Zhi-Feng Chen

Association of MTHFR C677T and SHMT1 C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China

ObjectiveTo assess the association between the C to T transition in the methylenetetrahydro folate reductase gene (MTHFR C677T) and the C to T transition in the serine hydroxymethyltransferase1gene (SHMT1 C1420T) and the increased risk of carcinogenesis of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a population of high incident region of Northern China.MethodsThe polymorphisms were genotyped by polymerase chain reaction–restriction fragment length polymorphism and PCR-confronting two-pair primers analysis respectively among 1051 cancer patients (584 ESCC and 467 GCA) and 540 healthy controls.ResultsThe MTHFR 677T/T genotype significantly increased susceptibility to both ESCC and GCA compared with the C/C genotype, the adjusted OR was 2.13 (95% CI = 1.50–3.02) and 1.28 (95% CI = 1.07–1.53, respectively. For the SHMT1 C1420T polymorphism, the C/C genotype was significantly associated with the increased risk of ESCC and GCA, compared with the C/T genotype (the adjusted OR = 1.43 and 1.35, 95% CI = 1.02–2.00 and 1.11–1.63, respectively). The interactive influence of the MTHFR and SHMT1 polymorphisms in the risk of ESCC and GCA was also observed.ConclusionThe association between the MTHFR C677T and SHMT1 C1420T polymorphisms and the risk of ESCC and GCA was demonstrated.

-251 T/A polymorphism of the interleukin-8 gene and cancer risk: a HuGE review and meta-analysis based on 42 case-control studies.

The −251T/A (rs4073), a single nucleotide polymorphism, has been identified in the promoter region of the interleukin-8 (IL-8) gene. It’s presence could influence the production of IL-8 protein by regulating the transcriptional activity of the gene. A large number of studies have been performed to evaluate the role of −251T/A polymorphism on various cancers, with inconsistent results being reported. In this paper, we summarized 13,189 cases and 16,828 controls from 42 case–control studies and attempted to assess the susceptibility of −251T/A polymorphism to cancers by a comprehensive meta-analysis. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analysis were also performed. Results showed that the carriers of the −251A allele had about a 12–21% increased risk for the reviewed cancer, in total. The carriers of −251A had an elevated risk to breast cancer, gastric cancer and nasopharyngeal cancer and a reduced risk to prostate cancer, but no evidence was found to indicate that the −251A allele predisposed its carriers to colorectal and lung cancers. When stratified separately by ‘racial descent’ and ‘study design’, it was found that the carriers of the −251A allele among the African group, Asian group and hospital-based case–control study group were at a higher risk for cancer, but not in European group and population-based case–control study. These results show that −251A allele is susceptible in the development of low-penetrance cancers.

Methylenetetrahydrofolate reductase C677T polymorphism and predisposition towards esophageal squamous cell carcinoma in a German Caucasian and a northern Chinese population

Purpose Folate deficiency is considered to increase the risk of developing esophageal cancer. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. A single C → T substitution at nucleotide 677 of the MTHFR cDNA influences enzyme activity. The purpose of this study is to compare the association of the MTHFR C677T polymorphism with susceptibility to esophageal squamous cell carcinoma (ESCC).Methods Using real-time PCR and melting curve analysis, the MTHFR C677T genotypes were determined in 430 patients with ESCC (241 German Caucasians and 189 northern Chinese) and 397 unrelated healthy controls (256 German Caucasians and 141 northern Chinese).Results A significant difference in MTHFR C677T genotype distribution was observed between German Caucasian controls (C/C, 41.8%, C/T, 44.9%, T/T, 13.3%) and northern Chinese controls (C/C, 17.7%, C/T, 38.3%, T/T, 44.0%) (χ2=52.19, P<0.001). The distribution of the MTHFR C677T genotypes among German ESCC patients (C/C, 39.0%, C/T, 48.1%, T/T, 12.9%) was not significantly different from that among healthy controls (χ2=0.531, P=0.767). In contrast, the frequency of the C/C genotype among Chinese ESCC patients (8.5%) was significantly lower than among Chinese healthy controls (17.7%) (χ2=6.37, P=0.012). The C/C genotype was correlated with a significantly reduced risk for the development of ESCC as compared to the combination of C/T and T/T genotypes (adjusted OR=0.38, 95% CI=0.16–0.88).Conclusions Our results suggest that, in contrast to German Caucasians, the MTHFR 677CC homozygous wild-type plays a protective role in the development of ESCC in the northern Chinese population.

