Esophageal Cancer Susceptibility Research Articles

Associations of long non-coding RNAs HOTAIR, LINC00951, POLR2E and HULC polymorphisms with the risk of esophageal and esophagogastric junction cancer in a western population: a case-control study

BackgroundThe incidence of single-nucleotide-polymorphisms with malignant potential in esophageal cancer tissues has only been sparsely investigated in the west. Hence, we explored the contribution of four long non-coding RNAs’ polymorphisms HOTAIR rs920778, LINC00951 rs11752942, POLR2E rs3787016 and HULC rs7763881 in esophageal cancer susceptibility.Methods and resultsFormalin-fixed paraffin-embedded tissue specimens from 95 consecutive patients operated for esophageal/esophagogastric junction carcinoma during 25/03/2014-25/09/2018 were processed. Demographic data, histopathological parameters, surgical and oncological outcomes were collected. DNA findings of the abovementioned population were compared with 121 healthy community controls. Both populations were of European/Greek ancestry. Sixty-seven patients underwent Ivor Lewis/McKeown esophagectomy for either squamous cell esophageal carcinoma (N = 6) or esophageal/esophagogastric junction Siewert I or II adenocarcinoma (N = 61). Twenty-eight patients were subjected to extended total gastrectomy for esophagogastric junction Siewert III adenocarcinoma. Neither LINC00951 rs11752942 nor HULC rs7763881 polymorphisms were detected more frequently in esophageal cancer patients compared with healthy community subjects. A significantly higher presence of HOTAIR rs920778 TT genotype in esophagogastric junction Siewert I/II adenocarcinoma was identified. POLR2E rs3787016 C allele and CC genotypes were overrepresented in the control group, and when found in esophageal cancer carriers were associated with earlier disease stages, as well as with minor lymph node involvement and lesser metastatic potential.ConclusionsHOTAIR rs920778 may serve as a potential therapeutic suppression target, while POLR2E rs3787016 may represent a valuable biomarker to evaluate esophageal cancer predisposition and predict treatment response and prognosis. Clinical implications of these findings need to be verified with further prospective studies with larger sample-size.

Mendelian randomization analysis of atopic dermatitis and esophageal cancer in East Asian and European populations

BackgroundEmerging observational studies showed an association between atopic dermatitis (AD) and gastrointestinal cancers. However, it remains unclear whether this association is causal, particularly in the case of cancers like esophageal cancer, which exhibit ancestral genetic traits. MethodsTo assess the potential causal relationship between AD and esophageal cancer across diverse ancestral backgrounds, we conducted a 2-sample Mendelian randomization study. Independent genetic instruments for AD from the FinnGen consortium (N case = 7024 and N control = 198 740), BioBank Japan (N case = 2385 and N control = 209 651) and Early Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium (N case = 18 900 and N control = 84 166, without the 23andMe study) were used to investigate the association with esophageal cancer in the UK Biobank study (N case = 740 and N control = 372 016) and BioBank Japan esophageal cancer sample (N case = 1300 and N control = 197 045). ResultsWhen esophageal cancer extracted from East Asian ancestry was used as a outcome factor, AD data extracted from BioBank Japan (OR = 0.90, 95% CI: 0.83–0.98), FinnGen consortium (OR = 0.86, 95% CI: 0.77–0.96), and EAGLE consortium (OR = 0.92, 95% CI: 0.81–1.06) were negatively associated with esophageal cancer susceptibility. However, AD as a whole did not show an association with esophageal cancer from European ancestry. ConclusionThis study provides support for a causal relationship between AD and esophageal cancer in East Asian populations but not between AD and esophageal cancer from European ancestry. The specific associations between esophageal cancer and AD appear to exhibit significant disparities between the East Asian and European regions.

