The functional polymorphism in monocyte chemoattractant protein-1 gene increases susceptibility to gastric cancer

Monocyte chemoattractant protein-1 (MCP-1, CCL2) has been suggested to be associated with gastric cancer. We investigated whether the functional single nucleotide polymorphism A-2518G in CCL2 gene influenced susceptibility to gastric cancer. The CCL2 genotypes were determined using polymerase chain reaction–restriction fragment length polymorphism in 1,216 individuals (608 gastric cancer patients and 608 age- and sex-matched controls). The gastric cancer patients showed a significant higher frequency of the variant G allele compared to the controls (P = 0.01). Compared with the wild-type AA carriers, the variant genotypes (GA + GG) of A-2518G polymorphism were associated with a higher risk of gastric cancer (adjusted odds ratio = 1.55, 95% confidence interval = 1.03–2.35). Moreover, the elevated risk of gastric cancer associated with the variant genotypes was especially noteworthy in rural subjects (adjusted odds ratio = 1.92, 95% confidence interval = 1.01–3.65). In addition, stratification of gastric cancer cases according to clinicopathological characters showed that the polymorphism was associated significantly with the depth of tumor infiltration. Our data suggest that the genetic polymorphism CCL2 A-2518G may not only be associated with an increased risk of gastric cancer, but also with advanced stage of gastric cancer in the Chinese population.

     

Myeloperoxidase G-463A polymorphism and the risk of gastric cancer: a case-control study

Several epidemiological studies have shown that the myeloperoxidase (MPO) G-463A polymorphism may influence the risk of many cancers, including lung, breast, bladder and laryngeal cancer. However, there is no study concerning the MPO polymorphism and gastric cancer risk. In this hospital-based, case-control study, we used polymerase chain reaction-restriction fragment length polymorphism protocols to examine the prevalence of MPO G-463A polymorphism in gastric cancer. A significantly different distribution of the MPO -463G/A genotype was demonstrated among the cases and controls (chi2=7.42, P=0.03). Subjects with the variant genotypes (the sum of GA and AA) had a 44% reduced risk of gastric cancer relative to those with GG [adjusted odds ratio (OR)=0.56; 95% CI: 0.32-0.97]. Stratified analyses revealed that the protective effect of A allele was significant in male (adjusted OR=0.51; 95% CI: 0.26-0.98) or younger subjects (age<58 years) (adjusted OR=0.42; 95% CI: 0.18-0.94), but not in female or older subjects. In addition, there was also a significantly reduced risk in subjects residing in rural areas (adjusted OR=0.41; 95% CI: 0.18-0.95) but not in urban areas. The interaction between the MPO G-463A polymorphism and smoking status was not observed in this study. Tumor differentiation was also not found to be associated with the MPO genotype. In conclusion, our results showed that the MPO -463 G to A variant may be associated with the decreased risk of gastric cancer in Chinese population.     

Gly82Ser polymorphism of the receptor for advanced glycation end products is associated with an increased risk of gastric cancer in a Chinese population.

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 < or =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.     

Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer

The MMPs (matrix metalloproteinases) are a family of secreted zinc metalloproteases that degrade the collagens of the extracellular matrix important in tissue remodeling and repair during development and inflammation. We investigated the associations between polymorphisms of MMP-1 (-1607 1G/2G, rs1799750), MMP-3 (-1171 5A/6A, rs3025058), and MMP-12 (-82AG, rs2276109, and 1082A/G, rs652438) and the risk of lung cancer in 2014 Caucasian lung cancer patients and 1323 healthy controls. The results were analyzed using logistic regression models, adjusting for covariates. The four polymorphisms were in Hardy-Weinberg disequilibrium. Except for the 1G-1082A, the other linkage disequilibrium tests between the four MMP polymorphisms were statistically significant (P < 0.001). There was no overall association between individual MMP polymorphism and the risk of lung cancer. The MMP polymorphisms jointly were associated with a non-statistically significant higher risk of lung cancer, with the adjusted odds ratio (AOR) of subjects with 5+ variant alleles versus zero variant allele of 1.31 [95% confidence interval (CI), 0.92-1.88]. Stronger associations were observed in never-smokers and males, with the corresponding AORs of 2.44 (95%CI, 1.10-5.43, P(trend) = 0.04) in never smokers and 1.35 (95%CI, 0.79-2.30, P(trend) = 0.04) in men. In haplotype analysis, the 1G-6A-82A-1082G haplotype was associated with higher risk of lung cancer among never smokers, with the AOR of 3.65 (95%CI, 1.62-8.20) when compared with the most common 1G-5A-82A-1082A haplotype. In conclusion, the combined MMP genotypes and associated haplotypes may be associated with higher risk of lung cancer, particularly among never smokers and men.     

