Single-cell Genomic Copy Number Evolution Reveals Frequent Loss of the Y chromosome in Esophageal Adenocarcinoma.

Issue Highlights

Screening and surveillance for Barrett esophagus.

Elucidating the role of microbes in precancer evolution could transform clinical risk prediction and management strategies. In the case of esophageal adenocarcinoma (EAC) progression, microbial communities have been detected across precancerous and neoplastic stages. However, unlike prior studies that statistically compare microbial abundances at single time-points, we employed mathematical modeling of microbial population dynamics within human hosts to determine likely modes of evolution that drive changes in microbial composition over time. We first aggregated whole genome sequencing (WGS) datasets from esophageal tissue samples taken across stages of EAC progression, which included healthy esophagus, gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), and EAC. In particular, we analyzed baseline WGS data from a case-control study of patients with BE who later progressed to EAC (“progressors”) versus those patients with BE who did not progress to cancer within 5 years (“non-progressors”). We employed a robust bioinformatics host filtration pipeline to remove human DNA reads, mapped remaining reads to a human-scrubbed Web of Life microbial database, and filtered out taxa with low genomic coverage. After extracting occurrence and abundance data for taxa in each disease stage, we applied mathematical models of both neutral and non-neutral microbial evolution. We found evidence of neutral dynamics across stages of normal to pre-cancer (goodness-of-fit to the neutral expectation R2 > 0.85 for normal esophagus and GERD, R2 > 0.65 for BE non-progressors and BE progressors) but not for EAC (R2 = 0.14 in EACs from the International Cancer Genome Consortium, and R2 = 0.34 in a validation set of 19 EACs who also had surrounding BE). We also found that Helicobacter pylori (H. pylori), a bacterium inversely associated with EAC risk, deviated significantly from the expected neutral model in BE non-progressor patients but not in BE progressor patients. To test hypotheses that accounted for potential selection effects, we performed simulations for both neutral and non-neutral processes. Using simulated data for the EAC cohorts, we found that assuming widely varying growth rates best reflected the data, implying that selection pressures likely influence largely niche-based population dynamics in the tumor microenvironment. For the BE non-progressor cohort, we found that assuming a lower death rate for H. pylori compared to other taxa recapitulated the data. This implies that H. pylori may have a selective advantage in non-progressing BE (as it does when present in the stomach), and further studies are needed to understand the impact on EAC progression. Overall, considering metagenomic data as the result of a dynamic process within a human host will enhance our understanding of the human microbiome's role in precancer and cancer evolution. Citation Format: Caitlin E. Guccione, Igor Sfiligoi, Antonio Gonzalez, Justin Shaffer, Mariya Kazachkova, Yuhan Weng, Daniel McDonald, Shailja Shah, Samuel S. Minot, Thomas Paulson, Ludmil Alexandrov, Rob Knight, Kit Curtius. Computational modeling of human microbiome evolution in the context of esophageal adenocarcinoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3692.

Cost-Effectiveness of Endoscopic Screening Followed by Surveillance for Barrett's Esophagus: A Review

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana(®) immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies.

Risk of progression in Barrett’s esophagus indefinite for dysplasia: a systematic review and meta-analysis

To investigate the relationship between Helicobacter pylori infection and Barrett's esophagus (BE), a rat model of chronic gastroesophageal reflux with H. pylori infection was established and the degree of inflammation, incidence of BE and esophageal adenocarcinoma (EA) were evaluated. Eight-week-old male specific-pathogen-free SD rats were divided into five groups randomly: pseudo-operation group; esophagojejunum anastomosis (EJA) group; EJA with H. pylori infection group; EJA with H. pylori infection and celecoxib-treated group; EJA with celecoxib-treated group. Rats were kept for 30 weeks after surgery. Esophageal lesion was evaluated grossly and microscopically. The expression of COX-2 and CDX2 was determined by RT-PCR and immunohistochemistry staining. The level of PGE₂ was assessed by enzyme-linked immunosorbent assay. Esophageal mucosal injury in the group of EJA with H. pylori infection was decreased than that in EJA group (p < .05). The incidence of BE and EA in rats undergoing EJA with H. pylori infection was increased than in rats undergoing EJA with no statistical difference. Celecoxib treatment decreased the incidence of EA in rats undergoing EJA with H. pylori infection (p < .05). The expression of CDX2 mRNA was decreased in rats with H. pylori infection or treated with celecoxib than in the rats of pseudo-operation group (p < .05). When compared with those in rats of pseudo-operation group, the expression of COX-2 mRNA and the level of PGE₂ were upregulated in rats undergoing EJA irrespective of H. pylori infection (p < .05) and downregulated in rats treated with celecoxib (p < .05). When H. pylori colonized in esophagus, the severity of inflammation and the incidence of BE and EA were increased significantly. Higher levels of COX-2 expression and PGE₂ were detected in rats with esophageal H. pylori colonization. When H. pylori infect in stomach, it may reduce the severity of inflammation. However, when colonizes in esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA. Celecoxib administration attenuates the incidence of EA by inhibiting COX-2 expression.

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

Central Adiposity and Risk of Barrett’s Esophagus

Multicenter Randomized Controlled Trial of Surveillance Versus Endoscopic Therapy for Barrett’s Esophagus With Low-grade Dysplasia: The SURVENT Trial: Study Rationale, Methodology, Innovation, and Implications

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

340 Proportion of Missed Cancer and High-grade Dysplasia During Barrett's Esophagus Diagnosis: a Systematic Review and Meta-Analysis

The incidence of esophageal adenocarcinoma and its precursor, Barrett's esophagus, have increased greatly over the past 40 years and continue to rise. This report summarizes the most recent data on the risk factors for Barrett's esophagus and esophageal adenocarcinoma. Other factors, highly correlated with increasing trends for obesity, are the dominant driver of the increase in incidence of esophageal adenocarcinoma, interacting with gastroesophageal reflux disease symptoms. Abdominal obesity, independently of gastroesophageal reflux disease symptoms, is associated with increased risk of Barrett's esophagus and this association is likely mediated by high levels of leptin and insulin. Use of aspirin, nonsteroidal anti-inflammatory drugs, statins, and proton pump inhibitors are associated with a reduced risk of Barrett's esophagus as well as lower risk of neoplastic progression in patients with Barrett's esophagus. An increasing number of genetic loci have been associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Recent advances in identifying risk factors and reporting of more precise estimates of effect for the main risk factors will positively impact clinical risk stratification efforts for Barrett's esophagus and esophageal adenocarcinoma. Large pooling studies are underway to derive and validate reliable clinical risk models.

Is Complete Endoscopic Resection Still a Viable Option for Barrett’s-Related Dysplasia and Neoplasia?