eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.

Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression.

Gastroesophageal reflux disease and Barrett esophagus: an overview of evidence-based guidelines.

Gastroesophageal reflux disease is an extremely common condition worldwide, with the published prevalence rates varying from 2.5% in China to 51.2% in Greece.

Management of Barrett esophagus: a practical guide for clinicians based on the BADCAT and BoB CAT recommendations.

We undertook two of the largest evidence-based reviews in clinical medicine to assess the rationale for the management of gastroesophageal reflux disease, Barrett esophagus (BE), dysplasia, and early invasive esophageal adenocarcinoma. These reviews involved over 150 world experts in 4 continents, and over 20 000 papers were assessed. Quality assessment of the publications was made using Grading of Recommendations Assessment, Development and Evaluation, and of over 240 questions formulated, we were able to answer 30% with an agreement of at least 80%.

Trefoil Factor Expression in a Human Model of the Early Stages of Barrett's Esophagus.

Background: Trefoil proteins are believed to have an important role in mucosal protection and repair in the gastrointestinal tract. They are well recognized in Barrett's esophagus and considered a potential biomarker for the condition. Metaplasia occurring in the esophageal remnant after esophagectomy is a human model for the early stages of development of Barrett's esophagus.

The correlation between reading and mathematics ability at age twelve has a substantial genetic component.

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve.

The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands.

Objective: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands.

Methods: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling.

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus.

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements.

A genome-wide association analysis of a broad psychosis phenotype identifies three loci for further investigation.

Background: Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories.

Methods: 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.

Why is there a change in patterns of GE cancer?

Recent decades have seen a worrying trend in incidence rates of distal oesophageal and proximal gastric cancers. Fuelled by radical changes in lifestyle, diet, physical activity and environmental exposures, as well as an ageing population and host genetic predisposition, the incidence of oesophageal adenocarcinoma (OAC) is on the rise in Western populations. While overall incidence of gastric cancers is declining, the ageing of society means that an increase in absolute numbers is expected over coming years.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.

Aspirin and NSAIDs; benefits and harms for the gut.

Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention.

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.

Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor.

Background: Little is known about the stem cell organisation of the normal oesophagus or Barrett's metaplastic oesophagus. Using non-pathogenic mitochondrial DNA mutations as clonal markers, the authors reveal the stem cell organisation of the human squamous oesophagus and of Barrett's metaplasia and determine the mechanism of clonal expansion of mutations.

Methods: Mutated cells were identified using enzyme histochemistry to detect activity of cytochrome c oxidase (CCO).

The clonal origins of dysplasia from intestinal metaplasia in the human stomach.

Background & Aims: Studies of the clonal architecture of gastric glands with intestinal metaplasia are important in our understanding of the progression from metaplasia to dysplasia. It is not clear if dysplasias are derived from intestinal metaplasia or how dysplasias expand. We investigated whether cells within a metaplastic gland share a common origin, whether glands clonally expand by fission, and determine if such metaplastic glands are genetically related to the associated dysplasia.

Chemoprevention in Barrett's esophagus: A pill a day?

Esophageal adenocarcinoma is increasing in incidence. The main risk factor is the premalignant condition of Barrett's esophagus. There is great interest in chemoprevention to prevent or slow malignant transformation.

Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence.

Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions.

Cytoplasmic beta-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas.

Aims: beta-Catenin is an important molecule in cancer biology. Membranous beta-catenin enhances cellular differentiation and inhibits invasion by its action on E-cadherin. The aim was to ascertain whether the cellular expression of these molecules in colorectal and oesophageal cancer specimens is associated with survival in patients with gastrointestinal cancer.

Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas.

Background & Aims: According to the somatic mutation theory, monoclonal colorectal lesions arise from sequential mutations in the progeny of a single stem cell. However, studies in a sex chromosome mixoploid mosaic (XO/XY) patient indicated that colorectal adenomas were polyclonal. We assessed adenoma clonality on an individual crypt basis and completed a genetic dependency analysis in carcinomas-in-adenomas to assess mutation order and timing.