Haixia Zhu

A functional polymorphism in Pre-miR-146a is associated with susceptibility to gastric cancer in a Chinese population.

MicroRNAs play an important role in regulating gene expression at the post-transcriptional level and are involved in numerous physiological processes. Aberrant expression of MicroRNAs is considered to participate in occurrence and progression of human cancers. A G>C polymorphism, rs2910164, which is located in the sequence of miR-146a precursor, could alter mature miR-146a expression and has been suggested to influence cancer risk. The present study was aimed to investigate whether this polymorphism has effects on susceptibility to gastric cancer in the Chinese population. We genotyped the miR-146a rs2910164 polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with gastric cancer risk. We found a significant association between rs2910164 polymorphism and increased gastric cancer risk [p = 0.038, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56; GG vs. CC/CG]. Similar results were observed in a follow-up replication study. Combined data from the two studies generated a more significant association [p = 0.001, OR = 1.27, 95% CI = 1.10-1.46; GG vs. CC/CG]. Besides, the increased risk associated with the rs2910164GG genotype was more evident in younger subjects (OR = 1.51, 95% CI = 1.25-1.81) rather than in older subjects. Our results suggest that the rs2910164 polymorphism in the sequence of miR-146a precursor may influence the susceptibility to gastric cancer in our Chinese population.

The association analysis of lncRNA HOTAIR genetic variants and gastric cancer risk in a Chinese population.

The HOX transcript antisense intergenic RNA (HOTAIR), a well-known long noncoding RNA, is involved in pathogenesis and progress of multiple tumors. Its ectopic expression and biological functions have been observed in gastric cancer. In this study, we conducted a two-stage case-control study to evaluate whether genetic variations of HOTAIR were associated with gastric cancer risk. We identified that a single nucleotide polymorphism (SNP) rs4759314 was significantly associated with the increased gastric cancer risk with an odds ratio (OR) of 1.39 [95% confidence interval (CI) = 1.13–1.71, P = 0.002] in the combined sets. Further functional experiments revealed the allele-specific effects on HOTAIR and HOXC11 expressions in gastric cancer tissues, of which HOTAIR and HOXC11 expressions of individuals carrying with AG genotype were much higher than those with AA genotype; similarly, the effects occurred in intronic promoter activities, of which the promoter activity of G allele was more pronounced than that of A allele. Interestingly, we identified a novel potential oncogene HOXC11 in gastric cancer pathogenesis with differential expression in gastric cancer tissues by association analysis with candidate gene strategy. These results suggest that SNP rs4759314 of HOTAIR acts as a potential biomarker for predicting gastric cancer, and the role of HOXC11 in gastric cancer etiology is warranted to further investigation.

A Novel Functional Polymorphism C1797G in the MDM2 Promoter Is Associated with Risk of Bladder Cancer in a Chinese Population

Purpose: MDM2 is believed to regulate the p53 level in modulating DNA repair, cell cycle control, cell growth, and apoptosis. We hypothesize that genetic variants in the MDM2 gene are associated with risk of bladder cancer. Experimental Design: We first conducted a case-control study of 234 bladder cancer cases and 253 cancer-free controls, using the haplotype-based tagging single nucleotide polymorphism (SNP) approach involving 13 common SNPs initially identified in 100 control subjects. We then examined the functionality of the important SNP. Results: We found that the C1797G polymorphism in the MDM2 promoter region is an important SNP because its homozygous variant genotype, but none of the haplotypes, was associated with risk of bladder cancer. Electrophoretic mobility shift assay indicated that the 1797C to 1797G transition within the CAAT/enhancer binding protein α (C/EBP α) core sequence greatly enhanced the C/EBPα binding affinity to the promoter region. The in vitro luciferase assays in various cell lines further showed an increased transcriptional activity of the 1797G allele compared with the 1797C allele. Additional experiments with tumor tissues revealed that the transcriptional activator C/EBPα containing the 1797G allele increased levels of the MDM2 mRNA and protein in bladder tumor tissues. Conclusions: These data suggested that the novel MDM2 promoter C1797G polymorphism may affect the MDM2 activity by altering the C/EBPα binding affinity to the promoter and, thus, may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Further validation of the functionality of the MDM2 C1797G polymorphism and its association with risk of bladder and other cancers in other ethnic populations is warranted.

A functional polymorphism in MIR196A2 is associated with risk and prognosis of gastric cancer.

