Integrative GEO and Mendelian randomization analysis reveals transcriptomic and lipidomic features of esophageal adenocarcinoma

Issue Highlights

To decode the pathology of Alzheimer's disease (AD), this study employs multi-omics approaches and bioinformatics analyses to explore AD-associated differentially expressed genes (DEGs), dissect the underlying mechanisms, and thereby facilitate the identification of core genes as well as the development of targeted therapeutic strategies. Six independent AD datasets were collected from the Gene Expression Omnibus (GEO) database, and data were processed and normalized using the R software. The evaluation of relationships between differentially expressed genes (DEGs) and AD encompassed differential expression analysis, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR) analysis. Additionally, gene set enrichment analysis (GSEA), immune cell correlation analysis, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed to investigate the functional roles and pathways of these genes. Machine learning approaches were applied to identify potential genes from differentially expressed genes (DEGs) associated with AD. The diagnostic performance of these candidate genes was assessed using a nomogram and receiver operating characteristic curves. The expression levels of the identified genes were further validated via quantitative real-time polymerase chain reaction (qRT-PCR). Differential gene analysis identified 294 highly expressed genes and 330 lowly expressed genes, and MR analysis identified 10 significantly co-expressed genes associated with AD, specifically METTL7A, SERPINB6, VASP, ENTPD2, CXCL1, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2. Noteworthy observations naive CD4+ T cells in AD, with this distinct from CIBERSORT analysis included the presence of unique immune cell subset further underscoring the critical role of immune processes in the pathogenesis and progression of the disease. METTL7A, SERPINB6, VASP, ENTPD2, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2 were selected for nomogram construction and machine learning-based assessment of diagnostic value, demonstrating considerable diagnostic potential. Furthermore, the significance of the identified key genes was corroborated using both the GEO validation set and qRT-PCR. METTL7A, SERPINB6, VASP, ENTPD2, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2 may regulate the progression of AD. These findings not only deepen our mechanistic understanding of AD pathology but also provide potential candidate genes for the development of targeted therapeutic strategies against AD.

The underlying molecular pathways of idiopathic pulmonary fibrosis (IPF), a progressive lung condition with a high death rate, are still mostly unknown. By using microarray datasets, this study aims to identify new genetic targets for IPF and provide light on the genetic factors that contribute to the development of IPF. We conducted a comprehensive analysis of three independent IPF datasets from the Gene Expression Omnibus (GEO) database, employing R software for data handling and normalization. Our evaluation of the relationships between differentially expressed genes (DEGs) and IPF included differential expression analysis, expression quantitative trait loci (eQTL) analysis, and Mendelian Randomization(MR) analyses. Additionally, we used Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to explore the functional roles and pathways of these genes. Finally, we validated the results obtained for the target genes. We identified 486 highly expressed genes and 468 lowly expressed genes that play important roles in IPF. MR analysis identified six significantly co-expressed genes associated with IPF, specifically C12orf75, SPP1, ZG16B, LIN7A, PPP1R14A, and TLR2. These genes participate in essential biological processes and pathways, including macrophage activation and neural system regulation. Additionally, CIBERSORT analysis indicated a unique immune cell distribution in IPF, emphasized the significance of immunological processes in the disease. The MR analysis was consistent with the results of the analysis of variance in the validation cohort, which strengthens the reliability of our MR findings. Our findings provide new insights into the molecular basis of IPF and highlight the promise of therapeutic interventions. They emphasize the potential of targeting specific molecular pathways for the treatment of IPF, laying the foundation for further research and clinical work.

Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

Screening and surveillance for Barrett esophagus.

