p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis

Abstract

Purpose: This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships.

Experimental design: A cohort of 371 patients with esophageal carcinoma enrolled in Boston, USA from 1999 to 2004 were genotyped for the p53 and MDM2 SNPs. Associations between genotypes and overall survival (OS; the primary outcome) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Cox proportional hazard models, adjusted for age, stage, performance status, and smoking were developed. Interaction analyses were done for histology (adenocarcinoma versus squamous cell carcinoma).

Results: At the median follow-up of 33 months, median survival (MS) and PFS were 29.1 and 15.7 months, respectively. p53 Pro/Pro was strongly associated with shorter survival in the entire cohort (MS of 11.8 versus 29.1 months, P < 0.0001; adjusted hazard ratio for death, 2.05; 95% confidence interval, 1.30-3.24; P = 0.002 for Pro/Pro versus Arg/Arg). MDM2 G/G was associated with markedly reduced survival in squamous cell carcinoma (MS of 10.3 versus 49.4 months; adjusted hazard ratio for death, 7.9; 95% confidence interval, 2.4-26.0; P = 0.0007 for G/G versus T/T) but not in adenocarcinoma (SNP-histology interaction P = 0.004).

Conclusions: In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma.

Fig. 1

Kaplan-Meier analysis of (A) OS and (B) PFS in all participants by p53 Arg72Pro genotype.

Fig. 2

Kaplan-Meier analysis of OS and PFS by MDM2 T309G genotype in histologic subgroups. The G/G genotype was associated with significantly shorter OS and PFS in the squamous cell carcinoma subgroup (A, B), but not in the adenocarcinoma subgroup (C, D; P = 0.004 for SNP-histology interaction).