Aberrant CpG Island Hypermethylation of RASSF1A in Gastric Cardia Adenocarcinoma

Ras-association domain family 1A (RASSF1A) gene, a candidate tumor suppressor gene, is inactivated in several human tumors, usually by hypermethylation of its promoter region. RASSF1A induces cell cycle arrest through inhibition of cyclin D1 accumulation. In this work, the promoter methylation status of the RASSF1A in 92 gastric cardia adenocarcinoma (GCA) and corresponding normal tissues were investigated using Methylation-specific PCR (MSP) approach, immunohistochemistry method and RT-PCR were used respectively to examine the protein expression and mRNA expression of RASSF1A in tumors and corresponding normal tissues. Cyclin D1 expression was examined by immunohistochemistry. RASSF1A was methylated in 54/92 (58.7%) tumor specimens, which was significantly higher than that in corresponding normal tissues (p <.001). Methylation frequencies of stage III and IV tumor tissues were significantly higher than that in stage I and II tumor tissues (p <.05). By immunostaining, 43/92 (46.7%) tumor tissues demonstrated heterogeneous, positive immunostaining of tumor tissues was significantly reduced with comparison to matched normal tissues (p <.001). mRNA expressions of RASSF1A in GCA tumor tissues were reduced significantly with comparison to the corresponding normal tissues (OD value: 0.2376 ± 0.2315 vs 0.6874 ± 0.2668, p <.001). RASSF1A mRNA expression in methylation group of GCA was significantly different from that in unmethylation group (p <.001). Cyclin D1 hyper-expression was found in 72/92 (78.3%) cases and correlated with RASSF1A methylation (p <.05). Our data suggested that epigenetic silencing of RASSF1A gene expression by promoter hypermethylation may play an important role in GCA.

PTEN polymorphisms and the risk of esophageal carcinoma and gastric cardiac carcinoma in a high incidence region of China

PTEN, as a tumor suppressor gene, plays an important role in regulating cell growth, proliferation, and apoptosis. Two common polymorphisms, -9C/G and IVS4 (-/+), may alter susceptibility to the disease. To test the hypothesis that the genetic variations of PTEN play a role in the etiology of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA), a population-based case-control study was conducted in 350 ESCC patients, 257 GCA patients, and 634 healthy controls from a high-incidence region of Hebei province, China. The PTEN polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). The results showed that the family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing ESCC and GCA (the age, gender and smoking status adjusted OR = 1.73 and 1.67; 95% CI = 1.29-2.32 and 1.28-2.19, respectively). The overall distribution of the PTEN -9C/G genotype was not significantly different between cancer patients and controls. Compared with the PTEN IVS4-/- genotype, the IVS4+/+ genotype significantly decreased the risk of ESCC and GCA development, the adjusted OR was 0.64 (95% CI = 0.44-0.94) and 0.63 (95% CI = 0.41-0.98), respectively. Stratification analysis by gender, age, smoking status and family history of UGIC showed that the PTEN IVS4-/+ genotype only reduced the risk of ESCC (adjusted OR = 0.55, 95%CI = 0.34-0.90) among subjects with family history of UGIC. While the IVS4+/+ genotype decreased the susceptibility to both ESCC and GCA (adjusted OR = 0.61 and 0.57, 95% CI = 0.37-0.98 and 0.34-0.98, respectively) among male subjects, the IVS4+/+ genotype only decreased the risk of ESCC development among subjects younger than 55 years (adjusted OR = 0.43, 95% CI = 0.21-0.85). In addition, the haplotype analysis found that the -9C/IVS4- haplotype increased the risk of developing ESCC and GCA (OR = 1.31 and 1.24, 95% CI = 1.08-1.58 and 1.001-1.53). Our results suggested that the PTEN IVS4+/+ homozygote may play a protective role in the development of ESCC and GCA, while the haplotype -9C/IVS4- might be the risk factor of the development of ESCC and GCA in the high incidence region population of Hebei province, China.

Polymorphisms in promoter region of FAS and FASL gene and risk of gastric cardiac adenocarcinoma

Background and Aim:  The FAS and FASL system play an important role in regulating apoptotic cell death. This study was designed to investigate the correlation of FAS‐1377 G/A, ‐670 A/G and FASL‐844 T/C polymorphisms with susceptibility to gastric cardiac adenocarcinoma in a population of a high‐incidence region of Hebei Province.

