MUC1 is associated with TFF2 methylation in gastric cancer.

BACKGROUND: Emerging evidence has shown that MUC1 and TFF2 play crucial roles in the H. pylori-infected pathogenesis of gastric cancer (GC). A recent study revealed that H. pylori infection induced obviously increased Tff2 methylation levels in Muc1-/- mice compared with controls. However, little is known of the molecular mechanism on MUC1 regulating the expression of TFF2. METHODS: We conducted a correlation analysis of MUC1 and TFF2 in public databases and our adjacent GC tissues. Besides, MUC1 overexpression vector or small interfering RNA (siRNA) was transfected into GC cells to assess the change in TFF2 expression. Furthermore, the methylation status of TFF2 was measured by bisulfite sequencing PCR (BSP). RESULTS: The expression of MUC1 was significantly lower in non-cardia and cardia tumor tissues than that in normal tissues. Downregulation of TFF2 expression was also observed in GC tissues. In addition, we found that MUC1 expression was positively associated with TFF2 expression in GC tissues, especially among GC patients with H. pylori infection. Overexpression of MUC1 in BGC-823 and SGC-7901 cell lines substantially increased the TFF2 expression, whereas knockdown of MUC1 reverted this effect. Moreover, MUC1 was negatively related to the methylation of TFF2 in the co-expression analysis. The results of BSP experiments showed that compared with negative vector group, the methylation level of TFF2 was decreased in GC cells transfected with MUC1 overexpression vector. Additionally, survival analysis indicated that GC patients with lower level of MUC1 or TFF2 had a worse outcome. CONCLUSION: Our results indicated that MUC1 was associated with the methylation of TFF2, which may have implications for TFF2 expression in GC. These findings warrant further research toward the underlying mechanism of MUC1 influenced the TFF2 methylation.

A genetic variation in the CpG island of pseudogene GBAP1 promoter is associated with gastric cancer susceptibility.

BACKGROUND: Previous genome-wide association studies (GWASs) have identified that several single nucleotide polymorphisms (SNPs) are implicated in gastric cancer (GC) risk. However, the multiple statistical comparisons of GWASs may reject some true biological positives with subthreshold P values. METHODS: This study annotated the genomic locations of all CpG islands in the genome using the Encyclopedia of DNA Elements (ENCODE). The SNPs in the regions were then genotyped using the Illumina 660W Quad chip. The effects of the prominent variations on GC risk were further confirmed in the other independent cohorts. RESULTS: SNP rs2990245, which is located in the promoter of pseudogene GBAP1, was associated with GC risk using GWASs data. An additional cohort of 1275 GC patients and 1424 controls validated that individuals with the CC genotype had a 62% decreased risk of GC compared with those who carried the TT genotype (P = 2.01E-04) in the codominant model. The significant association was observed in the additive, dominant, and recessive models. A meta-analysis combining the results from the GWASs and replication studies revealed that rs2990245 was significantly associated with decreased GC risk (P = 5.59E-12). Importantly, rs2990245 can regulate the expression of GBAP1 by influencing the methylation status of the GBAP1 promoter. GBAP1 can act as a competing endogenous RNA by binding competitively with micro-RNA-212-3p and then promoting GBA expression. CONCLUSION: rs2990245 is significantly associated with a decreased risk of GC. Pseudogene GBAP1 contributes to the development and progression of GC by sequestering the miR-212-3p from binding to GBA.

Polymorphism rs4787951 in IL-4R contributes to the increased risk of renal cell carcinoma in a Chinese population.

OBJECTIVE: Interleukins are important molecules involved in tumor formation. In this study, the association between renal cell carcinoma (RCC) risk and single nucleotide polymorphisms (SNPs) on IL-4/IL-13/IL-4R was assessed. METHODS: We recruited 620/623 cases/controls and conducted a case-control study. Five tagSNPs (i.e., IL-4R rs8832, IL-4R rs4787951, IL-13 rs1881457, IL-13 rs2066960 and IL-13 rs2069744) were selected. Odds ratios (ORs) with their 95% confidence intervals (CIs) were obtained to appraise the association between SNPs and RCC susceptibility. Luciferase report assay and EMSA were conducted to investigate whether SNPs could affect binding affinity of transcription factors to target genes. RESULTS: IL-4R rs4787951T>C was significantly associated with RCC susceptibility. Individuals carrying CC genotypes had a significant increment in RCC risk compared with TT genotype carriers (adjusted OR = 1.57, 95% CI = 1.07-2.28, P = 0.020). By stratified analyses, more pronounced association was found in the female, diabetic or without smoking, drinking and hypertension group. Besides, SNP rs4787951 could influence the binding affinity of IL-4R to transcription factors. Sequence surrounding allele T was prone to bind transcription factor NFATc. CONCLUSIONS: This study revealed that IL-4R rs4787951T>C was associated with susceptibility of RCC and could be a predictive biomarker for RCC risk.

Genetic variants in XDH are associated with prognosis for gastric cancer in a Chinese population.

