TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes.

Kathy L Mcgraw,P.K Epling-Burnette,Ling Zhang,Francesc Solé,Lubomir Sokol,Jaroslaw Maciejewski,Ashley A Basiorka,Mar Mallo,Alan F List,Brittany A Irvine,David A Sallman,Thomas Cluzeau,Dana E Rollison

doi:10.18632/oncotarget.5255

Abstract

P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome.

Highlights

The myelodysplastic syndromes (MDS) share phenotypic features of dysplastic and ineffective hematopoiesis accompanied by remarkable hematologic, genetic and clinical heterogeneity
We examine the effect of the combination of TP53 R72P and murine double minute-2 (MDM2) SNP309 on clinical features of del(5q) and non-del(5q) MDS, and find significant differences in survival based on genotypic interaction
We have shown that the predicted activity of p53 has prognostic importance in non-del(5q) MDS

Summary

INTRODUCTION

The myelodysplastic syndromes (MDS) share phenotypic features of dysplastic and ineffective hematopoiesis accompanied by remarkable hematologic, genetic and clinical heterogeneity. There have been a number of studies analyzing the effects of R72P and SNP309 interactions in solid tumors, demonstrating combined effects on clinical features and prognosis of disease [22,23,24]. Previous reports of these SNP combinations in MDS did not distinguish between del(5q) and non-del(5q) MDS patients [16]. We examine the effect of the combination of TP53 R72P and MDM2 SNP309 on clinical features of del(5q) and non-del(5q) MDS, and find significant differences in survival based on genotypic interaction

RESULTS

DISCUSSION

MATERIALS AND METHODS