The Single Nucleotide Polymorphisms rs4143370 and rs34904192 in MIR155HG Were Associated with Esophageal Cancer Risk in the Chinese Han Population

Introduction: MIR155HG has been found to play an important role in malignant tumors, but little research has been done on its association with esophageal cancer (ESCC). The aim of this study was to investigate the relationship between MIR155HG polymorphisms and ESCC susceptibility in the Chinese Han population. Methods: 511 ESCC patients and 487 healthy controls were selected for this study. All subjects were genotyped using the Agena MassARRAY platform. We assessed the association between seven single nucleotide polymorphisms (SNPs) of the MIR155HG and ESCC risk by genetic model analysis. The false discovery rate (FDR) test and Bonferroni correction were usually used to detect false positives for the results. Meanwhile, the interaction between SNPs was analyzed by multifactor dimensionality reduction software to predict the ESCC risk. Results: The C allele of rs4143370 and the A allele of rs34904192 in MIR155HG can increase the risk of ESCC (odds ratio (OR) = 1.33, p = 0.024; OR = 1.30, p = 0.013). Furthermore, rs4143370 and rs34904192 were associated with an increased risk of ESCC. Stratified analysis showed that MIR155HG SNPs (rs4143370 and rs34904192) significantly increased ESCC risk in males. MIR155HG SNPs (rs4143370, rs34904192, and rs928883) were also strongly associated with an increased risk of ESCC in people aged >64 years. In addition, haplotype analysis of the seven SNPs of the MIR155HG showed that the CC haplotype was associated with ESCC risk (OR = 1.34, p = 0.024). Conclusion: This study revealed that MIR155HG SNPs were associated with an increased risk of ESCC. The results provided clues for clarifying the role of MIR155HG in ESCC.

Association Between CYP1A1 Polymorphisms and Esophageal Cancer Susceptibility: A Case-control Study.

Environmental and genetic factors (such as polymorphisms) contribute to the development of esophageal cancer (EC), but the disease's molecular genetic markers are not fully understood. The purpose of this study was to investigate previously unstudied cytochrome P450 (CYP)1A1 polymorphisms (rs2606345, rs4646421 and rs4986883) in EC. We performed real-time polymerase chain reaction (qPCR) to identify CYP1A1 polymorphisms (rs2606345, rs4646421, and rs4986883) in 100 patients and 100 controls. Smoking and tandoor fumes were significantly higher in all EC and esophageal squamous cell carcinoma (ESCC) patients compared to the control group (p<0.0001). The risk of EC was two-fold higher in hot tea drinkers compared to non-drinkers, but this factor was not significant for ESCC or esophageal adenocarcinoma (EAC) (p>0.05). The rs4986883 T>C polymorphism was not found in our population. The rs2606345 C allele was significantly associated with EC risk in men, and C-carriers who drank hot black tea had a nearly threefold higher risk of EC than non-drinkers. In addition, EC risk in hot black tea drinkers was approximately 12 times higher in rs4646421 A carriers than in non-A carriers, and approximately 17 times higher in the presence of both rs2606345 C allele and rs4646421 A allele. Furthermore, the rs2606345 AA genotype may act as a protective factor for the rs4646421 GG genotype. Among the CYP1A1 polymorphisms, rs2606345 may increase the risk of EC only in men. The risk of EC in hot tea drinkers may increase in the presence of rs4986883 and rs2606345 polymorphisms.

Genetic polymorphisms in LINC-PINT are correlated with esophageal cancer susceptibility in the Hainan Han population

Genetic polymorphisms in LINC-PINT are correlated with esophageal cancer susceptibility in the Hainan Han population

