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Background: Oesophageal adenocarcinoma represents one of the fastest rising cancers in high-income countries. Barrett's oesophagus is the premalignant precursor of oesophageal adenocarcinoma. However, only a few patients with Barrett's oesophagus develop adenocarcinoma, which complicates clinical management in the absence of valid predictors. Within an international consortium investigating the genetics of Barrett's oesophagus and oesophageal adenocarcinoma, we aimed to identify novel genetic risk variants for the development of Barrett's oesophagus and oesophageal adenocarcinoma.
Methods: We did a meta-analysis of all genome-wide association studies of Barrett's oesophagus and oesophageal adenocarcinoma available in PubMed up to Feb 29, 2016; all patients were of European ancestry and disease was confirmed histopathologically. All participants were from four separate studies within Europe, North America, and Australia and were genotyped on high-density single nucleotide polymorphism (SNP) arrays. Meta-analysis was done with a fixed-effects inverse variance-weighting approach and with a standard genome-wide significance threshold (p<5 × 10). We also did an association analysis after reweighting of loci with an approach that investigates annotation enrichment among genome-wide significant loci. Furthermore, the entire dataset was analysed with bioinformatics approaches-including functional annotation databases and gene-based and pathway-based methods-to identify pathophysiologically relevant cellular mechanisms.
Findings: Our sample comprised 6167 patients with Barrett's oesophagus and 4112 individuals with oesophageal adenocarcinoma, in addition to 17 159 representative controls from four genome-wide association studies in Europe, North America, and Australia. We identified eight new risk loci associated with either Barrett's oesophagus or oesophageal adenocarcinoma, within or near the genes CFTR (rs17451754; p=4·8 × 10), MSRA (rs17749155; p=5·2 × 10), LINC00208 and BLK (rs10108511; p=2·1 × 10), KHDRBS2 (rs62423175; p=3·0 × 10), TPPP and CEP72 (rs9918259; p=3·2 × 10), TMOD1 (rs7852462; p=1·5 × 10), SATB2 (rs139606545; p=2·0 × 10), and HTR3C and ABCC5 (rs9823696; p=1·6 × 10). The locus identified near HTR3C and ABCC5 (rs9823696) was associated specifically with oesophageal adenocarcinoma (p=1·6 × 10) and was independent of Barrett's oesophagus development (p=0·45). A ninth novel risk locus was identified within the gene LPA (rs12207195; posterior probability 0·925) after reweighting with significantly enriched annotations. The strongest disease pathways identified (p<10) belonged to muscle cell differentiation and to mesenchyme development and differentiation.
Interpretation: Our meta-analysis of genome-wide association studies doubled the number of known risk loci for Barrett's oesophagus and oesophageal adenocarcinoma and revealed new insights into causes of these diseases. Furthermore, the specific association between oesophageal adenocarcinoma and the locus near HTR3C and ABCC5 might constitute a novel genetic marker for prediction of the transition from Barrett's oesophagus to oesophageal adenocarcinoma. Fine-mapping and functional studies of new risk loci could lead to identification of key molecules in the development of Barrett's oesophagus and oesophageal adenocarcinoma, which might encourage development of advanced prevention and intervention strategies.
Funding: US National Cancer Institute, US National Institutes of Health, National Health and Medical Research Council of Australia, Swedish Cancer Society, Medical Research Council UK, Cambridge NIHR Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, Else Kröner Fresenius Stiftung, Wellcome Trust, Cancer Research UK, AstraZeneca UK, University Hospitals of Leicester, University of Oxford, Australian Research Council.
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http://dx.doi.org/10.1016/S1470-2045(16)30240-6 | DOI Listing |
Cureus
November 2024
School of Medicine, Swansea University, Swansea, GBR.
Background Esophageal cancer is a prevalent and highly lethal malignancy worldwide, comprising two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). While both subtypes are frequently encountered, ESCC has historically been more common globally. However, in recent decades, EAC has emerged as the predominant type in industrialized nations, often developing from Barrett's esophagus, a condition driven by chronic gastroesophageal reflux disease (GERD).
View Article and Find Full Text PDFEur J Nutr
December 2024
Department of Thoracic Surgery, Med+X Center for Informatics, West China Hospital, Sichuan University, Chengdu, China.
Objective: Previous studies have indicated a potential correlation between cheese intake and risk of various diseases. However, establishing a causal relationship is challenging. To address this, we employed Mendelian randomization (MR) to simulate randomized trial groups and to investigate whether there is a causal link between cheese intake and the risk of gastroesophageal reflux disease (GERD) and Barrett's esophagus.
View Article and Find Full Text PDFClin Epigenetics
December 2024
Third Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-Machi, Hirakata, Osaka, 573-1010, Japan.
Interaction between host genotoxic changes and mucosa-associated microbiome (MAM) dysbiosis may have a role in various digestive cancers. We investigated MAM in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) progression sequence and its association with host genotoxic changes. 16S rRNA gene sequencing was performed in three different groups of biopsies from nonneoplastic BE from patients without cancer (N, normal group; n = 47) and with EAC (ADJ, adjacent group; n = 27).
View Article and Find Full Text PDFDig Dis Sci
December 2024
Division of Gastroenterology & Hepatology, Penn State College of Medicine, Hershey, PA, 17033, USA.
Gastroesophageal reflux disease (GERD) is a very common condition characterized by chronic symptoms, such as heartburn or epigastric and/or substernal pain, that are frequently associated with mucosal damage resulting from abnormal reflux of gastric contents into the esophagus (Fass et al. in Nat Rev Dis Primers 7:55, 2021; Richter and Rubenstein in Gastroenterology 154:267-276, 2018). However, this damage can manifest in patients who do not exhibit typical GERD symptoms.
View Article and Find Full Text PDFGastrointest Endosc
December 2024
Department of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida, USA.
This clinical practice guideline from the American Society for Gastrointestinal Endoscopy (ASGE) provides an evidence-based approach for strategies to diagnose and manage GERD. This document was developed using the Grading of Recommendations Assessment, Development, and Evaluation framework and serves as an update to the 2014 ASGE guideline on the role of endoscopy in the management of GERD. This updated guideline addresses the indications for endoscopy in patients with GERD as well as in the emerging population of patients who develop GERD after sleeve gastrectomy or peroral endoscopic myotomy.
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