Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) is increasingly common among patients with Barrett's esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS: We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS: Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS: We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

The diagnosis of primary eosinophilic oesophagitis in adults: missed or misinterpreted?

AIM: The diagnosis of adult eosinophilic oesophagitis (EOE) is rarely made in the UK despite projections of high frequency and prevalence within Western society. This study aimed to identify the frequency of diagnosis of EOE in our community, and to establish reasons for diagnostic failure or delay. METHODS: The pathology records of all gastroscopies performed (67 840) in Northumbria NHS trust during the years January 2001-November 2008 were reviewed for oesophageal eosinophilia. Case notes and investigations were then inspected to identify patients with a diagnosis of EOE in accordance with American Gastroenterology Association guidelines. RESULTS: In total, 37 patients fulfilled diagnostic criteria for EOE. The mean duration of symptoms before the diagnosis was 4 years (range 4 months-30 years) and 14 patients (38%) remained undiagnosed until the time of study. Reasons for diagnostic failure and delay included: delayed request for endoscopy in patients with dysphagia (49%, n=18 of 37); poor recognition of typical endoscopic appearances of EOE (16%, n=6 of 37); clinical mislabelling as gastro-oesophageal reflux disease (22%, n=8 of 37) and candida (13%, n=5 of 37); histological mislabelling as gastro-oesophageal reflux disease (19%, n=7 of 37), candida (5%, n=2 of 37), 'inflammation' (8%, n=3 of 37) and Barrett's oesophagus (3%, n=1 of 37); failed recognition or recording of maximal eosinophil concentrations within biopsies (35%, n=13 of 37). In 40% (n=15 of 37) of patients the decision to biopsy was based solely on a dysphagia protocol introduced in 2004. No cases were identified before the protocol implementation. CONCLUSION: EOE is underdiagnosed in our community owing to lack of clinical suspicion, failure to biopsy, and histopathological misinterpretation. Educating clinicians and pathologists before planning an endoscopy may improve the diagnostic sensitivity.

Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor.

BACKGROUND AND AIMS: Factors associated with the development and malignant progression of Barrett's esophagus are poorly understood. Gastrin is a mitogen capable of inducing growth in normal and malignant gastrointestinal mucosa. It is unknown whether gastrin can influence cellular events in the esophagus in Barrett's. METHODS: Reverse-transcription polymerase chain reaction (RT-PCR) and northern analysis for the cholecystokinin (CCK(2)) receptor were performed on normal, inflamed, metaplastic, and malignant esophageal mucosa. Real-time PCR quantified expression of the receptor. [(125)I]-G17-autoradiography localized the CCK(2) receptor in mucosal sections. [(3)H]-thymidine and bromodeoxyuridine (BrdU) incorporation determined proliferation in response to G17 in biopsy specimens incubated ex vivo. Proliferation and signaling studies were performed on OE33(E) cells transfected with the CCK(2) receptor. RESULTS: RT-PCR identified receptor expression in 3 of 9 controls, 5 of 7 patients with esophagitis, 10 of 10 patients with Barrett's metaplasia, and 7 of 12 esophageal adenocarcinomas. Real-time PCR quantified expression in 10 patients with Barrett's showing a level of expression 2 orders of magnitude higher than in 12 control patients. [(125)I]-G17 bound to epithelia within glandular regions of Barrett's mucosa. Ten nmol/L G17 induced a 2-fold (n = 7, P = 0.0257, t test) increase in [(3)H]-thymidine incorporation in mucosal biopsy specimens, abolished by the addition of the CCK(2) receptor antagonist L-740, 093. One nmol/L G17 induced a 1.94- +/- 0.13-fold (n = 6, t test, P = 0.001) increase in [(3)H]-thymidine incorporation in OE33(E)(GR) cells, abolished by L-740, 093. CONCLUSIONS: Gastrin induces proliferation via the CCK(2) receptor in Barrett's mucosa. This may have implications for the management of patients with Barrett's esophagus in whom gastrin is elevated by acid-suppression therapy.

Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: Role of Rho GTPase and menin.

BACKGROUND & AIMS: The gastric hormone gastrin regulates acid secretion, gene expression, and the functional development and cellular composition of the gastric mucosa. Using a gene array, we sought to identify major, novel, gastrin-regulated genes. METHODS: A cancer gene array was probed with samples from the gastric cancer cell line AGS, expressing the gastrin-cholecystokinin(B) receptor and stimulated with gastrin. The expression of gastrin-regulated genes was further characterized by Western blots and enzyme-linked immunosorbent assay in tissue and blood of hypergastrinemic patients. Gene expression was studied using promoter-luciferase reporter constructs. RESULTS: Plasminogen activator inhibitor 2 (PAI-2) was identified as a major, previously unknown target of gastrin in the gastric cancer cell line AGS. The relevance was confirmed by showing elevated tissue and plasma PAI-2 in hypergastrinemic patients (pernicious anemia and multiple endocrine neoplasia type 1). PAI-2 promoter-luciferase constructs showed that gastrin stimulated expression via pathways involving Galpha and Gbetagamma subunits, protein kinase C, RhoA, and the transcription factors CREB and AP1. The tumor suppressor menin inhibited transcription. In addition, gastrin stimulated expression in adjacent cells via a paracrine mechanism involving protein kinase C and RhoA but not CREB. CONCLUSIONS: A gene array showed PAI-2 to be a novel gastrin-regulated gene, stimulated in part through CREB and AP-1 and inhibited by the tumor suppressor menin.