Genetic polymorphism in the 3′-untranslated region of the E-cadherin gene is associated with risk of different cancers†

The genetic polymorphisms in E‐cadherin gene (CDH1) may affect invasive/metastatic disease development by altering gene transcriptional activity. In this paper, we investigated the effect of 3′‐UTR +54C/T polymorphism (rs1801026) in CDH1 gene on the risk and progression of several common cancers. Multiple completely independent case‐control analyses of 1081 cancer patients with esophageal squamous cell carcinoma (ESCC), gastric cardiac adenocarcinoma (GCA), non‐small‐cell lung cancer (NSCLC), and cervical cancer and 1131 control subjects in northern Chinese populations. The results showed that the carriers with T allele were significantly decreased the risk of developing GCA, NSCLC, and cervical cancer, with an adjusted odds ratio of 0.67 (95% CI = 0.48–0.91), 0.68 (95% CI = 0.49–0.92), and 0.66 (95% CI = 0.48–0.92), respectively. There were no association between the frequency of genotype and the clinicopathological features of ESCC, GCA, and NSCLC, but the frequency of T allele was significantly lower in patients of stage III cervical cancer (P = 0.026). These results suggested that the 3′‐UTR +54C/T polymorphism in CDH1 may be a marker for genetic susceptibility of cancer.

Aberrant Methylation of Thrombospondin-1 and Its Association with Reduced Expression in Gastric Cardia Adenocarcinoma

Aim. Investigate the promoter methylation of the Thrombospondin-1 (TSP1) gene in gastric cardia adenocarcinoma (GCA). Methods. MSP approach, immunohistochemistry method, and RT-PCR were used respectively to examine the promoter methylation of TSP1, its protein and mRNA expression in tumors and corresponding normal tissues. The expression and concentration of TGF-β1 were examined respectively by immunohistochemistry and ELISA method. The status of T cell immunity was examined by Flow cytometry analysis. Results. TSP1 was methylated in 34/96 (35.4%) tumor specimens, which was significantly higher than that in corresponding normal tissues (P < .001). Protein and mRNA expression of TSP1 in GCA tumor tissues were reduced significantly and were associated with TSP1 methylation. The protein expression of TGF-β1 was significantly higher in tumor tissues (P < .001) and was associated with TNM stage and histological differentiation. The concentration of active and total TGF-β1 did not show significant difference between the GCA patients with hypermethylation of TSP1 and without methylation of TSP1 (P > .05). The function of T cell immunity was significantly different between the GCA patients with hypermethylation of TSP1 and without methylation of TSP1. Conclusions. Epigenetic silencing of TSP1 gene by promoter hypermethylation may play an important role in GCA.

PLC-ε1 Gene Polymorphisms Significantly Enhance the Risk of Esophageal Squamous Cell Carcinoma in Individuals with a Family History of Upper Gastrointestinal Cancers

BACKGROUND AND AIMS Phospholipase C epsilon 1 (PLCε1) may regulate cell growth, differentiation, apoptosis and angiogenesis and play an important role in carcinogenesis and the progression of several cancers. This study was designed to validate the association of the PLCε1 rs2274223 single nucleotide polymorphism (SNP) with esophageal squamous cell carcinoma (ESCC) as identified by genome-wide association studies (GWAS) and further assess whether the rs11599672 SNP could affect an individuals susceptibility to ESCC. METHODS These two SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) in 527 ESCC patients and 527 controls. RESULTS Compared with the rs2274223 SNP AA genotype, other genotypes or combined genotypes all enhanced the risk of ESCC. Further analyses showed that AG/GG genotype carriers with a family history of upper gastrointestinal cancers (UGIC) had an increased risk of ESCC than those AA genotype carriers without UGIC family history (OR = 2.10, 95% CI = 1.46-3.10). Overall, rs11599672 SNP had no influence on ESCC susceptibility. However, UGIC family history elevated the risk of ESCC for subjects with the TT genotype (OR = 1.59, 95% CI = 1.13-2.24). CONCLUSIONS These results highlighted the role of a genetic factor in ESCC and suggested that the PLCε1 rs2274223 SNP might be an effective genetic marker to assess the risk of ESCC in individuals with a UGIC family history from a region of high incidence in northern China.

Polymorphisms in promoter region of FAS and FASL gene and risk of cardia gastric adenocarcinoma.

Background and Aim:  The FAS and FASL system play an important role in regulating apoptotic cell death. This study was designed to investigate the correlation of FAS‐1377 G/A, ‐670 A/G and FASL‐844 T/C polymorphisms with susceptibility to gastric cardiac adenocarcinoma in a population of a high‐incidence region of Hebei Province.