title: TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes.
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.
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Hematology Department, CHU of Nice, Nice, France.|University Nice Sophia Antipolis, Faculty of Medicine, Nice, France.|Mediterranean Center of Molecular Medicine, INSERM U1065, Nice, France.|French Group of Myelodysplasia, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cluzeau
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sallman
authors.affiliation: Moffitt Cancer Center and Research Institute and The Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA.
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Irvine
authors.affiliation: Department of Pathology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.affiliation: Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Rollison
authors.affiliation: Institut de Recerca Contra la Leucèmia Josep Carreras (IJC) Badalona, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mallo
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.affiliation: Institut de Recerca Contra la Leucèmia Josep Carreras (IJC) Badalona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Solé
authors.affiliation: Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
authors.affiliation: Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; TP53; myelodysplastic syndromes; single nucleotide polymorphisms; survival