Ramirez, Francisco C

Abstract Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett’s esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett’s esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82–0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86–0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66–0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7–0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett’s esophagus surveillance. Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett’s esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

Background. Adenoma detection rate (ADR) is a validated quality measure for screening colonoscopy, but there are little data for other indications. The distribution of adenomas is not well described for these indications. Aim. To describe ADR and the adenoma distribution in the proximal and distal colon based on colonoscopy indication. Methods. Outpatient colonoscopies are subdivided by indication. PDR and ADR for the entire colon and for proximal and distal colon. Data were compared using generalized estimating equations to adjust for clustering amongst endoscopists while controlling for patient age and gender. Results. 3436 colonoscopies were reviewed (51.2%: men (n=1759)). Indications are screening 49.2%, surveillance 29.3%, change in bowel habit 8.4%, bleeding 5.8%, colitides 3.0%, pain 2.8%, and miscellaneous 1.5%. Overall ADR was 37% proximal ADR 28%, and distal ADR 17%. PDR and ADR were significantly higher in surveillance than in screening (PDR: 69% versus 51%; ADR: 50% versus 33%; p=0.0001). Adenomas were more often detected in the proximal than in the distal colon, for all indications. Conclusions. Prevalence of polyps and adenomas differs based on colonoscopy indication. Adenoma detection is highest in surveillance and more commonly detected in the proximal colon. For quality assurance, distinct ADR and PDR targets may need to be established for different colonoscopy indications.