Leaky transporters and sphincters in Barrett's oesophagus?
Authors: Stephen J Meltzer
Journal: The Lancet Oncology (2016)

Barrett's oesophagus is a metaplastic epithelial condition caused by chronic gastro-oesophageal reflux that predisposes to development of oesophageal adenocarcinoma. Barrett's oesophagus and oesophageal adenocarcinoma are not often thought of as hereditary diseases—ie, a positive family history of either disease in first-degree relatives or probands is usually not obtained.1van Nistelrooij AM Dinjens WN Wagner A Spaander MC van Lanschot JJ Wijnhoven BP Hereditary factors in esophageal adenocarcinoma.Gastrointest Tumors. 2014; 1: 93-98Crossref PubMed Google Scholar However, since these diseases could be polygenic in origin, with each locus contributing only weakly to disease development, clinical family history might underestimate the hereditary genetic component. Estimates suggest that 24% of cases of oesophageal adenocarcinoma are hereditary and 76% are sporadic,2Lu Y Ek WE Whiteman D et al.Most common ‘sporadic’ cancers have a significant germline genetic component.Hum Mol Genet. 2014; 23: 6112-6118Crossref PubMed Scopus (67) Google Scholar whereas up to 35% of cases of Barrett's oesophagus have a hereditary genetic component.3Ek WE Levine DM D'Amato M et al.Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux.J Natl Cancer Inst. 2013; 105: 1711-1718Crossref PubMed Scopus (76) Google Scholar Therefore, several research groups have sought to identify disease loci using genome-wide association studies. Su and colleagues4Su Z Gay LJ Strange A et al.Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.Nat Genet. 2012; 44: 1131-1136Crossref PubMed Scopus (137) Google Scholar reported an association between Barrett's oesophagus and variants at the MHC locus and at chromosome 16q24.1. Similarly, Levine and co-workers5Levine DM Ek WE Zhang R et al.A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.Nat Genet. 2013; 45: 1487-1493Crossref PubMed Scopus (150) Google Scholar identified associated loci in the gene CRTC1 at 19p13, in BARX1 at 9q22, and near FOXP1 at 3p14. Subsequently, single nucleotide polymorphisms (SNPs) within the CDKN2A and TP53 tumour suppressor genes were reported to associate with oesophageal adenocarcinoma.6Buas MF Levine DM Makar KW et al.Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma.Carcinogenesis. 2014; 35: 2740-2747Crossref PubMed Scopus (26) Google Scholar Palles and colleagues7Palles C Chegwidden L Li X et al.Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.Gastroenterology. 2015; 148: 367-378Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar identified an association between Barrett's oesophagus and polymorphisms near the genes TBX5 (2p24) and GDF7 (12q24), and between both Barrett's oesophagus and oesophageal adenocarcinoma and a locus within ALDH1A2 (15q21.2). In a focused analysis of 16 genes coding for the androgen pathway,8Ek WE Lagergren K Cook M et al.Polymorphisms in genes in the androgen pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.Int J Cancer. 2016; 138: 1146-1152Crossref PubMed Scopus (11) Google Scholar associations were noted between Barrett's oesophagus and SNPs within CYP17A1 (10q24.32), and between oesophageal adenocarcinoma and JMJD1C (10q21.3). Prioritising this broad array of loci across multiple studies has been difficult. In a review and meta-analysis of existing data,9Findlay JM Middleton MR Tomlinson I Genetic biomarkers of Barrett's esophagus susceptibility and progression to dysplasia and cancer: a systematic review and meta-analysis.Dig Dis Sci. 2016; 61: 25-38Crossref PubMed Scopus (24) Google Scholar 17 germline markers of susceptibility to Barrett's oesophagus were identified, in addition to five somatic markers of neoplastic progression and one marker of relapse after photodynamic therapy. In The Lancet Oncology, Puya Gharahkhani and colleagues from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), the Esophageal Adenocarcinoma GenEtics Consortium (EAGLE), and the Wellcome Trust Case Control Consortium 2 (WTCCC2)10Gharakhani P Fitzgerald RC Vaughan TL et al.the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON)the Esophageal Adenocarcinoma GenEtics Consortium (EAGLE)the Wellcome Trust Case Control Consortium 2 (WTCCC2)Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.Lancet Oncol. 2016; (published online August 12.)http://dx.doi.org/S1470-2045(16)30240-6Google Scholar report their attempts to systematically prioritise genetic loci by doing a meta-analysis of all publicly available data from genome-wide association studies. Nine new loci were identified from this meta-analysis, which were within or near the genes CFTR, MSRA, LINC00208 and BLK, KHDRBS2, TPPP and CEP72, TMOD1, SATB2, HTR3C and ABCC5, and LPA. Furthermore, for the first time, a risk locus specific to oesophageal adenocarcinoma and independent of risk for Barrett's oesophagus was found—rs9823696, close to HTR3C and ABCC5. A pathway analysis showed an association of these nine loci with muscle-cell differentiation, which is relevant because Barrett's oesophagus and oesophageal adenocarcinoma are caused proximally by defective relaxation of the muscular lower oesophageal sphincter. The novel locus with the strongest risk for oesophageal adenocarcinoma was located within CFTR; mutations within this gene are associated with cystic fibrosis. Gastro-oesophageal reflux has been associated with cystic fibrosis and is considered part of its phenotypic spectrum. Thus, this particular locus is a candidate that potentially links two common syndromes previously thought to be unrelated. The CFTR protein belongs to the ATP-binding cassette (ABC) class of transporters that transmits ions across cell membranes; its defective function (leaky—ie, permitting defective ion transport) is pathogenic in patients with cystic fibrosis. Moreover, the risk locus unique to oesophageal adenocarcinoma, rs9823696 (close to HTR3C and ABCC5), also encodes an ABC-family ion-channel transporter. Thus, these two particular associations might link leaky ion transport with a leaky lower oesophageal sphincter. This association could represent a new area of research into the pathogenesis of Barrett's oesophagus and oesophageal adenocarcinoma. The research by Gharahkhani and colleagues provides some much-needed perspective on the wealth of data now accumulating in this area of medicine. Even if not proven to be disease causing, loci highlighted by this study might become valuable, singly or in aggregate, for the risk stratification of patients with gastro-oesophageal reflux disorder, Barrett's oesophagus, or perhaps those at risk of either of these two syndromes. In particular, rs9823696 could be useful for identifying individuals with Barrett's oesophagus who are at highest risk of developing oesophageal adenocarcinoma. Moreover, if one or more of these variants prove to have a pathophysiological role in Barrett's oesophagus or oesophageal adenocarcinoma, they could become pivotal in the design of novel preventative or therapeutic strategies. I declare no competing interests. Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysisOur 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. Full-Text PDF Open Access