September 18, 2008
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Abstract |
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Transforming growth factor-beta 1 (TGF-β1) inhibits the proliferation of tumors in early stages of cancers, whereas it promotes tumor growth and metastasis in later stages of cancers. To examine the effect of the TGF-β1 polymorphisms on gastric cancer risk, we studied the association between C–509T and T+29C (Leu10Pro) polymorphisms in TGF-β1 and gastric cancer risk in 414 cases and 414 controls in the Chinese population. When the overall gastric cancer cases were compared with the controls, no significant difference was found in genotype distributions for both the polymorphisms examined. However, when stratified by tumor stage, the –509T and +29C allele carriers had a 0.57-fold (95% CI = 0.36–0.90) and a 0.58-fold (95% CI = 0.36–0.91) decreased risk of TNM stage I+II gastric cancer, respectively, as compared with non-carriers. We conclude that TGF-β1–509T and +29C alleles may have a protective role in the development of stage I+II gastric cancer.
Key Words: TGF-β1 • gastric cancer • single nucleotide polymorphism • genetic susceptibility
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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Gastric cancer is one of the most common malignant neoplasms worldwide, with one-third of cases occurring in China (1,2). Genetic and other environmental/lifestyle factors and Helicobacter pylori infection have been reported to be associated with the etiology of gastric cancer (3,4). Among the genetic factors, several polymorphic genes have been implicated as risk factors for gastric cancer (5–12). The transforming growth factor-beta 1 (TGF-β1) gene is a good candidate to modulate gastric cancer risk, as it is involved in multiple important cellular processes and plays a biphasic role in carcinogenesis (13). In early stages of cancer, TGF-β1 acts as a tumor suppressor by inhibiting cellular proliferation or by promoting cellular differentiation and apoptosis (13–15). In later stages of cancer, however, the role of TGF-β1 shifts to that of a tumor promoter by stimulating angiogenesis and cell motility, suppressing immune response and increasing the interaction of tumor cells with the extracellular matrix, which leads to progressive invasion and metastasis (13–16). This biphasic nature of TGF-β1 action has also been demonstrated in animal models in which the TGF-β1 pathway has been altered (17,18).
The production of TGF-β1 is under genetic control (19,20) and several common single nucleotide polymorphisms (SNPs) with possible functional significance have been reported in the TGF-β1 gene, including C–509T (rs1800469) and T+29C (Leu10Pro, rs1800470). Several studies have shown that the T allele of C–509T and C allele of T+29C polymorphisms are associated with increased serum levels of TGF-β1 (21–24), suggesting that the polymorphic variants of TGF-β1 are functionally distinct and these differences may influence cancer risk. It has been reported that the variant alleles of the TGF-β1 gene appear to be potential risk factors for cancers of the lung, esophagus, breast, liver, nasopharynx, kidney, prostate, gallbladder and colorectum (25–33). The relationship between C–509T or T+29C and gastric cancer remains unclear. Three previous studies have shown that TGF-β1 T+29C was not associated with gastric cancer risk (34–36), whereas C–509T correlated with a reduced risk of gastric cancer among a high risk Chinese population (36). However, all studies lacked information on tumor stage, which hindered their ability to examine the potential difference in the association of TGF-β1 polymorphisms with gastric cancer by tumor stage. Because of the distinct roles that TGF-β1 plays in early and later stage of tumors, we hypothesized that polymorphisms in TGF-β1 may affect risk of gastric cancer differently at different tumor stages.
In the present study, we examined the association between C–509T and T+29C polymorphisms in TGF-β1 and risk of gastric cancer in a case–control study of 414 patients with gastric cancer and 414 controls frequency matched to the cases by sex and age in a Chinese population. We also examined whether the potential association of TGF-β1 polymorphisms with gastric cancer risk differs according to tumor stage status.
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PATIENTS AND METHODS |
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Subjects
Four hundred and fourteen newly diagnosed incident gastric cancer patients who underwent surgery at the Sixth People’s Hospital and Tongji hospital, Shanghai, China from 2004 to 2006 were recruited and their blood samples were collected. Final diagnoses of primary gastric adenocarcinoma were confirmed by routine histopathologic examination. None of the patients had received chemotherapy or radiation therapy preoperatively. Four hundred and fourteen cancer-free subjects were randomly selected from a cancer-screening program for early detection of cancer at the same hospitals and their blood samples were also obtained at the interview. The selection criteria for the controls included no individual history of cancer and frequency matched to cases by sex and age (±5 years). The exclusion criteria were past or present gastric ulcer, immunosuppressive disorders and other major systemic diseases. Each subject provided written consent to participate in the study. The research protocol was approved by the Institutional Review Board of the two participant hospitals.