Atrial fibrillation (AF) is a common persistent arrhythmia characterized by rapid and chaotic atrial electrical activity, potentially leading to severe complications such as thromboembolism, heart failure, and stroke, significantly affecting patient quality of life and safety. As the global population ages, the prevalence of AF is on the rise, placing considerable strains on individuals and healthcare systems. This study utilizes bioinformatics and Mendelian Randomization (MR) to analyze transcriptome data and genome-wide association study (GWAS) summary statistics, aiming to identify biomarkers causally associated with AF and explore their potential pathogenic pathways. We obtained AF microarray datasets GSE41177 and GSE79768 from the Gene Expression Omnibus (GEO) database, merged them, and corrected for batch effects to pinpoint differentially expressed genes (DEGs). We gathered exposure data from expression quantitative trait loci (eQTL) and outcome data from AF GWAS through the IEU Open GWAS database. We employed inverse variance weighting (IVW), MR-Egger, weighted median, and weighted model approaches for MR analysis to assess exposure-outcome causality. IVW was the primary method, supplemented by other techniques. The robustness of our results was evaluated using Cochran's Q test, MR-Egger intercept, MR-PRESSO, and leave-one-out sensitivity analysis. A "Veen" diagram visualized the overlap of DEGs with significant eQTL genes from MR analysis, referred to as common genes (CGs). Additional analyses, including Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and immune cell infiltration studies, were conducted on these intersecting genes to reveal their roles in AF pathogenesis. The combined dataset revealed 355 differentially expressed genes (DEGs), with 228 showing significant upregulation and 127 downregulated. Mendelian randomization (MR) analysis identified that the autocrine motility factor receptor (AMFR) [IVW: OR = 0.977; 95% CI, 0.956-0.998; P = 0.030], leucine aminopeptidase 3 (LAP3) [IVW: OR = 0.967; 95% CI, 0.934-0.997; P = 0.048], Rab acceptor 1 (RABAC1) [IVW: OR = 0.928; 95% CI, 0.875-0.985; P = 0.015], and tryptase beta 2 (TPSB2) [IVW: OR = 0.971; 95% CI, 0.943-0.999; P = 0.049] are associated with a reduced risk of atrial fibrillation (AF). Conversely, GTPase-activating SH3 domain-binding protein 2 (G3BP2) [IVW: OR = 1.030; 95% CI, 1.004-1.056; P = 0.024], integrin subunit beta 2 (ITGB2) [IVW: OR = 1.050; 95% CI, 1.017-1.084; P = 0.003], glutaminyl-peptide cyclotransferase (QPCT) [IVW: OR = 1.080; 95% CI, 1.010-0.997; P = 1.154], and tripartite motif containing 22 (TRIM22) [IVW: OR = 1.048; 95% CI, 1.003-1.095; P = 0.035] are positively associated with AF risk. Sensitivity analyses indicated a lack of heterogeneity or horizontal pleiotropy (P > 0.05), and leave-one-out analysis did not reveal any single nucleotide polymorphisms (SNPs) impacting the MR results significantly. GO and KEGG analyses showed that CG is involved in processes such as protein polyubiquitination, neutrophil degranulation, specific and tertiary granule formation, protein-macromolecule adaptor activity, molecular adaptor activity, and the SREBP signaling pathway, all significantly enriched. The analysis of immune cell infiltration demonstrated associations of CG with various immune cells, including plasma cells, CD8T cells, resting memory CD4T cells, regulatory T cells (Tregs), gamma delta T cells, activated NK cells, activated mast cells, and neutrophils. By integrating bioinformatics and MR approaches, genes such as AMFR, G3BP2, ITGB2, LAP3, QPCT, RABAC1, TPSB2, and TRIM22 are identified as causally linked to AF, enhancing our understanding of its molecular foundations. This strategy may facilitate the development of more precise biomarkers and therapeutic targets for AF diagnosis and treatment.

The incidence of esophageal adenocarcinoma has been increasing rapidly among many countries. Antioxidant intake is a potentially modifiable protective factor, although the results from individual studies are inconclusive. We conducted a systematic review and statistical synthesis of studies that evaluated the associations between vitamin C, vitamin E, or beta-carotene/vitamin A and the risk of esophageal adenocarcinoma or the adjacent gastric cardia (gastroesophageal junction) adenocarcinoma. Studies were included if they reported (a) a measure of dietary antioxidant intake; (b) esophageal or cardia adenocarcinoma occurrence; and (c) a relative risk or odds ratio (OR) with confidence intervals (CI), or sufficient data to permit their calculation. We identified 10 studies (1 cohort, 9 case-control; 1,057 esophageal and 644 cardia cases). Summary estimates stratified by cancer site suggested that higher intakes of vitamin C, beta-carotene/vitamin A, and vitamin E were inversely associated with the risk of esophageal adenocarcinoma (vitamin C, OR 0.49, 95% CI 0.39-0.62, P(heterogeneity)= 0.10; beta-carotene, OR 0.46, 95% CI 0.36-0.59, P(heterogeneity)= 0.82; vitamin E intake, OR 0.80, 95% CI 0.63-1.03, P(heterogeneity)= 0.59). Beta-carotene intake was also inversely associated with the risk of cardia adenocarcinoma (OR 0.57, 95% CI 0.46-0.72, P(heterogeneity)= 0.17). Dose effects were observed for most associations. Pooled results from observational studies suggest that antioxidant intake may be protective against esophageal adenocarcinoma; the data do not support a consistent association between antioxidant intake and the risk of cardia carcinoma. These findings suggest possible etiological differences between these two adjacent malignancies.

To investigate individual susceptibility to gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma, the authors studied the frequency of the common G870A polymorphism of CCND1, which encodes cyclin D1, a key cell cycle regulatory protein. The study population included 307 patients who were enrolled in a prospective case-control study to evaluate lifestyle risk factors and molecular alterations in gastroesophageal reflux disease (n = 126 patients), Barrett esophagus (n = 125 patients), and esophageal adenocarcinoma (n = 56 patients). A control group included 95 strictly asymptomatic individuals. Genomic DNA was extracted from cases and controls, and polymerase chain reaction was used to amplify exon 4 of CCND1. After digestion with BsrI, acrylamide gel electrophoresis was used to identify the wild type and common G870A polymorphic alleles. The frequency of alleles (G/G, G/A, A/A) was compared between cases and controls. Immunohistochemistry was used to study cyclin D1 distribution in among patients in the case group. Compared with the asymptomatic control group, and adjusted for age and gender, increasing frequencies were seen for the A/A genotype in patients with gastroesophageal reflux disease (odds ratio [OR], 2.83; 95% confidence interval [95% CI], 1.09-7.34), Barrett esophagus (OR, 3.69; 95% CI, 1.46-9.29), and esophageal adenocarcinoma (OR, 5.99; 95% CI, 1.86-18.96). No association was seen between genotype and cyclin D1 overexpression. The CCND1 A/A genotype was associated with increased risk for gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma. The contribution of this polymorphism to susceptibility of defined stages of progression to esophageal adenocarcinoma suggested potential application in endoscopic Barrett surveillance programs.