Myeloperoxidase and superoxide dismutase polymorphisms are associated with an increased risk of developing pancreatic adenocarcinoma

BACKGROUND: Pancreatic cancer risk has been linked to chronic pancreatitis and periodontitis, suggesting a role for inflammation in disease etiology. Myeloperoxidase (MPO) and superoxide dismutase (SOD2) are enzymes that regulate reactive oxygen species and contain recognized single nucleotide polymorphisms (SNPs) that confer altered enzyme activity. METHODS: One hundred twenty-two patients with pancreatic cancer and 331 age- and sex-matched controls were analyzed for polymorphisms of the MPO - guanine 463 adenine (-G463A) and the SOD2 alanine (Ala)-to-valine (Val) polymorphism at codon 16 (Ala16Val) genes. Cases and controls were analyzed for associations between these polymorphisms, adjusting for sex, age, history of alcohol use and smoking history. RESULTS: The variant A allele of MPO -G463A was associated with a lower risk of pancreatic cancer (adjusted odds ratio [OR] for pancreatic cancer, 0.57; 95% confidence interval [95% CI], 0.4-0.9; P = .02). The SOD2 homozygous variant genotype (Val/Val) was associated with a greater risk of pancreatic cancer (adjusted OR, 1.96; 95% CI, 1.0-3.8; P = .04). Compared with individuals who carried both low-risk alleles (A/- and Ala/-), significantly more cases than controls carried both high-risk genotypes (G/G and Val/Val; adjusted OR, 4.31; 95% CI, 1.8-10; P = .001), or 1 high-risk genotype (adjusted OR, 1.96; 95% CI, 1.1-3.4; P = .01). CONCLUSIONS: Polymorphisms of the inflammatory pathway genes MPO -G463A and SOD2 Ala16Val are associated with elevated pancreatic cancer risk. Oxidative stress may play an important role in pancreatic cancer carcinogenesis.     

Variant alleles of TGFB1 and TGFBR2 are associated with a decreased risk of gastric cancer in a Chinese population

Growing evidence suggests that the transforming growth factor beta (TGF-beta) signaling pathway occupies a central position in the signaling networks that control cell growth and differentiation. TGF-beta1 and its receptor TGF-betaRII have been correlated with the development of certain forms of cancer, including gastric cancer. We hypothesized that functional genetic variants in TGFB1 and TGFBR2 are associated with gastric cancer risk. To test this hypothesis, we genotyped C-509T and Leu10Pro polymorphisms in TGFB1 and G-875A variant in TGFBR2, using the primer-introduced restriction analysis (PIRA)-PCR assay, in a case-control study of 675 gastric cancer cases and 704 healthy controls in a Chinese population. We found that the variant alleles of the promoter polymorphisms, TGFB1 C-509T and TGFBR2 G-875A, were associated with a significantly decreased risk of gastriccancer [adjusted odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.52-0.82 for -509CT/TT and adjusted OR = 0.67, 95% CI = 0.53-0.85 for -875GA/AA]. Furthermore, subjects with both variant genotypes of the TGFB1 C-509T and TGFBR2 G-875A were associated with a significantly (56%) decreased risk of gastric cancer (adjusted OR = 0.44, 95% CI = 0.32-0.62). These findings indicate, for the first-time, that the functional variants in the promoter of TGFB1 and TGFBR2 might contribute to gastric cancer susceptibility.     

Association of endothelin-converting enzyme-1b C-338A polymorphism with gastric cancer risk: a case-control study

To investigate the association between endothelin-converting enzyme-1b (ECE-1b) C-338A polymorphism and gastric cancer risk, we conducted a hospital-based case–control study of 256 gastric cancer cases and 256 controls matched on age and gender. The genotypes were identified by polymerase chain reaction-restriction fragment length polymorphism. We found that the genotype frequencies were significantly different (P = 0.005) between cases and controls. Compared with the wild genotype CC, the variant genotypes (CA + AA) were associated with a 64% increased risk of gastric cancer [adjusted odds ratio (OR) = 1.64, 95% confidence interval (CI) 1.15–2.33]. Further stratification analyses indicated that the increased risk was especially noteworthy in older subjects (age 58) (adjusted OR = 1.91, 95% CI 1.18–3.09), women (adjusted OR = 2.30, 95% CI 1.11–4.79) and non-smokers (adjusted OR = 1.79, 95% CI 1.19–2.67). Our results suggest that the ECE-1b C-338A polymorphism may be associated with increased risk of gastric cancer.     

