Germline Determinants of Esophageal Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Lee M
PROVIDER: S-EPMC10592248 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Germline Determinants of Esophageal Adenocarcinoma.
Lee Minyi M Eng George G Handte-Reinecker Anna A Deshpande Vikram S VS Yilmaz Omer H OH Gala Manish K MK
Gastroenterology 20230726 5
Similar Datasets
Project description:Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a chronic inflammatory state that can progress through a series of transformative dysplastic states before tumor development. While molecular and genetic changes of EAC tumors have been studied, immune microenvironment changes during Barrett's progression to EAC remain poorly understood. In this study, we identify potential immunologic changes that can occur during BE-to-EAC progression. RNA sequencing (RNA-Seq) analysis on tissue samples from EAC patients undergoing surgical resection demonstrated that a subset of chemokines and cytokines, most notably IL6 and CXCL8, increased during BE progression to EAC. xCell deconvolution analysis investigating immune cell population changes demonstrated that the largest changes in expression during BE progression occurred in M2 macrophages, pro-B cells, and eosinophils. Multiplex immunohistochemical staining of tissue microarrays showed increased immune cell populations during Barrett's progression to high-grade dysplasia. In contrast, EAC tumor sections were relatively immune poor, with a rise in PD-L1 expression and loss of CD8+ T cells. These data demonstrate that the EAC microenvironment is characterized by poor cytotoxic effector cell infiltration and increased immune inhibitory signaling. These findings suggest an immunosuppressive microenvironment, highlighting the need for further studies to explore immune modulatory therapy in EAC.
| S-EPMC7821593 | biostudies-literature
Project description:BackgroundEsophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.MethodsWe used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.ResultsWe estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.ConclusionsWe have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
| S-EPMC3833931 | biostudies-literature
Project description:ContextBarrett esophagus (BE) occurs in 1% to 10% of the general population and is believed to be the precursor of esophageal adenocarcinoma (EAC). The incidence of EAC has increased 350% in the last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, and management. Genome-wide multiplatform approaches may lead to the identification of genes important in BE/EAC development.ObjectiveTo identify risk alleles or mutated genes associated with BE/EAC.Design, setting, and patientsModel-free linkage analyses of 21 concordant-affected sibling pairs with BE/EAC and 11 discordant sibling pairs (2005-2006). Significant germline genomic regions in independent prospectively accrued series of 176 white patients with BE/EAC and 200 ancestry-matched controls (2007-2010) were validated and fine mapped. Integrating data from these significant genomic regions with somatic gene expression data from 19 BE/EAC tissues yielded 12 "priority" candidate genes for mutation analysis (2010). Genes that showed mutations in cases but not in controls were further screened in an independent prospectively accrued validation series of 58 cases (2010).Main outcome measuresIdentification of germline mutations in genes associated with BE/EAC cases. Functional interrogation of the most commonly mutated gene.ResultsThree major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P < .001). In addition, 13 patients (11.2%) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030-0.130; P < .001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P = .09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1-mutation carriers showed increased nuclear expression of CCND1.ConclusionMSR1 was significantly associated with the presence of BE/EAC in derivation and validation samples, although it was only present in a small percentage of the cases.
| S-EPMC3574553 | biostudies-literature
Project description: Not available
| ST001942 | MetabolomicsWorkbench
Project description:Background & aimsSuperficial (T1) esophageal adenocarcinoma (EAC) commonly is treated by endoscopic resection, yet little is known about factors that predict outcomes of this approach. We assessed clinical and histologic variables associated with the overall survival times of patients with T1 EAC who received therapy.MethodsIn a retrospective analysis, we collected data from patients who underwent endoscopic mucosal resection (EMR) for T1 EAC (194 patients with T1a and 75 patients with T1b) at the Mayo Clinic, from 1995 through 2011. EMR specimens were reviewed systematically for depth of invasion, presence of lymphovascular invasion, grade of differentiation, and status of resection margins. Kaplan-Meier curves and proportional hazards regression models were used in statistical analyses.ResultsDemographic characteristics were similar between patients with T1a and T1b EAC. Overall survival at 5 years after EMR was 74.4% for patients with T1a (95% confidence interval [CI], 67.6%-81.8%) and 53.2% for patients with T1b EAC (95% CI, 40.3%-70.1%). Of surviving patients with T1a EAC, 94.1% remained free of cancer (95% CI, 89.8%-98.5%), and 94.7% of surviving patients with T1b EAC remained free of cancer (95% CI, 85.2%-100%). A multivariable model associated older age (per 10-year increment), evidence of lymphovascular invasion, and deep margin involvement with reduced overall survival in patients with T1 EAC.ConclusionsSystematic assessment of EMR specimens can help predict mortality and potentially guide treatment options for patients with T1 EAC.
| S-EPMC4336231 | biostudies-literature
Project description:Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.
| S-EPMC8052954 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-25 | GSE254946 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE37200: Gene expression profiling of Barrett’s esophageal tissues and esophageal adenocarcinoma specimens GSE37201: Gene expression profiling of esophageal adenocarcinoma Refer to individual Series
2012-04-10 | E-GEOD-37203 | biostudies-arrayexpress