Association of GSTP1 and PLCE1 gene polymorphisms with primary esophageal cancer

To assess the association of polymorphisms of glutathione S-transferase P1 (GSTP1) and phospholipase C epsilon-1 (PLCE1) genes with the susceptibility of primary esophageal cancer and their interaction with environmental factors. 162 patients with primary esophageal cancer and 162 healthy controls were recruited in this cross-sectional study. Basic information such as gender, age, history of smoking and alcohol consumption and family history of esophageal cancer were collected. Single nucleotide polymorphisms at A105G locus of GSTP1 gene and rs3765524, rs2274223 and rs3781264 loci of PLCE1 gene were detected. A logistic regression model was established to analyze the risk factors of esophageal cancer and the interaction among the factors. The proportions of individuals with smoking history, family history of esophageal cancer and hot diet in esophageal cancer group were higher than those in the control group (P<0.05). Conditional Logistic regression analysis showed that smoking, family history of esophageal cancer and GG genotype at the rs2274223 locus of PLCE1 gene were the risk factors for esophageal cancer (P<0.05), and AG/GG genotypes at the A105G locus of GSTP1 gene were the protective factors for esophageal cancer (P<0.05). In the two-factor interaction model, both AA genotype at A105G locus of GSTP1 gene and GG genotype at rs2274223 locus of PLCE1 gene had an interaction with smoking, and the risk of esophageal cancer has increased by 83.6% and 85.7%, respectively (P<0.05). AA genotype at A105G locus of GSTP1 gene, GG genotype at rs2274223 locus of PLCE1 gene and smoking constituted the best three-factor interaction model, and the risk of esophageal cancer has increased by 244.0% (P<0.05). Four-factor interaction model analysis showed that the risk of esophageal cancer among individuals with AA genotype at A105G locus of GSTP1 gene, GG genotype at rs2274223 locus of PLCE1 gene, smoking and family history of esophageal cancer has increased by 264.4% (P<0.05). The AG and GG genotypes at the A105G locus of GSTP1 gene are protective factors for esophageal cancer, and the GG genotype at rs2274223 locus of PLCE1 gene is a risk factor, both of them may interact with smoking and affect the susceptibility to esophageal cancer.

Contribution of ZBTB20 Polymorphisms to Esophageal Cancer Risk Among the Chinese Han Population.

BackgroundZBTB20 was overexpressed in esophageal cancer (EC). The study aimed to identify genotypes of ZBTB20 polymorphisms and their correlation with EC occurrence in a Chinese Han population.MethodsFour single nucleotide polymorphisms (SNPs) in ZBTB20 were randomly selected for genotyping through Agena MassARRAY system among 525 EC patients and 522 healthy controls. Multiple genetic models were applied to assess the association of ZBTB20 polymorphisms with EC susceptibility by calculating odds ratios (ORs) with 95% confidence intervals (CIs).ResultsRs10934270 was associated with lower EC susceptibility (OR = 0.64, p = 0.004) with statistical power >90% in overall analysis. Specifically, the correlation of rs10934270 with EC susceptibility was found in subgroups including patients with esophageal squamous cell carcinoma (ESCC), males, subjects aged ≤65 years, subjects with BMI ≤ 24 kg/m2, and smokers. Rs9841504 might be a risk-increasing factor for ESCC. Moreover, rs9288999 in subjects aged ≤65 years and rs73230612 in females were related to lower EC risk.ConclusionOur research is the first to report that ZBTB20 rs10934270 is associated with reduced EC susceptibility in the Chinese Han population. These data provide a scientific basis for understanding the influence of the ZBTB20 gene on EC occurrence.

Tryptophan Metabolites as Biomarkers for Esophageal Cancer Susceptibility, Metastasis, and Prognosis.

BackgroundPerturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.MethodA total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.ResultsLevels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively).ConclusionThis study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.

Association between XPD Lys751Gln polymorphism and esophageal cancer susceptibility in China: a meta-analysis based on 12 case-control studies

Abstract Many studies have analyzed the relation about xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism on esophageal cancer risk; however, the results were inconclusive. The present study was designed to assess the relationship in China. We searched the relevant articles from the databases of PubMed, Springer Link, Ovid, Chinese Wanfang Database, CNKI and Chinese Biology Medicine up to December 2019. An OR with the corresponding 95%CI was adopted to evaluate this association. This meta-analysis included 12 studies with 4195 esophageal cancer cases and 4762 controls. Overall, a positive association between XPD Lys751Gln and esophageal cancer risk was found in all the analysis model (Gln vs. Lys, OR= 1.26, 95% CI= 1.14-1.44; Gln/Gln vs. Lys/Lys, OR= 1.73, 95% CI= 1.29-2.31; Gln/Gln vs. Lys/Lys + Asp/Asn, OR= 1.63, 95% CI= 1.22-2.18; Gln/Gln+ Asp/Asn vs. Lys/Lys, OR= 1.25, 95% CI= 1.13-1.39). Subgroup analyses by geographic area and source of controls were further conducted; there was no substantial change in subgroup analyses. Our study suggested that XPD Lys751Gln polymorphism could increase the risk of esophageal cancer in China. Further studies in other ethnic populations are wanted to confirm these conclusions.

THYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND SUSCEPTIBILITY TO ESOPHAGEAL CANCER: A CASE-CONTROL STUDY.

ABSTRACTBACKGROUND:The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer.AIMS:This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival.METHODS:A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer.RESULTS:There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02–4.83).CONCLUSIONS:There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.

PCR-RFLP genotyping analysis of TP53 Arg72Pro polymorphism and susceptibility to esophageal cancer in Pakistani population

Background and objectiveTumor suppressor gene TP53 is necessary for prevention of inappropriate cell proliferation and maintenance of genome integrity. TP53 Arg72Pro is the most studied single nucleotide polymorphism (SNP) associated with different cancers including esophageal cancer (EC). The study was established to investigate relationship between Arg72Pro polymorphism and EC susceptibility. Materials and methodsDNA from a total of 200 individuals (100 EC patients and 100 controls) were genotyped for TP53 codon 72 (Arg72Pro) polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression was used to estimate odds ratios and 95% confidence interval. ResultsSignificant differences in genotypes of Arg72Pro polymorphism between cases and controls were observed (P < 0.05). The patients represented 34% Pro/Pro, 44% Arg/Pro and 22% Arg/Arg whereas controls had 19% Pro/Pro, 42% Arg/Pro and 39% Arg/Arg genotypes. Pro/Pro variant showed 3.17-fold (95% CI: 1.47–6.83, P = 0.003) and Arg/Pro 1.71-fold (95% CI: 0.85–3.45, P = 0.071) increased EC risk compared with Arg/Arg. The Pro/Pro genotype was found to be significantly, whereas Arg/Pro was non-significantly associated with the esophageal cancer risk. Both males and females with Pro/Pro genotype were highly susceptible to cancer. Preserved meat consumers with Pro/Pro genotype were 4.8 fold (95% CI: 1.7–13.8) and subjects aged >50 with Pro/Pro were 4.6 fold (95% CI: 1.8–11.8) at increased risk of esophageal cancer. ConclusionsOur study suggests that Pro72 variant of TP53 polymorphism is highly correlated with increased EC. Further, the interaction between this polymorphism and tobacco consumption significantly affected EC development in Pakistani population.

TP53 Intronic Polymorphisms and Risk of Esophageal Cancer in Southern Thai Population

Objective: The study aimed to determine the frequency of intron 3 16 base pair (bp) duplication polymorphism and intron 6 G to C substitution (G&gt;C) of the TP53 gene and to evaluate the association these two intronic variants with the risk of esophageal cancer (EC).Material and Methods: A case-control study was conducted to evaluate the frequency and association of cancer. Cases were patients with squamous cell carcinoma of esophagus and controls were age and sex-matched non-cancer patients. Blood samples were also obtained from healthy blood donors. Polymerase chain reaction (PCR) was used to detect intron 3 16 bp duplication and PCR-restriction fragment length polymorphism was applied to detect intron 6 G&gt;C. Logistic regression was used for the analysis.Results: Heterozygous intron 3 16 bp duplication (Del/Ins) was found in 10.1% (31/308) of blood donors, 9.3% (28/302) of controls and 8.6% (26/301) of EC cases. Intron 6 G&gt;C was found in 0.3% (1/308) of blood donors, in 2.6% (8/310) of controls and 3.9% (12/307) of EC cases. Both variants displayed no significant association with risk of esophageal cancer (odd ratio (OR) = 1.16 [95% confidence interval (CI) = 0.64–2.11] for intron 3 16 bp duplication and OR = 0.81 [95% CI = 0.47-4.61] for intron 6 G&gt;C.Conclusion: Southern Thai population have low frequency of intron 3 16 bp duplication polymorphism and intron 6 G&gt;C variant, both of which are not likely to be associated with esophageal cancer susceptibility.