Each subject was personally interviewed by trained personnel using a questionnaire to determine demographic and lifestyle characteristics such as age at diagnosis for cases and at interview for controls, sex, habits of cigaret smoking and alcohol drinking and first-degree family history of gastric cancer. The serologic tests for IgG antibodies to H. pylori infection by enzyme-linked immunosorbent assay were performed by commercially available products (Bioseed, USA). Tumor characteristics such as tumor location, tumor size, the depth of tumor invasion, Lauren classification, histological grade, status of lymph node metastasis and distant metastasis, were made on the basis of pathology reports of the specimens obtained by surgery. All histology slides were reviewed by one specialist pathologist and staged according to the new TNM staging (sixth edition).
Tgf-β1 genotyping
Genomic DNA was extracted from peripheral blood lymphocytes by proteinase K digestion and phenol/chloroform extraction. A modified method of polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) originally described by Kang et al. (37) was performed to identify the TGF-β1 C–509T and T+29C genotypes. The PCR primers for the C–509T and T+29C polymorphisms were 5'-GGG TCC CTC TGG GCC CAG TT-3' (forward) and 5'-GGG GGC AAC AGG ACA CCC GA-3' (reverse); and 5'-ACC ACA CCA GCC CTG TTC-3' (forward) and 3'-GAT GGC CTC GAT GCG CTT-3' (reverse), respectively. PCR was performed at 94°C for 2 min for initial denaturation, followed by 35 cycles of 30 s at 94°C, 30 s at 60°C for C–509T and 59°C for T+29C and 30 s at 72°C, with a final step of 7 min at 72°C to allow for the complete extension of all PCR fragments. The PCR products were digested overnight at 37°C with AvaI for C–509T and MspA1I for T+29C genotypes (New England BioLabs, Beverly, MA, USA). After the overnight digestion, the products were separated by 120 V for 45 min on a vertical 9% non-denaturing polyacrylamide gel stained with ethidium bromide. Negative and positive controls were assessed during the analysis to ensure that PCR products were not contaminated and that the enzyme digestion worked correctly. In addition, laboratory staff were kept ignorant of group status and the extent of random misclassification was controlled by randomly genotyping 10% of the samples twice. To confirm the genotyping results, selected PCR-amplified DNA samples (n = 2 for each genotype) were examined by DNA sequencing, and the results were 100% concordant.
Statistical methods
Differences in sex, age, cigaret smoking, alcohol drinking, H. pylori infection status and first-degree family history of gastric cancer between gastric cancer cases and controls were evaluated using the 
2-test. The associations between TGF-β1 polymorphisms and gastric cancer risk were estimated by computing the ORs and their 95% CIs from multivariate logistic regression analyses with adjustment for age (modeled as a continuous variable), sex (male versus female), cigaret smoking (yes versus no), alcohol drinking (yes versus no), H. pylori (positive versus negative) and family history of gastric cancer (yes versus no). Hardy–Weinberg equilibrium was tested using the asymptotic Pearson’s 2-test. A value of P < 0.05 was considered statistically significant. All these statistical analyses were conducted using the Stata 9.0 (Stata Corporation, College Station, TX, USA) statistical package. The linkage disequilibrium (LD) among the polymorphisms was quantified using the Haploview 3.1.1 software (38). The haplotypes and their frequencies were estimated on the basis of a Bayesian algorithm using the Phase program (39) that is available at http://www.stat.washington.edu/stephens/phase.html.
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RESULTS |
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The general characteristics of the cases and controls are shown in Table 1. Distributions of age, sex, cigaret smoking, alcohol drinking and H. pylori infection were similar in cases and controls. Cases were found to have more frequency of first-degree family history of gastric cancer than the controls (P = 0.009).
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The results of TGF-β1 C–509T and T+29C polymorphisms are summarized in Table 2. The genotype distributions of both polymorphisms among controls and cases were in Hardy–Weinberg equilibrium (all P > 0.412). When the overall gastric cancer cases were compared with the controls, no significant difference was found in the distributions of the genotypes for both polymorphisms examined (Table 2). A similar magnitude of the ORs was observed when the cases were stratified by Lauren classification (Table 2). However, when they were stratified by tumor stages, the distributions of the C–509T and T+29C genotypes in the stage I+II cases differed from those of the controls, with a P value of 0.039 and 0.05, respectively. The –509T and +29C allele carriers had a 0.57-fold (95% CI = 0.36–0.90, P = 0.016) and a 0.58-fold (95% CI = 0.36–0.91, P = 0.018) decreased risk of TNM stage I+II gastric cancer, respectively, as compared with non-carriers (Table 3). Lauren classification-stratified analysis of the stage I+II cases was not performed further, because the sample size was too small to be meaningful.
