Association of the MDM2 T309G polymorphism and gastroesophageal reflux disease (GERD) with overall survival (OS) in esophageal adenocarcinoma (EAC).

Abstract

Background: MDM2 is an oncogene that regulates p53. The MDM2 T309G polymorphism has been found to be prognostic in several cancers. GERD is an important risk factor for the development of EAC. This study aims to validate the prognostic significance of MDM2 T309G in patients (pts) with EAC, and to assess the impact of GERD on the genotype-outcome relationship. Methods: A cohort of 348 pts with EAC from 1999-2004 were included. DNA was extracted and genotyped for MDM2 T309G (rs2279744) using TaqMan. Clinical data including GERD history and survival were collected for all pts. Associations between genotype, GERD, and genotype-GERD strata with OS were assessed using Kaplan-Meier Method and log rank test. Adjusted hazard ratios (AHR) and genotype-GERD interactions were determined using Cox proportional hazards models, adjusting for age, stage, performance status (PS), and smoking status. Results: Median age was 64 (range 21-91). Pts were 89% male, 82% PS 0-1, Stage I or II (31%), Stage III (50%), Stage IV (19%). 69% of pts were treated with cisplatin-based therapy. 216 (62%) pts had a history of GERD. Median follow up was 32 mo and median survival was 29 mo. In the 348 pts the polymorphism followed Hardy-Weinberg equilibrium (37% T/T, 49% T/G, 14% G/G). For the entire cohort, G/G was associated with significantly shorter survival (median OS 20.9 mo for G/G vs. 30.4 mo for T/-, p<0.001; AHR 1.6, 95% C.I. 1.1-2.3). GERD status alone was not prognostic (p=0.52). When genotype was analyzed by GERD status, G/G was associated with significantly shorter survival in pts without GERD (median OS 9.2 mo for G/G vs. 29.1 mo for T/-, p<0.001; AHR 3.4, 95% C.I. 2.0-5.9). There was no association between G/G and survival in pts with GERD (median OS 27.1 mo for G/G vs. 32.6 mo for T/-, p=0.19; AHR 1.1, 95% C.I. 0.7-1.7). The genotype-GERD interaction was significant (p=0.002). Conclusions: In a large EAC cohort, the MDM2 T309G G/G genotype was associated with decreased OS. When analyzed by GERD, G/G was associated with a 3.4 fold increased risk of death in pts without GERD, but not prognostic in pts with GERD. This suggests that there may be important biological differences between GERD positive and GERD negative EAC.