P53 Arg72Pro, MDM2 T309G, CCND1 G870A polymorphisms, histology and esophageal cancer prognosis

Abstract

11033 Background: Regulation of cell cycle and apoptosis are central to the biology of cancer. Three key genes in these pathways contain functional single nucleotide polymorphisms (SNPs) (p53 Arg72Pro, MDM2 T309G and CCND1 G870A) which have been implicated in the behavior and prognosis of several cancers. We evaluated the prognostic significance of these SNPs on overall survival (OS) and progression-free survival (PFS) in a large cohort of patients with esophageal cancer. The role of tumor histologic subtype in these relationships was explored. Methods: 371 patients with esophageal carcinoma were genotyped for the p53, MDM2 and CCND1 SNPs. Most patients were treated with tri-modality cisplatin-based therapy. Associations between genotypes and OS and PFS were assessed using the Kaplan-Meier method with log-rank test. Cox proportional hazard models, adjusted for age, stage, performance status (PS) and smoking were developed. Stratified and interaction analyses were performed for adeno- (ADC) and squamous cell carcinoma (SCC) subgroups. Results: Median age was 64 (range 21 - 91). Patients were 86% male, 98% Caucasian, 86% PS 0–1 and Stage I (7%), II (41%), III (28%) and IV (24%). Tumor histology was ADC in 81%, SCC in 17% and poorly differentiated in 2%. At 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 worse outcome in the entire cohort (MS 11.8 vs 29.1 mo, p<0.0001). MDM2 G/G had markedly reduced survival in SCC (MS 10.3 vs 49.4 mo; AHR 7.9 (95% CI 2.4 - 26.0), p = 0.0007 and PFS 5.3 vs. 24.8 mo; AHR 9.8 (95% CI 3.0 - 31.9), p= 0.0002) but not ADC. Results remain significant after Bonferroni correction. CCND1 genotype was not associated with outcomes in any subgroup. Conclusions: In a large prospective study of esophageal cancer prognosis, p53 Arg72Pro Pro/Pro is associated with worse outcome and MDM2 T309G G/G is associated with worse outcome in SCC. In contrast to prior studies, no association between CCND1 G870A genotype and outcome was detected. Genotypes and survival outcomes in entire study cohort Overall Survival Progression-FreeSurvival Genotype GenotypeFrequency(%) MS(mo) LogRank AHR(95% CI) p* PFS(mo) LogRank AHR(95% CI) p* p53 72 Pro/Pro(vs. Arg/Arg) 9 vs.51 11.8 vs.29.1 <0.0001 2.05 (1.30- 3.24) 0.002 7.9 vs.17.4 0.0018 2.03 (1.29- 3.18) 0.002 MDM2 309 G/G(vs. T/T) 12 vs.40 22.0 vs. 29.6 0.06 1.15 (0.76 - 1.74) 0.51 10.5 vs. 18.0 0.09 1.14 (0.76- 1.72) 0.52 CCND1 870 A/A(vs G/G) 21 vs.28 27.3 vs.33.7 0.47 1.14 (0.76- 1.70) 0.53 12.0 vs.19.7 0.24 1.17 (0.80- 1.70) 0.41 * corresponding to Cox proportional hazards model, adjusted for age, stage, PS and pack-years smoking No significant financial relationships to disclose.