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Similar to the early studies (29,40), we found that the two polymorphisms were in strong LD in our data set (D'=0.94). The distributions of the TGF-β1 haplotypes in overall or stage III+IV gastric cancer cases did not differ from those of the controls (Tables 2 and 3). However, consistent with the results of the single-locus analyses, the –509T/+29C haplotype was associated with a significantly decreased risk of stage I+II gastric cancer as compared with the most common haplotype of –509C/+29T (OR = 0.68, 95% CI = 0.49–0.93, P = 0.016) (Table 3).
The potential associations of the TGF-β1 C–509T and T+29C polymorphisms with tumor progression of gastric cancer are presented in Table 4. The –509T and +29C alleles were found more often in stage III+IV cases than in stage I+II cases, and the –509T and +29C allele carriers had a 1.79-fold (95% CI = 1.11–2.89, P = 0.017) and a 1.93-fold (95% CI = 1.20–3.12, P = 0.007) increased risk for stage III+IV of gastric cancer, respectively, as compared with non-carriers. Haplotype analysis revealed similar findings under a recessive model (Table 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONFundingReferences |
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Although the role of C–509T and T+29C polymorphisms in TGF-β1 has been implicated in various human cancers, three previous studies showed that the T+29C polymorphism was not associated with gastric cancer (34–36), whereas C–509T correlated with a reduced risk of gastric cancer among a high risk Chinese population (36). In line with these results for T+29C but not for C–509T, our data did not support the existence of an association between both polymorphisms and gastric cancer risk among overall cases. However, in this study, we demonstrated for the first time that there is an association between the C–509T and T+29C polymorphisms and decreased gastric cancer risk among stage I+II cases. Lack of information on tumor stage in Jin et al.’s study (36) hindered their ability to examine the difference in the association of C–509T polymorphism of the TGF-β1 gene with gastric cancer by tumor stage. Because there are only minor differences in –509T allele frequencies in control subjects, ethnic differences in TGF-β1 allele frequencies are unlikely to be the explanation for the discrepancies between the current study and the study by Jin et al. The difference may owing, at least partly, to different compositions of various tumor stages in these two studies, and the possible inclusion of more cases with stage I+II gastric cancer may have rendered the overall association in their study. Moreover, sampling difference cannot be excluded since the magnitude of the LD between C–509T and T+29C polymorphisms in our study cases was noticeably stronger than that noted in Jin et al.’s study cases.
The exact underlying mechanism(s) responsible for our finding that the TGF-β1–509T and +29C alleles have conferred a decreased risk for stage I+II gastric cancer remains unclear. Assuming that TGF-β1 acts as a tumor suppressor in early stages of cancer, the inverse association of the two polymorphisms with stage I+II gastric cancer is consistent with what would be expected. During the multistage carcinogenesis, the growth inhibitory effects and apoptotic effects of TGF-β1 are lost, and other TGF-β1 functions that favor malignant tumor progression prevail (15,41), therefore, the TGF-β1–509T and +29C alleles may have an increased risk-effect on tumor progression. In line with this hypothesis, we observed an association between the C–509T and T+29C polymorphisms and increased risk for stage III+IV of gastric cancer. These observations suggest that the functional C–509T and T+29C polymorphisms of the TGF-β1 gene may play a possible dual role in gastric cancer development. Nevertheless, it must be emphasized that these post hoc analyses of TGF-β1 polymorphisms on tumor progression in the present study were not performed to test previously defined hypotheses. Further studies, therefore, should be performed to analyze this potential role of the TGF-β1 polymorphisms for malignant tumor progression of gastric cancer.
In conclusion, we found that TGF-β1–509T and +29C alleles and their haplotypes may have a protective role in the development of stage I+II gastric cancer. Yet, since the numbers in the subgroups were relatively small, larger molecular epidemiological studies are needed to confirm our observations.
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Funding |
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This work was supported by a grant (No. 06MA27) from Medical Science and Technology Research Foundation for the 11th 5-Year Program of PLA, Nanjing branch, P.R. China.
Conflict of interest statement
None declared.
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Footnotes |
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* These two authors contributed equally to the work.
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References |
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