Patients With Barrett's Esophagus and Persistent Low-grade Dysplasia Have an Increased Risk for High-grade Dysplasia andCancer.

BACKGROUNDEsophageal adenocarcinoma (EAC) is an aggressive disease with high mortality and an overall 5-year survival rate of less than 20%. Barrett’s esophagus (BE) is the only known precursor of EAC, and patients with BE have a persistent and excessive risk of EAC over time. Individuals with BE are up to 30-125 times more likely to develop EAC than the general population. Thus, early detection of EAC and BE could significantly improve the 5-year survival rate of EAC. Due to the limitations of endoscopic surveillance and the lack of clinical risk stratification strategies, molecular biomarkers should be considered and thoroughly investigated.AIMTo explore the transcriptome changes in the progression from normal esophagus (NE) to BE and EAC.METHODSTwo datasets from the Gene Expression Omnibus (GEO) in NCBI Database (https://www.ncbi.nlm.nih.gov/geo/) were retrieved and used as a training and a test dataset separately, since NE, BE, and EAC samples were included and the sample sizes were adequate. This study identified differentially expressed genes (DEGs) using the R/Bioconductor project and constructed trans-regulatory networks based on the Transcriptional Regulatory Element Database and Cytoscape software. Enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) terms was identified using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. The diagnostic potential of certain DEGs was assessed in both datasets.RESULTSIn the GSE1420 dataset, the number of up-regulated DEGs was larger than that of down-regulated DEGs when comparing EAC vs NE and BE vs NE. Among these DEGs, five differentially expressed transcription factors (DETFs) displayed the same trend in expression across all the comparison groups. Of these five DETFs, E2F3, FOXA2, and HOXB7 were up-regulated, while PAX9 and TFAP2C were down-regulated. Additionally, the majority of the DEGs in trans-regulatory networks were up-regulated. The intersection of these potential DEGs displayed the same direction of changes in expression when comparing the DEGs in the GSE26886 dataset to the DEGs in trans-regulatory networks above. The receiver operating characteristic curve analysis was performed for both datasets and found that TIMP1 and COL1A1 could discriminate EAC from NE tissue, while REG1A, MMP1, and CA2 could distinguish BE from NE tissue. DAVID annotation indicated that COL1A1 and MMP1 could be potent biomarkers for EAC and BE, respectively, since they participate in the majority of the enriched KEGG and GO terms that are important for inflammation and cancer.CONCLUSIONAfter the construction and analyses of the trans-regulatory networks in EAC and BE, the results indicate that COL1A1 and MMP1 could be potential biomarkers for EAC and BE, respectively.

Medications (NSAIDs, Statins, Proton Pump Inhibitors) and the Risk of Esophageal Adenocarcinoma in Patients With Barrett's Esophagus

Risk of Esophageal Adenocarcinoma and Mortality in Patients With Barrett's Esophagus: A Systematic Review and Meta-analysis

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Concern has been expressed that antacid drugs increase the risk of esophageal and gastric adenocarcinomas. This population-based case-control study recruited patients with incident esophageal adenocarcinoma (n = 220), gastric cardiac adenocarcinoma (n = 277), or distal gastric adenocarcinoma (n = 441) diagnosed between 1992 and 1997, and 1,356 control participants in Los Angeles County. Unconditional polychotomous multivariable logistic regression analyses were done to evaluate the association between antacid drug use and these cancers. Among participants who took nonprescription acid neutralizing agents for >3 years, the odds ratio for esophageal adenocarcinoma was 6.32 compared with never users (95% confidence interval, 3.14-12.69; P(trend) < 0.01). Analyses stratified by history of physician diagnosed upper gastrointestinal (UGI) disorders revealed a greater increase in esophageal adenocarcinoma risk associated with nonprescription antacid use among persons with no UGI disorder than among those with an UGI disorder (homogeneity of trends P = 0.07). Regular use of nonprescription acid neutralizing agents was not associated with risk of adenocarcinomas of the gastric cardia or distal stomach. Regular use of prescription acid suppressive drugs was not associated with risk for any of these cancers. We found risk of esophageal adenocarcinoma was greater among long-term nonprescription acid neutralizing drugs in participants without physician-diagnosed UGI conditions than among those with these conditions; this may represent self medication for undiagnosed precursor conditions or it may be that nonprescription acid neutralizing drugs, taken without limitation on amount used when symptoms are most intense, may permit alkaline bile reflux into the lower esophagus, thereby increasing esophageal adenocarcinoma risk.

89 Low Incidence of Esophageal Adenocarcinoma in Barrett's Esophagus – Time to Rethink Surveillance Guidelines?