Genetic variations in miRNAs have been demonstrated to be capable of altering miRNA expression, consequently affecting many cancer‐related biological processes. The MIR196A2 rs11614913 (T > C) polymorphism has been reported to be associated with various cancers development and progression. In our study, we aim to explore whether this polymorphism is relevant to the genetic susceptibility and prognosis of gastric cancer in a Chinese population. We analyzed the correlations of rs11614913 polymorphism with gastric cancer susceptibility in test and validation sets. The test set comprised 749 cases and 900 controls, while the validation set enrolled 940 cases and 1046 controls. Moreover, we evaluated the association between the polymorphism and gastric cancer prognosis in the validation set with follow‐up information. The variant rs11614913 CC genotype was associated with a significantly reduced risk of gastric cancer in both sets (adjusted odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.62–0.99 for the test set and 0.64, 0.52–0.80 for the validation set) compared with the CT/TT genotypes. Furthermore, the CC genotype was associated with a significantly increased survival of gastric cancer compared with the CT/TT genotypes (adjusted hazard ratio [HR] = 0.72, 95% CI = 0.55–0.95), and the association was more prominent among patients with non‐cardia gastric cancer than those with cardia gastric cancer (adjusted HR = 0.57, 95% CI = 0.40–0.83 for NCGC and 1.00, 0.65–1.53 for CGC). Our results suggested that the genetic variation of MIR196A2 may play a role in gastric cancer tumorigenesis.

Clinical significance of SOD2 and GSTP1 gene polymorphisms in Chinese patients with gastric cancer

Excessive reactive oxygen species (ROS) accumulation is a common phenomenon in carcinogenesis. However, the rationale behind ROS involvement in gastric cancer is unclear. In this study, the authors investigated the clinical significance of the single nucleotide polymorphisms (SNPs) of 2 ROS metabolic process‐related genes: superoxide dismutase 2 (SOD2) and glutathione S‐transferase π (GSTP1).

Genetic variation of CTNNB1 gene is associated with susceptibility and prognosis of gastric cancer in a Chinese population

UNLABELLED Gastric cancer is the second leading cause of cancer-related death worldwide with a low 5-year survival (S5y) after initial diagnosis. Although aberrant Wnt/β-catenin (CTNNB1) signaling has been observed in multiple human cancers, there is no information on the role of CTNNB1 polymorphisms in gastric cancer risk and S5y. We performed a genetic association study to analyse the correlation between the five tagged SNPs (tSNPs) (rs4135385, rs1798808, rs1880481, rs11564465 and rs2293303) of CTNNB1 and gastric cancer risk and survival. A total of 944 patients with complete follow-up information and 848 cancer-free controls were enrolled in this study. The rs1880481 polymorphism was correlated with decreased risk of gastric cancer [AC/AA vs. CC: adjusted odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.63-0.91], whereas the three other SNPs showed opposite effect (AG/AA vs. GG: adjusted OR = 1.31, 95% CI = 1.08-1.57 for rs4135385; GG vs. AA/AG: 2.09, 1.02-4.28 for rs11564475; TT vs. CC/CT 4.87, 2.72-8.71 for rs2293303). We further investigated if these tSNPs were related to the S5y of gastric cancer, and the results displayed that only the SNP rs4135385 AG/AA genotypes were significantly associated with a favorable gastric cancer survival compared with the GG genotype [adjusted hazard ratio (HR) = 0.80, 95% CI = 0.66-0.97], and the association was more prominent among patients with non-cardia gastric cancer (NCGC) than those with cardia gastric cancer (CGC) (Log-rank P = 0.007 for NCGC and 0.417 for CGC). Our results indicated that the genetic variants of CTNNB1 could be used as predictors of gastric cancer susceptibility and prognosis.

A Polymorphism (rs2295080) in mTOR Promoter Region and Its Association with Gastric Cancer in a Chinese Population