Polymorphisms of MTHFD, plasma homocysteine levels, and risk of gastric cancer in a high-risk Chinese population.

PURPOSE: Accumulative evidence suggests that folate has a protective effect on gastric cancer. The methylenetetrahydrofolate dehydrogenase (MTHFD) plays an important role in folate and homocysteine metabolisms, and polymorphisms of MTHFD may result in disturbance of the folate-mediated homocysteine pathway. The aim of this study is to test the hypothesis that genetic variants of MTHFD and plasma homocysteine levels are associated with risk of gastric cancer and modulated by genotypes of methylenetetrahydrofolate reductase (MTHFR). EXPERIMENTAL DESIGN: We genotyped G1958A and T401C in MTHFD and C677T in MTHFR and detected total plasma homocysteine (tHcy) levels in a case-control study of 589 gastric cancer cases and 635 cancer-free controls in a high-risk Chinese population. RESULTS: The variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric cancer [adjusted odds ratio (OR), 2.05; 95% confidence interval (95% CI), 1.34-3.13 for 1958AA; adjusted OR, 1.43; 95% CI, 1.14-1.80 for 401CC] compared with 1958GG/GA and 401TT/TC genotypes, respectively. Both of the effects were more evident in the subjects carrying MTHFR 677CT/TT genotypes. The average tHcy level was significantly higher in gastric cancer cases than in controls (P < 0.01), and the upper quartile of tHcy (>13.6 micromol/L) was associated with an 82% significantly increased risk of gastric cancer, compared with the lowest quartile of tHcy (相似文献   

Promoter polymorphisms of IL2, IL4, and risk of gastric cancer in a high‐risk Chinese population

Interleukin 2 (IL2) is a typical Th1 cytokine, and interleukin 4 (IL4) is an inducible Th2 cytokine. These cytokines are critical mediators of the Th1/Th2 balance and apoptosis potential and involved in the process of inflammation‐mediated carcinogenesis in human organs, including the gastrointestinal tract. Therefore, we tested the hypothesis that functional variants in IL2 and IL4 were associated with risk of gastric cancer by genotyping two promoter polymorphisms in IL2 G‐330T (rs2069762) and IL4 T‐168C (rs2070874) in a case‐control study of 1045 patients with incident gastric cancer and 1100 cancer‐free controls in a high‐risk Han Chinese population. We found that, compared with the IL4 ‐168TT genotype, heterozygous ‐168TC and combined ‐168TC/CC genotypes were associated with a significantly decreased gastric cancer risk [adjusted odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67–0.98 for ‐168TC; OR = 0.83, 95% CI = 0.69–1.00 for ‐168TC/CC, respectively]. Furthermore, this significant protective effect was more evident for gastric cardia cancer patients (adjusted OR = 0.73, 95% CI = 0.56–0.95 for ‐168TC/CC vs. ‐168TT). For IL2 G‐330T, subjects carrying GT/TT genotypes also had a significantly reduced risk of gastric cardia cancer (adjusted OR = 0.68, 95% CI = 0.46–0.99), compared with those carrying the GG genotype. Our results indicate that IL4 T‐168C and IL2 G‐330T promoter polymorphisms may contribute to the etiology of gastric cardia cancer in Chinese populations. © 2008 Wiley‐Liss, Inc.     

