TP53 R72P and MDM2 SNP309 polymorphisms in modification of childhood acute lymphoblastic leukemia susceptibility
TP53 R72P and MDM2 SNP309 polymorphisms in modification of childhood acute lymphoblastic leukemia susceptibility
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DOI：
10.1016/j.cancergencyto.2009.05.009
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发表时间：
2009-11-01
影响因子：
--
通讯作者：
Dorak, M. Tevfik
中科院分区：
文献类型：
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作者：
Do, Thuy N.;Ucisik-Akkaya, Esma;Dorak, M. Tevfik
基因组和免疫监测机制在预防癌症方面至关重要。肿瘤抑制蛋白P53由TP53编码，是基因组监测的主要调节因子。在TP53的自然序列变体中，rs1042522(R72P)改变了实体肿瘤的风险。为探讨其与儿童急性淋巴细胞性白血病(ALL)易感性的关系，我们对114例Wales(UK)患儿和414例新生儿对照进行了TP53(R72P)及其负调控基因MDM2(单核苷酸多态性SNP309，rs2279744)的基因分型，并筛选出与TP53相互作用的人类白细胞抗原复合体基因。Tp53R72P与基因剂量效应相关(P=0.002)，与纯合子基因相关(OR=2.9，95%CI=1.5~5.6)，无性别效应。SNP309与儿童ALL的原发易感性没有任何关联，即使在按性别分层后也是如此。然而，携带SNP309等位基因的女性儿童ALL发病较早(女性确诊时的中位年龄为36个月，而男性为60个月；P=0.002)。人类白细胞抗原复合体基因与R72P无统计学意义的相互作用。因此，我们确定TP53R72P可能是儿童ALL的风险修饰物，MDM2与发病年龄和性别效应的关联表明，产前激素计划是儿童ALL易感性的一个因素。(C)2009 Elsevier Inc.保留所有权利。
Genomic and immunologic surveillance mechanisms are crucial in protection from cancer. The tumor suppressor protein p53, encoded by TP53, is a major regulator of genome surveillance. Among the natural sequence variants of TP53, rs1042522 (R72P) modifies the risk for solid tumors. To investigate its relevance in childhood acute lymphoblastic leukemia (ALL) susceptibility, we genotyped 114 cases and 414 newborn controls from Wales (UK) for polymorphisms in TP53 (R72P), its negative regulator MDM2 (single-nucleotide polymorphism SNP309, rs2279744), and selected HLA complex genes whose products interact with TP53. TP53 R72P showed a risk association with gene dosage effect (P=0.002) resulting in a strong association of homozygous genotype (OR=2.9, 95% CI=1.5-5.6) and no sex effect. SNP309 did not show any association with primary susceptibility to childhood ALL, even after stratification by sex. However, females with SNP309 minor allele had earlier onset of childhood ALL (median age at diagnosis was 36 months in females, but 60 months in males; P=0.002). The HLA complex genes did not show any statistically significant interaction with R72P. We have therefore identified TP53 R72P as a possible risk modifier for childhood ALL and the association of MDM2 with age at onset with sex effect suggests prenatal hormonal programming of childhood ALL susceptibility. (C) 2009 Elsevier Inc. All rights reserved.