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author:("Yang, jingmen")
1.  Pri-miR-124 rs531564 and pri-miR-34b/c rs4938723 Polymorphisms Are Associated with Decreased Risk of Esophageal Squamous Cell Carcinoma in Chinese Populations 
PLoS ONE  2014;9(6):e100055.
MicroRNAs are a new class of small non-protein-coding RNAs that sometimes function as tumor suppressors or oncogenes. Aberrant expression and structural alteration of microRNAs have been reported to be involved in tumorigenesis and cancer development. Recently, rs531564/pri-miR-124-1, rs4938723/pri-miR-34b/c, rs7372209/pri-miR-26a-1, rs895819/pre-miR-27a, and rs11134527/pri-miR-218 were reported to be associated with risks of various cancers. In order to evaluate the relationship of these SNPs and esophageal squamous cell carcinoma (ESCC) risk, we conducted a case-control study with 1109 ESCC patients and 1275 control subjects to examine the potential association of these pri/pre-miRNA polymorphisms with ESCC susceptibility. As a result, two SNPs were associated with a significant risk of ESCC. We found that the GG genotype of pri-miR-124-1 rs531564 was associated to a significantly decreased risk of ESCC comparing with the CC/CG genotypes (p = 0.005; OR = 0.61, 95% CI = 0.43–0.86). In addition, the CC genotype of pri-miR-34b/c rs4938723 was associated with a significant decreased risk of ESCC (CC VS. TT/TC: p = 0.007, OR = 0.82, 95% CI = 0.71–0.95) in Chinese population. The present study provides the first evidence that pri-miR-124-1 rs531564 and pri-miR-34 rs4938723 were associated with the risk of ESCC in Chinese population.
PMCID: PMC4063769  PMID: 24945256
2.  GWAS Identifies Novel Susceptibility Loci on 6p21.32 and 21q21.3 for Hepatocellular Carcinoma in Chronic Hepatitis B Virus Carriers 
PLoS Genetics  2012;8(7):e1002791.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Author Summary
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
PMCID: PMC3395595  PMID: 22807686
3.  Potentially Functional Variants of PLCE1 Identified by GWASs Contribute to Gastric Adenocarcinoma Susceptibility in an Eastern Chinese Population 
PLoS ONE  2012;7(3):e31932.
Recent genome-wide association studies (GWAS) have found a single nucleotide polymorphism (SNP, rs2274223 A>G) in PLCE1 to be associated with risk of gastric adenocarcinoma. In the present study, we validated this finding and also explored the risk associated with another unreported potentially functional SNP (rs11187870 G>C) of PLCE1 in a hospital-based case-control study of 1059 patients with pathologically confirmed gastric adenocarcinoma and 1240 frequency-matched healthy controls.
Methodology/Principal Findings
We determined genotypes of these two SNPs by the Taqman assay and used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that a significant higher gastric adenocarcinoma risk was associated with rs2274223 variant G allele (adjusted OR = 1.35, 95% CI = 1.14–1.60 for AG+GG vs. AA) and rs11187870 variant C allele (adjusted OR = 1.26, 95% CI = 1.05–1.50 for CG+CC vs. GG). We also found that the number of combined risk alleles (i.e., rs2274223G and rs11187870C) was associated with risk of gastric adenocarcinoma in an allele-dose effect manner (Ptrend = 0.0002). Stratification analysis indicated that the combined effect of rs2274223G and rs11187870C variant alleles was more evident in subgroups of males, non-smokers, non-drinkers and patients with gastric cardia adenocarcinoma. Further real-time PCR results showed that expression levels of PLCE1 mRNA were significantly lower in tumors than in adjacent noncancerous tissues (0.019±0.002 vs. 0.008±0.001, P<0.05).
Our results further confirmed that genetic variations in PLCE1 may contribute to gastric adenocarcinoma risk in an eastern Chinese population.
PMCID: PMC3295761  PMID: 22412849
4.  Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance 
Neuro-Oncology  2010;12(7):679-686.
Aberrant activation of the translesion DNA synthesis (TLS) pathway has been suggested to play a role in tumorigenesis by promoting genetic mutations. We therefore examined glioma specimens for the expression of specialized DNA polymerases involved in TLS and assessed their prognostic significance. The expression levels of DNA polymerase κ (Pol κ), Pol ι, and Pol η were assessed in 40 primary glioma samples and 10 normal brain samples using quantitative real-time PCR and Western blot analysis. Their prognostic significance was evaluated using a population-based tissue microarray derived from a cohort of 104 glioma patients. Overexpression of Pol κ and Pol ι was observed in 57.5% (23–40) and 27.5% (11–40) of patients, respectively, whereas no significant expression of Pol η was seen in the specimens. Immunohistochemical studies revealed positive Pol κ and Pol ι staining in 72 (69.2%) and 33 (31.7%) of the 104 glioma specimens, respectively. Pol κ expression was associated with advanced stages of the disease. Both Pol κ– and Pol ι–positive staining were associated with shorter survival in glioma patients (P < .001 and P = .014, respectively). A multivariate survival analysis identified Pol κ as an independent prognostic factor for glioma patients (P < .001). These findings demonstrate, for the first time, that the expression of Pol κ and Pol ι is deregulated in gliomas, and upregulation of Pol κ is associated with poorer prognosis in glioma patients.
PMCID: PMC2940659  PMID: 20164241
glioma; mutagenesis; prognosis; specialized polymerase; tumorigenesis
5.  REV3L confers chemoresistance to cisplatin in human gliomas: The potential of its RNAi for synergistic therapy 
Neuro-Oncology  2009;11(6):790-802.
The REV3L gene, encoding the catalytic subunit of human polymerase ζ, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of certain tumors. However, the role of REV3L in regulating the sensitivity of glioma cells to chemotherapy remains unknown. In this study, we investigated the expression of the REV3L gene in 10 normal brain specimens and 30 human glioma specimens and examined the value of REV3L as a potential modulator of cellular response to various DNA-damaging agents. Reverse transcriptase PCR/real-time PCR analysis revealed that REV3L was overexpressed in human gliomas compared with normal brain tissues. A glioma cell model with stable overexpression of REV3L was used to probe the role of REV3L in cisplatin treatment; upregulation of REV3L markedly attenuated cisplatin-induced apoptosis of the mitochondrial apoptotic pathway. We therefore assessed the REV3L-targeted treatment modality that combines suppression of REV3L expression using RNA interference (RNAi) with the cytotoxic effects of DNA-damaging agents. Downregulation of REV3L expression significantly enhanced the sensitivity of glioma cells to cisplatin, as evidenced by the increased apoptosis rate and marked alterations in the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax) expression levels, and reduced mutation frequencies in surviving glioma cells. These results suggest that REV3L may potentially contribute to gliomagenesis and play a crucial role in regulating cellular response to the DNA cross-linking agent cisplatin. Our findings indicate that RNAi targeting REV3L combined with chemotherapy has synergistic therapeutic effects on glioma cells, which warrants further investigation as an effective novel therapeutic regimen for patients with this malignancy.
PMCID: PMC2802399  PMID: 19289490
chemoresistance; cisplatin; glioma; REV3L; RNAi

Results 1-5 (5)