OBJECTIVE: We explored the association between single nucleotide polymorphisms (SNPs) rs207454 and rs494852 located in xanthine dehydrogenase (XDH) and gastric cancer (GC) survival. METHODS: A total of 940 patients with gastric cancer were enrolled and genotyped using TaqMan allelic discrimination method. The Kaplan-Meier test and log-rank examine were used to assess the effect of genetic variation. RESULTS: Patients carrying rs207454 CC genotype had a longer survival time than those with the AA genotype (P = 0.042). The similar association was detected in the recessive model (P = 0.017). We conducted expression quantitative trait loci (eQTL) analysis and found that gastric cancer patients carrying rs207454 CC genotype had significant lower XDH levels than those with AA/AC genotype, suggesting that rs207454 polymorphism effected the expression of XDH. Additionally, the Kaplan-Meier curves showed that gastric cancer patients with high expression of XDH had remarkably poor survival outcome than those with low expression (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.29-1.82). CONCLUSIONS: Genetic variants in XDH were associated with the survival of gastric cancer and may act as prognostic markers for individual suffered from gastric cancer.

Association between obesity and bladder cancer recurrence: A meta-analysis.

BACKGROUND: The association between obesity and bladder cancer prognosis is not well-defined. This meta-analysis was performed to explore whether obesity is related to overall survival (OS) and bladder cancer recurrence. METHODS: Relevant English-language studies were identified by searching PubMed® up to November 1, 2017. We pooled the hazard ratios (HR) and 95% confidence intervals (CIs) using a random effect model. Dose-response relationship, subgroup and sensitivity were also analyzed. RESULTS: Eleven studies were included. Recurrence rate of bladder cancer was significantly greater in obese (HR = 1.76, 95% CI: 1.36-2.28) vs normal weight patients. Stratification analysis showed that females had higher recurrence risk than males (HR = 1.17, 95% CI: 1.05-1.31). Obesity was not significantly associated with bladder cancer OS (HR = 1.21, 95% CI: 0.97-1.52). Dose-response relationship analysis revealed a linear association between BMI and risk of recurrence. Each one kg/m2 increase in BMI was related to a 1.3% increased risk of bladder cancer recurrence (HR = 1.01, 95% CI = 1.01 to 1.02). CONCLUSIONS: This meta-analysis revealed that obesity may be a risk factor for bladder cancer recurrence.

The association of rs710886 in lncRNA PCAT1 with bladder cancer risk in a Chinese population.

OBJECTIVE: The long noncoding RNA PCAT1 is an important gene involved in urinary tumors. In this study, we aimed to explore the association between polymorphisms in PCAT1 and bladder cancer susceptibility. METHODS: A two-stage case-control study was conducted to assess the association between four tagging SNPs (i.e., rs4871771, rs1902432, rs16901904 and rs710886) and bladder cancer risk. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with unconditional univariate and multivariate logistic regression. RESULTS: At the first stage of discovery, we identified that SNP rs710886A>G was significantly associated with bladder cancer risk (OR=0.86, 95% CI=0.74-0.99, P=0.046). At the following stage of validation, individuals with GG genotype were found to have a significant reduction in bladder cancer risk compared with those carrying AA genotype (adjusted OR=0.83, 95% CI=0.74-0.93, P=0.001). Furthermore, stratified analyses showed that protective effect of rs710886 was more pronounced in subgroup of age>60 and never smoking, and had little to do with sex. Besides, rs710886 was identified as an eQTL for PCAT1. G allele was consistent with lower PCAT1 expression. CONCLUSION: This study indicates that genetic variants in lncRNA PCAT1 were associated with bladder cancer susceptibility and the SNP rs710886 may act as a potential biomarker for bladder cancer risk.

KCNMA1 cooperating with PTK2 is a novel tumor suppressor in gastric cancer and is associated with disease outcome.

BACKGROUND: Inactivation of tumor suppressor genes by promoter hypermethylation plays a key role in the tumorgenesis. It is necessary to uncover the detailed pattern of whole genome-wide abnormal DNA methylation during the development of gastric cancer (GC). METHOD: We performed a genome-wide methylation detection using 12 paired of GC tissues and their corresponding normal tissues. Methylation-specific PCR (MSP) and bisulphite sequencing (BSP) were used to measure methylation status of specific CpG site. Based on the bioinformatic analysis, the cell phenotypes and mouse model experiments were constructed to detect effect of the target gene. Using the Kaplan-Meier survival curve, the clinical value of KCNMA1 was assessed in GC patients. RESULTS: The CpG site cg24113782 located at the promoter of KCNMA1 showed the most significant difference, contributing to the commonly silenced KCNMA1in gastric cancer cells and primary GC tissues. The promoter methylation of KCNMA1 was detected in 68.7% (77/112) of tumor tissues, compared with 16.2% (18/112) of normal tissues (P < 0.001). The survival curve indicated that KCNMA1 hypermethylation was significantly associated with the shortened survival in GC patients (P = 0.036). KCNMA1 significantly inhibited biological malignant behavior of gastric cancer cell by inducing cell apoptosis in vitro, and suppressed xenograft tumor growth in subcutaneous mouse models (both P < 0.001). Furthermore, the anti-tumor effect of KCNMA1was mediated through suppressing the expression of PTK2. CONCLUSION: KCNMA1 is a critical tumor suppressor in gastric carcinogenesis and its hypermethylation is an independent prognostic factor in patients with gastric cancer.