A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.
Levine DM., Ek WE., Zhang R., Liu X., Onstad L., Sather C., Lao-Sirieix P., Gammon MD., Corley DA., Shaheen NJ., Bird NC., Hardie LJ., Murray LJ., Reid BJ., Chow W-H., Risch HA., Nyrén O., Ye W., Liu G., Romero Y., Bernstein L., Wu AH., Casson AG., Chanock SJ., Harrington P., Caldas I., Debiram-Beecham I., Caldas C., Hayward NK., Pharoah PD., Fitzgerald RC., Macgregor S., Whiteman DC., Vaughan TL.
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.