CYP1B1, CYP1A1, MPO, and GSTP1 polymorphisms and lung cancer risk in never-smoking Korean women

Polymorphisms in metabolic genes encoding phase I and phase II enzymes are thought to modulate the risk of lung cancer via changes in enzymatic activity. Recently, the effect of these metabolic enzymes and their interaction with environmental factors has been studied in both smokers and also never-smokers, since never-smokers are a good model in which to study genetic susceptibility at low-dose carcinogen exposure. Here, we investigated the association of CYP1A1 Ile462Val, CYP1B1 Leu432Val, GSTP1 Ile105Val, MPO G-463A polymorphisms and lung cancer risk in never-smoking Korean women. In this case-control study of 213 lung cancer patients and 213 age-matched healthy controls, we found that carrying one variant allele of the CYP1A1 Ile462Val polymorphism was associated with a significantly decreased risk of lung adenocarcinoma (adjusted odds ratio (OR)=0.63; 95% confidence interval (CI), 0.41-0.99). Furthermore, the combination of risk genotypes of CYP1B1 Leu432Val with CYP1A1 Ile462Val was associated with the risk of lung adenocarcinoma (adjusted OR=2.16; 95% CI, 1.02-4.57) as well as overall lung cancer (adjusted OR=2.23; 95% CI 1.01-4.89). The polymorphisms of GSTP1 Ile105Val and MPO G-463A showed no significant association with lung cancer. Theses results suggest that the CYP1A1 Ile462Val polymorphism is associated with a reduced risk of lung adenocarcinoma in never-smoking Korean women, whereas specific combinations of variant genotypes for metabolic enzymes increase lung cancer risk considerably.     

A functional polymorphism in the matrix metalloproteinase-2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma

Matrix metalloproteinase-2 (MMP-2) has been shown to play an importantrole in multiple ways to all stages of cancer initiation and development.We have reported previously a strong association between a functional single nucleotide polymorphism (-1306C/T) in the MMP2 promoter and risk of lung cancer (C. Yu et al., Cancer Res., 62: 6430-6433, 2002). This case control study was to assess the contribution of this MMP2 polymorphism to risk of development and metastasis of gastric cardia adenocarcinoma (GCA). MMP2 genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 356 patients with GCA and 789 frequency-matched controls in an ethnic Chinese population. We found that subjects with the CC genotype had >3-fold increased risk [adjusted odds ratio 3.36, 95% confidence interval 2.34-4.97] for developing GCA compared with those with the variant CT or TT genotype. Furthermore, the increased risk was found to be more pronounced in smokers and younger subjects. However, no significant association was demonstrated between the MMP2 polymorphism and risk of metastasis of the cancer at the time of diagnosis, with the odds ratio being 0.90 (95% confidence interval 0.36-2.20) for the CC genotype. These findings are consistent with our initial observation for lung cancer and further support the hypothesis that MMP2 genotype may influence individual susceptibility to the development of certain cancer.     

Tissue inhibitor of metalloproteinase-2 G-418C polymorphism is associated with an increased risk of gastric cancer in a Chinese population

Aims

To examine the effect of the TIMP-2 G-418C polymorphism on gastric cancer risk.

Methods

We conducted a hospital-based, case–control study using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method in 412 individuals (206 gastric cancer patients and 206 age, sex matched cancer-free controls).

Results

The genotype and allele frequencies were significantly different (P = 0.007 and 0.005, respectively) between cases and controls. Further analysis showed that the variant TIMP-2 genotypes (CC + GC) had a 51% increased risk of gastric cancer compared with GG [adjusted odds ratio (OR) 1.51, 95% confidence interval (CI) 1.00–2.26, P = 0.049]. The elevated gastric cancer risk was especially evident in younger individuals (age < 58 years old) (adjusted OR 2.21, 95% CI 1.18–4.16) and smokers (adjusted OR 2.61, 95% CI 1.01–6.72). However, no significant association was observed between the variant genotypes and clinicopathological features of gastric cancer.

Conclusions

These findings suggest that the TIMP-2 G-418C polymorphism is a genetic predisposing factor for gastric cancer.     

Influences of chymase and angiotensin I-converting enzyme gene polymorphisms on gastric cancer risks in Japan.

