Association of MDM2 T309G and p53 Arg72Pro polymorphisms and gastroesophageal reflux disease with survival in esophageal adenocarcinoma

Abstract

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.