Genetics of Barrett's esophagus and Esophageal adenocarcinoma
Principal Investigator: Dr Claire Palles
Approved Research ID: 35182
Approval date: November 1st 2016
Barretts Oesophagus (BO) occurs when normal oesophageal squamous epithelium is replaced by columnar epithelium. Patients with BO have a high risk of developing oesophageal adenocarcinoma (OAC) compared to the general population. Heritability of BO/OAC has been estimated at >10%. We previously analysed 1,852 BO cases and 5,172 UK controls in a genome wide association study (GWAS) and identified 5 of the 8 currently known genome-wide significantly associated loci. We propose to study UK Biobank participants to try to new predisposition loci. 1-5% of patients undergoing endoscopy have BO. These patients have a high risk of developing OAC, a cancer with a very poor prognosis. Identification of multiple genetic loci explaining BO/OAC susceptibility would enable identification of patients at high risk of OAC. They could be offered additional endoscopy screening to detect OAC early and might also benefit from acid suppression, which is being trialled at the moment (gastroduodenal reflux is a risk factor for BO and OAC). This proposed study fulfils the aim of the UK Biobank to improve prevention and treatment of serious illnesses. The frequency of inherited genetic variants in partipants with OAC/BO will be compared to cancer and esophageal disease free participants. Biobank data will be combined with existing similar case control studies in the UK and internationally. We also aim to determine the frequency of the 8 known BO/OAC loci (and any subsequently discovered ones) in patients with Gastro-oesophageal reflux disease (GORD), oesophagitis (no BO) or hiatal hernia. These disorders are associated with BO and may share genetic risk loci. Oesophageal cell lines will be used in functional studies to identify the genes responsible for the association signals. We would include all participants with OAC and or BO as cases and all remaining participants without a cancer diagnosis as controls. The data showcase suggests there may be ~100 OAC cases and ~1000 BO cases available. This would make a very valuable addition to our existing data. We would also like to compare allele frequencies of known BO/OAC risk variants in individuals with GORD, oesophagitis (without evidence of BO) and hiatus hernia (HH) to the frequencies of these variants in the remaining controls. We anticipate that there will be 11,000 HH cases and 22,000 GORD cases.