Meta-analysis Identifies New Genetic Variants for Barrett’s Esophagus and Esophageal Adenocarcinoma


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As reported in The Lancet Oncology, Puya Gharahkhani, PhD, of QIMR Berghofer Medical Research Institute, Brisbane, Australia, and colleagues identified several new genetic risk variants for the development of Barrett’s esophagus and esophageal adenocarcinoma through a large-scale meta-analysis of genome-wide studies.

The study involved a meta-analysis of four genome-wide association studies of Barrett’s esophagus and esophageal adenocarcinoma. All patients were of European ancestry and were from studies in Europe, North America, and Australia.

Patients were genotyped on high-density single-nucleotide polymorphism arrays. Overall, the population consisted of 6,167 patients with Barrett’s esophagus, 4,112 with esophageal adenocarcinoma, and 17,159 representative controls from the 4 studies.

New Risk Variants

A total of eight new risk loci were found to be associated with either Barrett’s esophagus or esophageal adenocarcinoma. They were located within or near the genes CFTR (rs17451754, P = 4.8 × 10-10), MSRA (rs17749155, P = 5.2 × 10-10), LINC00208 and BLK (rs10108511, P = 2.1 × 10-9), KHDRBS2 (rs62423175, P = 3.0 × 10-9), TPPP and CEP72 (rs9918259, P = 3.2 × 10-9), TMOD1 (rs7852462, P = 1.5 × 10-8), SATB2 (rs139606545, P = 2.0 × 10-8), and HTR3C and ABCC5 (rs9823696, P = 1.6 × 10-8). The locus near HTR3C and ABCC5 was specifically associated with risk for esophageal adenocarcinoma (P = 1.6 × 10-8) and was independent of the risk for Barrett’s esophagus (P = .45). An additional novel locus was identified within the LPA gene (rs12207195, posterior probability 0.925) after reweighting with enriched annotations. The strongest disease pathways (P < 10-6) involved muscle cell differentiation and mesenchyme development and differentiation.

The investigators concluded: “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.”

The study was funded by the U.S. National Cancer Institute and the National Institutes of Health, the National Health and Medical Research Council of Australia, the Swedish Cancer Society, the Medical Research Council UK, and Cambridge NIHR Biomedical Research.

Gharahkhani P, et al: Lancet Oncol 17:1363-1373, 2016. 



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