BACKGROUNDS AND AIMS: The renin-angiotensin system plays an important role in homeostasis. Angiotensin II, which is generated by chymase and angiotensin I-converting enzyme (ACE), controls blood pressure as well as angiogenesis and cell proliferation. The aim of this study was to clarify the association of the chymase gene (CMA/B) and ACE polymorphisms with susceptibility to gastric cancer and peptic ulcer. METHODS: We assessed CMA/B A/G and ACE insertion/deletion (I/D) polymorphisms in H. pylori-positive gastric cancers (n = 119), gastric ulcers (n = 127), and duodenal ulcers (n = 105), and controls (n = 294) consisting of H. pylori-positive gastritis alone (n = 162) and H. pylori-negative subjects (n = 132) by PCR methods. RESULTS: In CMA/B polymorphism, the age- and sex-adjusted odds ratios (OR) of A/A and A/G genotypes relative to the G/G genotype for gastric cancer risk were 7.115 (95% confidence interval, 1.818-27.845) and 1.956 (95% confidence interval, 1.137-3.366), respectively. There was an increased risk for gastric ulcer in the A/A genotype (OR, 3.450; 1.086-10.960). However, there was no association between ACE polymorphism and susceptibility to gastric cancer and peptic ulcer. In allele combination analysis of CMA/B and ACE polymorphisms, the A/I allele combinations (CMA/B G/A or A/A and ACE I/I genotype) significantly increased the risk of gastric cancer development (OR, 4.749, 2.050-11.001) compared with the G/I allele combinations (CMA/B G/G and ACE I/I genotype). CONCLUSIONS: The CMA/B polymorphism was associated with an increased risk for gastric cancer and gastric ulcer development. The genotyping test of the renin-angiotensin system could be useful for the screening of individuals with higher risks of gastric cancer and gastric ulcer.     

A nonsynonymous polymorphism in IL23R gene is associated with risk of gastric cancer in a Chinese population

Interleukin‐23 receptor (IL‐23R) is a key element in T helper (Th)17 cell‐mediated inflammatory process, which plays an important role in pathogenesis of gastric cancer. Genetic variants of IL‐23R have been identified as the predisposing factors for immunopathologic process. In this study, we hypothesized that the functional genetic variants of IL‐23R gene may modify the risk of gastric cancer. To test this hypothesis, we conducted a case–control study including 1043 gastric cancer patients and 1089 controls in a Chinese population to assess the association between two potentially functional single nucleotide polymorphisms (SNPs) rs6682925 T>C and rs1884444 T>G of IL‐23R and risk of gastric cancer. We found that the variant allele (G) of rs1884444 T>G, with amino acid His substituted by Gln at codon 3, was significantly associated with a decreased risk of gastric cancer [adjusted allelic odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.68–0.88]. In the stratified analysis, we found that this protective effect of rs1884444 G allele was mainly evident in intestinal‐type gastric cancer (adjusted allelic OR = 0.75, 95% CI = 0.65–0.87) other than in diffuse‐type gastric cancer (adjusted allelic OR = 0.96, 95% CI = 0.76–1.22). However, we did not find any significant association of rs6682925 T>C with gastric cancer risk. These findings indicate, for the first time, that the nonsynonymous variant rs1884444 T>G of IL‐23R may contribute to gastric cancer susceptibility, especially in intestinal‐type gastric cancer, in Chinese population. © 2010 Wiley‐Liss, Inc.     

The progesterone receptor exon 4 Val660Leu G/T polymorphism and risk of breast cancer in Australian women.

An Alu insertion polymorphism of the progesterone receptor (PR) wasreported recently to be associated with a reduced risk of breast cancer, with risks of 0.8- and 0.3-fold associated with the heterozygote and homozygote genotypes, respectively. This intronic variant is considered to be in linkage disequilibrium with an exon 4 hinge region G to T Val660Leu polymorphism. We investigated whether the exon 4 PR polymorphism was associated with breast cancer in Australian women, using a population-based study of 1452 cases and 793 controls, half of whom were <40 years of age, and the other half were 40-59 years of age. There was no difference in genotype distribution between cases and controls (P = 0.5) and no evidence of risk associated with either the GT or TT genotypes compared with the common GG genotype. The adjusted odds ratios (ORs) were 0.97 (95% confidence interval, 0.79-1.19) and 1.52 (95% confidence interval, 0.87-2.66), respectively (P = 0.8 and 0.1), and the results were independent of age and family history of breast cancer. Our data provided no support for the previously reported decreased risk of breast cancer associated with the T allele, with 80% power to detect an OR of 0.8 or less for the heterozygote genotype and 90% power to detect an OR of 0.3 or less for the rare homozygous TT genotype. There was also no support for a greatly increased risk of breast cancer associated with the T allele, given that we had 80% power to detect risks of 1.3 and 2.0 associated with the GT and TT genotypes, respectively. We therefore conclude that this polymorphism is not associated with a markedly reduced or increased risk of breast cancer in Australian women <60 years of age. However, despite its considerable size, our study cannot exclude a small reduced or increased risk associated with the T allele, especially the rare TT genotype.