McGraw Kathy L, Cluzeau Thomas, Sallman David A, Basiorka Ashley A, Irvine Brittany A, Zhang Ling, Epling-Burnette P K, Rollison Dana E, Mallo Mar, Sokol Lubomir, Solé Francesc, Maciejewski Jaroslaw, List Alan F
Department of Malignant Hematology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Hematology Department, CHU of Nice, Nice, France.
Oncotarget. 2015 Oct 27;6(33):34437-45. doi: 10.18632/oncotarget.5255.
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.
P53是许多细胞过程的关键调节因子，受小鼠双微体2（MDM2）E3泛素连接酶的人类同源物负调控。这两个基因单独或联合的单核苷酸多态性（SNP）均与癌症易感性、疾病进展及治疗反应相关。我们分析了TP53 R72P和MDM2 SNP309 SNP的相互作用与骨髓增生异常综合征（MDS）患者预后的关系。对208例MDS病例的DNA进行了桑格测序。利用基于预测的p53活性从+2到 -2的新型功能性SNP评分系统，我们发现功能评分低的非del(5q) MDS患者的总生存期（OS）（p = 0.02）和无进展生存期（PFS）（p = 0.02）存在统计学显著差异。在单变量分析中，仅国际预后评分系统（IPSS）和功能性SNP评分可预测非del(5q)患者的OS和PFS。在多变量分析中，功能性SNP评分在OS和PFS方面独立于IPSS。这些数据强调了TP53 R72P和MDM2 SNP309 SNP在MDS中的重要性，并提供了一种独立于IPSS的新型评分系统，可预测疾病预后。