Background As an imperative part of PI3K/Akt/mTOR pathway, mammalian target of rapamycin (mTOR) has been demonstrated to increase in gastric cancer cells and tumors. Our research explored the relationship between single nucleotide polymorphism (SNP) rs2295080 in mTOR promoter region and the risk of gastric cancer (GC). Methods Seven hundred and fifty-three (753) gastric adenocarcinoma patients and 854 matched healthy subjects were recruited in the cancer association study and 60 tissues were used to test the expression of mTOR. Unconditional logistic regression was selected to evaluate the association between the rs2295080 T>G polymorphism and GC risk. We then examined the functionality of this promoter genetic variant by luciferase assay and EMSA. Results Individuals with G allele had a 23% decreased risk of GC, comparing with those carrying T allele (adjusted OR = 0.77, 95% CI = 0.65–0.92). This protective effect of G allele stood out better in male group. Meanwhile, GC patients carrying TG/GG genotype also displayed a decreased mRNA level of mTOR (P = 0.004). In luciferase assay, T allele tended to enhance the transcriptional activity of mTOR with an approximate 0.5-fold over G allele. Furthermore, EMSA tests explained that different alleles of rs2295080 displayed different affinities to some transcriptional factor. Conclusion The mTOR promoter polymorphism rs2295080 was significantly associated with GC risk. This SNP, which effectively influenced the expression of mTOR, may be a new biomarker of early diagnosis of gastric cancer and a suitable indicator of utilizing mTOR inhibitor for treatment of GC.

Intron 3 Sixteen Base Pairs Duplication Polymorphism of P53 Contributes to Breast Cancer Susceptibility: Evidence from Meta-Analysis

Background P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive. Methods A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association. Results The overall results suggested that the variant genotypes were associated with a significantly increased breast cancer risk (Del/Ins vs Del/Del: OR = 1.18, 95% CI: 1.00–1.40; Ins/Ins vs Del/Del: OR = 1.42, 95% CI = 1.09–1.84; Ins/Ins+Del/Ins vs Del/Del: OR = 1.21, 95% CI = 1.03–1.41). When stratifying by sample size of studies, a significantly elevated risk was also observed among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). Conclusion These results suggested that the 16-bp duplication polymorphism of p53 may contribute to susceptibility to breast cancer. Additional well-designed large studies were required to validate this association in different populations.

A common genetic variation in the promoter of miR-107 is associated with gastric adenocarcinoma susceptibility and survival

BACKGROUND Global miRNA expression profile has been widely used to characterize human cancers. It is well established that genetic variants in miRNAs can modulate miRNA biogenesis and disease risk. METHODS Genome-wide miRNA microarray was employed for assessment of miRNA expression profile of gastric adenocarcinoma (GAC). The variants of significantly dysregulated miRNA were genotyped in test (715 cases and 804 controls) and validation (940 cases and 1050 controls) subject sets. RESULTS MiRNA microarray revealed that 12 miRNAs including miR-107 significantly dysregulated in GAC tissues. The sequencing of the promoter of miR-107 identified 3 SNPs (rs11185777, rs78591545, and rs2296616) with minor allele frequency (MAF)>5%. Analyzing their association with GAC risk and prognosis revealed that the C allele of rs2296616 (T>C) was significantly associated with the decreased risk of GAC among the test, validation and combined sets (TC/CC vs. TT, adjusted OR=0.39, 95% CI=0.31-0.49 for the combined set). However, the C allele was related to an unfavorable prognosis of Cardia GAC (CGAC) (adjusted HR=1.49, 95% CI=1.01-2.20). In vivo evidence showed that the individuals with the rs2296616C allele had lower miR-107 expression compared with the homozygous T allele carriers. CONCLUSION miR-107 is dysregulated in GAC pathogenesis and the SNP rs2296616 may play a role in the process.

Circulating MicroRNA-26a in Plasma and Its Potential Diagnostic Value in Gastric Cancer

Background In the past decades, a good deal of studies has provided the possibility of the circulating microRNAs (miRNAs) as noninvasive biomarkers for cancer diagnosis. The aim of our study was to detect the levels of circulating miRNAs in tissues and plasmas of gastric cancer (GC) patients and evaluate their diagnostic value. Methods Tissue samples were collected from 85 GC patients. Plasma samples were collected from 285 GC patients and 285 matched controls. Differentially expressed miRNAs were filtered with by Agilent Human miRNA Microarray and TaqMan low density array (TLDA) with pooled samples, followed by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation. Receiver operating characteristic (ROC) curves were structured to evaluate the diagnostic accuracy of the miRNAs. The plasma level of miR-26a in GC patients of different clinical stages was compared. Results Four miRNAs (miR-26a, miR-142-3p, miR-148a, and miR-195) revealed coincidentally decreased levels in tissue and plasma of the GC patients compared with controls, and ROC curves were constructed to demonstrate that miR-26a had a highest area under the ROC curve (AUC) of 0.882. Furthermore, miR-26a was stably detected in the plasma of GC patients with different clinical characteristics. Conclusion Plasma miR-26a may provide a novel and stable marker of gastric cancer.