Polymorphisms of matrix metalloproteinases affect the susceptibility of esophageal cancer: Evidence from 20412 subjects, systematic review and updated meta-analysis.

The results of how matrix metalloproteinases (MMPs) polymorphisms affect esophageal cancer (EC) risk are not consistent, especially for MMP1,2,7 and 9. A meta-analysis focused on the impact of MMPs to digestive cancers, but not a precise analysis to EC, therefore, we designed the current study to make a clear understanding of the association between MMPs polymorphisms and EC. Up to March 2020, we searched several databases to find case-control cohorts concerned about the risk of MMPs polymorphisms to EC risk. Odds ratios with 95% confidence intervals under five genetic models to generate the risk predicted value. The Q test and I2 statistics are used to estimate heterogeneity. Sensitivity analysis, Egger test, and Begg's funnel plot were employed to assess the results. In-silico analysis was performed to study the association between the polymorphism and mRNA expression. 19 case-control studies were enrolled, including 8371 EC patients and 12041 health controls. We observed the increased risk in BA vs. AA and BB + BA vs. AA models of MMP1-rs1799750 polymorphism. The protective effectiveness of EC was found in the MMP2 rs243865 polymorphism in B vs. A, BA vs. AA, and BB + BA vs. AA models. Meanwhile, the risk effect was also observed in the MMP7 rs11568818 polymorphism in most genetic models. In the furthermore bioinformatics analysis, we found that MMP1, MMP3, MMP7, MMP9, MMP12, MMP13 all increased in the tumor tissues, and the genetic alteration in the polymorphisms could impact the mRNA expression of the above MMPs. MMP1 rs1799705 and MMP7 rs1156818 polymorphisms will take part in the tumorigenesis of EC, while MMP2 rs243865 acts as a protective role to decrease the risk of EC.

Evaluation of TP53 codon 72 polymorphism in esophageal cancer susceptibility in Eastern Anatolia Region of Turkey

Evaluation of TP53 codon 72 polymorphism in esophageal cancer susceptibility in Eastern Anatolia Region of Turkey

Genetic variants in GHR and PLCE1 genes are associated with susceptibility to esophageal cancer.

BackgroundEsophageal cancer (EC) is the leading cause of cancer‐related mortality worldwide. The underlying genetic risk factors remain unclear. The association between gene growth hormone receptor (GHR) and phospholipase C epsilon 1 (PLCE1) polymorphisms and the EC risk were identified in this study.MethodsA total of 506 EC cases and 507 controls were included in this research. Two SNPs (rs6898743 of GHR and rs2274223 of PLCE1) were selected and genotyped. The associations between gene polymorphisms and the EC risk were assessed by logistic regression analysis. The databases RegulomeDB, GTEx, and UALCAN were used for functional annotations.ResultsIn the allelic frequencies analysis, the rs6898743 of GHR was associated with decreased susceptibility of EC (OR = 0.83, 95% CI: 0.70–1.00, p = 0.049), while rs2274223 of PLCE1 was associated with increased 0.25‐fold EC risk (OR = 1.25, 95% CI: 1.02–1.53, p = 0.037). The “GC” genotype of rs6898743 was associated with a 0.24‐fold decreased risk of EC under co‐dominant model (OR = 0.76, 95% CI: 0.58–0.99, p = 0.046), and the “GA” genotype of rs2274223 was associated with increased EC risk under co‐dominant model (OR = 1.36, 95% CI: 1.04–1.77, p = 0.023). Using GTEx database, rs2274223 was found to be significant associated with increased PLCE1 expression (p = 4.1 × 10−7) in esophagus muscularis. The UALCAN database demonstrated that the GHR gene was under‐expressed in esophageal cancer tissues (p = 0.017).ConclusionThe gene GHR and PLCE1 polymorphisms are associated with EC in the general population and the results need to be verified in future.

