Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:34437-34445. https://doi.org/10.18632/oncotarget.5255

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Abstract

Kathy L. McGraw1,*, Thomas Cluzeau1,2,3,4,5,*, David A. Sallman1, Ashley A. Basiorka6, Brittany A. Irvine1, Ling Zhang7, P.K. Epling-Burnette8, Dana E. Rollison9, Mar Mallo10, Lubomir Sokol1, Francesc Solé10, Jaroslaw Maciejewski11, Alan F. List1

1Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

2Hematology Department, CHU of Nice, Nice, France

3University Nice Sophia Antipolis, Faculty of Medicine, Nice, France

4Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France

5French Group of Myelodysplasia, France

6Moffitt Cancer Center and Research Institute and The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA

7Department of Pathology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

8Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

9Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA

10Institut de Recerca Contra la Leucèmia Josep Carreras (IJC) Badalona, Barcelona, Spain

11Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA

*These authors have contributed equally to this work

Correspondence to:

Kathy L. McGraw, e-mail: [email protected]

Keywords: TP53, MDM2, myelodysplastic syndromes, single nucleotide polymorphisms, survival

Received: June 02, 2015     Accepted: September 14, 2015     Published: September 25, 2015

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.


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