Conflicts of interest: None of the authors has any relevant conflicts of interest to declare.
Association of MDM2 T309G and p53 Arg72Pro polymorphisms and gastroesophageal reflux disease with survival in esophageal adenocarcinoma
Article first published online: 22 AUG 2013
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 28, Issue 9, pages 1482–1488, September 2013
How to Cite
Renouf, D. J., Zhai, R., Sun, B., Xu, W., Cheung, W. Y., Heist, R. S., Kulke, M. H., Cescon, D., Asomaning, K., Marshall, A. L., Li, S., Christiani, D. C. and Liu, G. (2013), Association of MDM2 T309G and p53 Arg72Pro polymorphisms and gastroesophageal reflux disease with survival in esophageal adenocarcinoma. Journal of Gastroenterology and Hepatology, 28: 1482–1488. doi: 10.1111/jgh.12286
GL and DCC are co-senior authors. DR and RZ are co-first authors.
- Issue published online: 22 AUG 2013
- Article first published online: 22 AUG 2013
- Accepted manuscript online: 4 JUN 2013 05:10AM EST
- Manuscript Accepted: 12 MAY 2013
- Alan Brown Chair (in Molecular Genomics (GL), Cancer Care Ontario Chair in Experimental Therapeutics and Population Studies (GL)
- Posluns Family Fund
- esophageal cancer;
Background and Aim
Although gastroesophageal reflux disease (GERD) is a risk factor for esophageal adenocarcinoma (EAC), some patients develop EAC in the absence of GERD. A putative mechanism of reflux-induced tumorigenesis involves disruptions in the p53 pathway. We assessed the interaction of GERD and p53 pathway polymorphisms on EAC prognosis.
In a prospective cohort of 358 EAC patients, clinical data (including GERD history and survival) were collected. Germline DNA was genotyped for MDM2 T309G and p53 Arg72Pro. Cox proportional hazards models were used to determine adjusted hazard ratios (AHR) for associations between genotype, GERD, and genotype-GERD interactions with survival.
Compared with other genotypes, MDM2 G/G (median overall survival 21 vs 30 months; P < 0.001) and p53 Pro/Pro (12 vs 30 months; P = 0.004) were associated with shorter survival. When analyzed by GERD, MDM2 G/G was associated with shorter survival in patients without GERD (AHR 3.4, 95% CI 2.0–6.0), but not in patients with GERD (AHR 1.1 [0.7–1.8]); the MDM2-GERD interaction was significant (P = 0.003). A similar trend was seen for p53 Pro/Pro (AHRs 2.5 without GERD vs 1.4 with GERD). Combined analysis of at-risk variants (MDM2 G or p53 Pro), revealed each additional at-risk variant was associated with shorter survival in patients without GERD (AHR 1.6) but not with GERD (AHR 1.0).
MDM2 G/G and the combination of MDM2 G and p53 Pro were negative prognostic factors for EAC patients without GERD but not for those with GERD. There may be biological differences between GERD positive and GERD negative EAC.