IL-1B rs2853550 polymorphism contributes to esophageal cancer susceptibility in Chinese Han population of Northwest China

BackgroundEsophageal cancer (EC) is one of the most common human cancers, with a particularly aggressive behavior and increased incidence worldwide. The aim of this study was to assess the associations of single-nucleotide polymorphisms (SNPs) in IL-1B with the risk of EC in a northwest Chinese Han population.MethodsIn order to evaluate the correlations between IL-1B polymorphisms and EC risk, an Agena MassARRAY platform was used to determine the genotype of the candidate SNPs among 384 EC patients and 499 controls. The associations between IL-1B variants and EC risk were examined using logistic regression analysis with adjustment for gender and age. Haplotype construction and analysis were performed to detect the potential associations between haplotypes within IL-1B and EC susceptibility. Additionally, bioinformatics databases were used for gene expression analysis and SNP functional prediction.ResultsA significant relationship was found between IL-1B rs2853550 and an increased risk of EC in the allele model [odds ratio (OR) = 1.38, 95% confidence interval (95% CI): 1.01–1.89, p = 0.041), the codominant model (A/G, OR = 1.63, 95% CI: 1.10–2.42, p = 0.011), and the dominant model (OR = 1.49, 95% CI: 1.02–2.18, p = 0.041). Functional analysis revealed the potential effects of rs2853550, which further reinforced its influence on EC susceptibility. However, there were no statistically significant differences for other SNPs or haplotypes between EC cases and healthy controls. Expression analysis conducted with dataset indicated that the expression level of IL-1B was higher in EC cases than that in normal samples.ConclusionsThis study demonstrated that rs2853550 in IL-1B might increase EC susceptibility in the Chinese Han population of Northwest China.

Hypomethylation-Linked Activation of PLCE1 Impedes Autophagy and Promotes Tumorigenesis through MDM2-Mediated Ubiquitination and Destabilization of p53.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignant diseases. Multiple studies with large clinic-based cohorts have revealed that variations of phospholipase C epsilon 1 (PLCE1) correlate with esophageal cancer susceptibility. However, the causative role of PLCE1 in ESCC has remained elusive. Here, we observed that hypomethylation-mediated upregulation of PLCE1 expression was implicated in esophageal carcinogenesis and poor prognosis in ESCC cohorts. PLCE1 inhibited cell autophagy and suppressed the protein expression of p53 and various p53-targeted genes in ESCC. Moreover, PLCE1 decreased the half-life of p53 and promoted p53 ubiquitination, whereas it increased the half-life of mouse double minute 2 homolog (MDM2) and inhibited its ubiquitination, leading to MDM2 stabilization. Mechanistically, the function of PLCE1 correlated with its direct binding to both p53 and MDM2, which promoted MDM2-dependent ubiquitination of p53 and subsequent degradation in vitro. Consequently, knockdown of PLCE1 combined with transfection of a recombinant adenoviral vector encoding wild-type p53 resulted in significantly increased levels of autophagy and apoptosis of esophageal cancer in vivo. Clinically, the upregulation of PLCE1 and mutant p53 protein predicted poor overall survival of patients with ESCC, and PLCE1 was positively correlated with p53 in ESCC cohorts. Collectively, this work identified an essential role for PLCE1- and MDM2-mediated ubiquitination and degradation of p53 in inhibiting ESCC autophagy and indicates that targeting the PLCE1-MDM2-p53 axis may provide a novel therapeutic approach for ESCC. SIGNIFICANCE: These findings identify hypomethylation-mediated activation of PLCE1 as a potential oncogene that blocks cellular autophagy of esophageal carcinoma by facilitating the MDM2-dependent ubiquitination of p53 and subsequent degradation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2175/F1.large.jpg.

Genetic variations of CARMN affect risk of esophageal cancer in northwest China.

