Dataset Information

Rates and predictors of progression to esophageal carcinoma in a large population-based Barrett's esophagus cohort.

ABSTRACT: Rates of progression to esophageal adenocarcinoma in subjects with Barrett's esophagus (BE) are lower than previously estimated. Identification of predictors of progression will enable risk stratification of BE subjects, potentially making current surveillance programs more efficient. We aimed to assess the potential of demographic and lifestyle factors, obesity, and medications in predicting progression in BE.BE subjects were identified from the General Practice Research Database using validated diagnostic codes. BE subjects developing esophageal cancer (EC) 12 months after their index BE diagnosis were defined as progressors. Time-to-event analysis was used to assess the overall risk of progression to EC. Cox proportional hazards models and time-varying marginal structural models were used to assess predictors of progression.Included in the analysis were 9660 BE patients. The mean age (SD) of the study subjects was 63 (13.5) years; 62.6% were men. One hundred three subjects (1.1%) progressed to EC. The mean (SD) follow-up since initial diagnosis was 4.8 (3.3) years. The incidence of EC was 2.23 per 1000 person-years of follow-up. Increasing age, male gender, and being overweight (body mass index, 25-29.9) were found to be independent predictors of progression. When time-varying models were used, proton pump inhibitor (PPI) and statin use were protective against progression.In this large population-based cohort of patients with BE, increasing age, male gender, and being overweight predicted progression to EC, whereas PPI and statin use were protective against EC development. These factors may aid in developing a risk score to predict the risk of progression and chemopreventive strategies in patients with BE.

SUBMITTER: Krishnamoorthi R

PROVIDER: S-EPMC4912845 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Rates and predictors of progression to esophageal carcinoma in a large population-based Barrett's esophagus cohort.

Krishnamoorthi Rajesh R Borah Bijan B Heien Herbert H Das Ananya A Chak Amitabh A Iyer Prasad G PG

Gastrointestinal endoscopy 20160107 1

<h4>Background and aims</h4>Rates of progression to esophageal adenocarcinoma in subjects with Barrett's esophagus (BE) are lower than previously estimated. Identification of predictors of progression will enable risk stratification of BE subjects, potentially making current surveillance programs more efficient. We aimed to assess the potential of demographic and lifestyle factors, obesity, and medications in predicting progression in BE.<h4>Methods</h4>BE subjects were identified from the Gener ...[more]

PMID: 26772891

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Project description:Esophageal adenocarcinoma (EAC) is strongly associated with Barrett's esophagus (BE), a pre-malignant condition resulting from gastric reflux. Esophageal squamous cell carcinoma (ESCC), the other major subtype of esophageal cancer, shows strong association with smoking and alcohol intake and no association with gastric reflux. In this study, we constructed and validated gene expression signatures of EAC vs. ESCC tumors using publicly available datasets, and subsequently assessed the enrichment levels of these signatures in commonly used EAC and ESCC cell lines, normal esophageal tissues and normal esophageal cell lines, and primary BE tissues and BE cell lines. We found that unlike ESCC cell lines which were quite similar to primary ESCC tumors, EAC cell lines were considerably different from primary EAC tumors but still more similar to EAC tumors than ESCC tumors, as the genes up in EAC vs. ESCC (EAChi) had considerably lower expression in EAC cell lines than EAC tumors. However, more surprisingly, unlike various normal cell lines (EPC2, Het-1A) which were very similar to various tissues from normal esophagus, BE cell lines (BAR-T, CP-A) were extremely different from primary BE tissues, as BE cell lines had substantially lower levels of EAChi and substantially higher levels of ESCChi gene expression. This ESCC-like profile of the BAR-T remained unaltered even after prolonged exposure to an acidic bile mixture in vitro resulting in malignant transformation of this cell line. However, primary BE tissues had EAC-like gene expression profiles as expected. Only one EAC case from the Cancer Genome Atlas resembled BE cell lines, and while it had the clinical profile and some mutational features of EAC, it had some mutational features, the copy number alteration profile, and the gene expression profile of ESCC instead. These incomprehensible changes in gene expression patterns may result in ambiguous changes in the phenotype and warrants careful evaluation to inform selection of appropriate in vitro tools for future studies on esophageal adenocarcinoma.

Project description:BackgroundThe enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host.MethodsHere, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest.ResultsProfiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment of Campylobacter species as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found between Campylobacter and napsin B aspartic peptidase. Targeted culture of Campylobacter species from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for these Campylobacter strain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to the Campylobacter isolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression.ConclusionsWe provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

Dataset Information

Rates and predictors of progression to esophageal carcinoma in a large population-based Barrett's esophagus cohort.

Publications

Rates and predictors of progression to esophageal carcinoma in a large population-based Barrett's esophagus cohort.

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