Barrett’s Oesophagus, Oesophageal Adenocarcinoma Risk Loci ‘Doubled’

Novel risk loci add to understanding of Barrett’s oesophagus and oesophageal adenocarcinoma

medwireNews: A meta-analysis has identified nine new risk loci associated with Barrett’s oesophagus or oesophageal adenocarcinoma, extending knowledge of the pathogenesis of, and transition between, the diseases.

Noting that their study “represents a doubling of the number of known risk loci”, the researchers report that the strongest variant is located within CFTR, a gene associated with cystic fibrosis, a condition characterised by an increased incidence of gastro-oesophageal reflex.

“Therefore, our data suggest that cystic fibrosis, Barrett's oesophagus, and oesophageal adenocarcinoma might have a common pathophysiological feature of gastro-oesophageal reflux, with CFTR playing an important part in this process”, they write.

The research included 6167 patients with Barrett’s oesophagus, 4112 patients with oesophageal adenocarcinoma and 17,159 unaffected individuals participating in four genome-wide association studies based in Europe, North America and Australia.

Genome-wide analysis of the Barrett’s oesophagus patients identified five loci significantly associated with the reflux-associated condition, including three novel loci.

Assessment of the oesophageal adenocarcinoma patients detected five loci significantly linked to the malignancy, four of which have not previously been reported, say Puya Gharahkhani, from QIMR Berghofer Medical Research Institute in Brisbane, Queensland, Australia, and co-workers.

And combined analysis of the patient groups identified 14 genome-wide significant associated loci – including seven novel loci – with all but one of the new loci also significantly linked to disease in both the individual analyses for Barrett’s oesophagus and oesophageal adenocarcinoma, the team reports in The Lancet Oncology.

The exception – locus rs9823696 on chromosome 3q27 near HTR3C and ABCC5 – was found only in patients with oesophageal adenocarcinoma, with an odds ratio of 1.17.

“This variant might constitute a novel marker for the prediction of transition from Barrett's oesophagus to oesophageal adenocarcinoma”, the researchers hypothesize.

Stephen Meltzer, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, explains in an accompanying comment that the defective CTFR protein in cystic fibrosis, known to cause cell membranes to be “leaky” to ions, may connect two common syndromes thought previously unrelated.

“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”, he writes.

“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.”


Gharahkhani P, Fitzgerald RC, Vaughan TL, et al. Genome-wide association studies in oesophageal adenocarcinoma and Barrett’s oesophagus: a large-scale meta-analysis. Lancet Oncol 2016; Advance online publication 12 August . DOI:

Meltzer SJ. Leaky transporters and sphincters in Barrett’s oesophagus. Lancet Oncol 2016; Advance online publication 12 August . DOI:

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