As one of the common malignant tumors, esophageal cancer has significant heterogeneity in morbidity and mortality between gender, geographic distribution, race and histology. We used single nucleotide polymorphism (SNP) to identify disease-related alleles, and to explore the relationship between gene variations and esophageal cancer susceptibility in northwest China. Six candidate SNPs (rs13177623, rs12654195, rs11168100, rs353303, rs353300, rs353299) selected from cancer related gene Cardiac mesoderm enhancer-associated non-coding RNA (CARMN) were genotyped by Agena MassARRAY platform. SPSS 18.0 software was used for logistic regression analysis of genotyping results, and Haploview 4.2 software was utilized for linage disequilibrium (LD) analysis. We observed a significant association between genotype TT of rs353299 and the decreasing esophageal cancer risk (OR=0.42, 95% CI=0.18-0.97, p=0.042). The stratified analysis revealed that the influence of three CARMN polymorphisms (rs11168100, rs353300 and rs353299) on esophageal cancer risk is age-, gender-, smoking-, drinking- and lymph node metastasis status- dependent (p<0.05). Haplotype analysis results indicated that Trs11168100Ars353303Trs353300Crs353299 acts as a protective factor of esophageal cancer with OR of 0.71 (95% CI=0.52-0.98, p=0.038), while Ars11168100Grs353303Crs353300 and Ars11168100Ars353303 have 1.49-fold (OR=1.49, 95% CI=1.02-2.19, p=0.041) and 1.57-fold (OR=1.57, 95% CI=1.05-2.35, p=0.027) increased risk of esophageal cancer, respectively. The results of our study suggested that CARMN variations may affect the risk of esophageal cancer.

Cumulative Evidence for Associations between Genetic Variants and Risk of Esophageal Cancer.

A large number of studies have been conducted to investigate associations between genetic variants and esophageal cancer risk in the past several decades. However, findings from these studies have been generally inconsistent. We aimed to provide a summary of the current understanding of the genetic architecture of esophageal cancer susceptibility. We performed a comprehensive field synopsis and meta-analysis to evaluate associations between 95 variants in 70 genes or loci and esophageal cancer risk using data from 304 eligible publications, including 104,904 cases and 159,797 controls, through screening a total of 21,328 citations. We graded levels of cumulative epidemiologic evidence of a significant association with esophageal cancer using the Venice criteria and false-positive report probability tests. We constructed functional annotations for these variants using data from the Encyclopedia of DNA Elements Project and other databases. Thirty variants were nominally significantly associated with esophageal cancer risk. Cumulative epidemiologic evidence of a significant association with overall esophageal cancer, esophageal squamous cell carcinoma, or esophageal adenocarcinoma was strong for 13 variants in or near 13 genes (ADH1B, BARX1, CDKN1A, CHEK2, CLPTM1L, CRTC1, CYP1A1, EGF, LTA, MIR34BC, PLCE1, PTEN, and PTGS2). Bioinformatics analysis suggested that these variants and others correlated with them might fall in putative functional regions. Our study summarizes the current literature on the genetic architecture of esophageal cancer susceptibility and identifies several potential polymorphisms that could be involved in esophageal cancer susceptibility. These findings provide direction for future studies to identify new genetic factors for esophageal cancer.

Correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility: An updated meta-analysis.

BackgroundThe aim of this study was to investigate the correlation between MDM2 T309G single nucleotide polymorphism (SNP) and esophageal cancer susceptibility through pooling the open published data.MethodsBy systematic searching the databases of Medline, EMBASE, CBM and CNKI, the case‐control or cohort studies related to MDM2 T309G single nucleotide polymorphism and esophageal cancer risk were screened. Genetic phenotype data of T309G single nucleotide was extracted from the original included studies. The correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility was demonstrated by the odds ratio (OR) and its corresponding 95% confidence interval (95% CI). Publication bias was investigated by Egger's line regression test and begg's funnel plot.ResultsAfter systematic searching of the relevant database, nine publications were finally included in the present study. The combined data demonstrated that the subjects with the G genotype had an increased risk of developing esophageal cancer in dominant (OR = 1.13, 95% CI: 1.00–1.27, P = 0.043), recessive (OR = 1.27, 95% CI: 1.12–1.45, P = 0.000) and homozygous (OR = 1.34, 95% CI:1.04–1.74, P = 0.024) genetic model through random or fixed data pooling method. Both begg's and Egger's line regression test indicated no significant publication bias.ConclusionBased on the present data, there was a significant correlation between MDM2 T309G single nucleotide polymorphism and esophageal cancer susceptibility. Individuals with G genotype may have an increased risk of developing esophageal cancer.