MDM2 SNP309 and TP53 Arg72Pro interact to alter therapy-related acute myeloid leukemia susceptibility
MDM2 SNP309 and TP53 Arg72Pro interact to alter therapy-related acute myeloid leukemia susceptibility
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DOI：
10.1182/blood-2007-11-126508
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发表时间：
2008-08-01
期刊：
影响因子：
20.3
通讯作者：
Onel, Kenan
中科院分区：
文献类型：
--
作者：
Ellis, Nathan A.;Huo, Dezheng;Onel, Kenan
P53肿瘤抑制因子可引导细胞对多种不同的DNA损伤因子的反应，在治疗相关的急性髓系白血病(t-AML)的发病机制中被选用。我们假设p53通路中的结构性遗传变异会影响t-AML的风险。因此，我们测试了t-AML患者(n=171)与两种常见的功能性P53途径变异，MDM2 SNP309和TP53密码子72多态之间的相关性。虽然两种基因多态性都不单独影响t-AML的风险，但发现了交互作用，使得MDM2 TT TP53 Arg/Arg双纯合子以及同时携带MDM2 G等位基因和TP53 Pro等位基因的个体患t-AML的风险增加(交互作用的P值为0.009)。这种交互作用在以前接受化疗的患者中观察到，但在接受放射治疗的患者中观察到，在5号和/或7号染色体丢失的患者中观察到，这些患者与之前接触烷化化疗有关的获得性异常。此外，在MDM2 GG患者中，与TT纯合子相比，女性患者t-AML潜伏期更短，但在男性患者中没有，在年轻患者中，但在老年患者中没有。这些数据表明，MDM2和TP53变异相互作用，调节对基因毒性治疗的反应，是t-AML风险的决定因素。
The p53 tumor suppressor directs the cellular response to many mechanistically distinct DNA-damaging agents and is selected against during the pathogenesis of therapy-related acute myeloid leukemia (t-AML). We hypothesized that constitutional genetic variation in the p53 pathway would affect t-AML risk. Therefore, we tested associations between patients with t-AML (n = 171) and 2 common functional p53-pathway variants, the MDM2 SNP309 and the TP53 codon 72 polymorphism. Although neither polymorphism alone influenced the risk of t-AML, an interactive effect was detected such that MDM2 TT TP53 Arg/Arg double homozygotes, and individuals carrying both a MDM2 G allele and a TP53 Pro allele, were at increased risk of t-AML (P value for interaction is.009). This interactive effect was observed in patients previously treated with chemotherapy but not in patients treated with radiotherapy, and in patients with loss of chromosomes 5 and/or 7, acquired abnormalities associated with prior exposure to alkylator chemotherapy. In addition, there was a trend toward shorter latency to t-AML in MDM2 GG versus TT homozygotes in females but not in males, and in younger but not older patients. These data indicate that the MDM2 and TP53 variants interact to modulate responses to genotoxic therapy and are determinants of risk for t-AML.