A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus
David M Levine, Weronica E Ek, Rui Zhang, Xinxue Liu, Lynn Onstad, Cassandra Sather, Pierre Lao-Sirieix, Marilie D Gammon, Douglas A Corley, Nicholas J Shaheen, Nigel C Bird, Laura J Hardie, Liam J Murray, Brian J Reid, Wong-Ho Chow, Harvey A Risch, Olof Nyrén, Weimin Ye, Geoffrey Liu, Yvonne Romero, Leslie Bernstein, Anna H Wu, Alan G Casson, Stephen J Chanock, Patricia Harrington, Isabel Caldas, Irene Debiram-Beecham, Carlos Caldas, Nicholas K Hayward, Paul D Pharoah, Rebecca C Fitzgerald, Stuart MacGregor, David C Whiteman, Thomas L Vaughan
Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett’s esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett’s esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10-10) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10-9) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10-9) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett’s esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.