Genetic Predictors of AML Treatment Response

描述(申请人提供)：尽管急性髓系白血病(AML)对儿童和成人都造成了巨大的治疗负担，但AML的治疗反应仍不完全清楚。这项申请提出了一项关于儿童急性髓细胞白血病治疗反应的全基因组关联研究(GWAS)。两个假设构成了这一应用的基础。首先，体细胞遗传变异将改变AML复发和治疗相关的感染风险。其次，临床试验模拟(CTS)可以定义如何使用遗传变异数据来修改AML治疗。这些假设将在三个具体目标上得到检验。目的1将使用Illumina Human 610 HH珠芯片对840名患者进行GWA，以确定与AML复发和感染性并发症风险相关的基因类型。Aim 2将使用Illumina Infinium“芯片验证在AIM 1中发现的4%的SNPs，这些SNP在1,160名高加索患者和750名非高加索患者中被发现。Aim 3将使用CTS来测试在前两个AIM中发现和验证的感染易感基因的临床适用性。作为AML中的第一个GWA，这一应用具有重要意义，并作为将遗传变异数据转化为患者临床护理的新步骤。此外，由于儿童和成人AML具有共同的分子病理学和治疗策略，这项研究可能为成人和儿童AML患者的护理提供参考。

DESCRIPTION (provided by applicant): Although acute myeloid leukemia (AML) causes substantial treatment burden in both children and adults, AML treatment response remains incompletely understood. This application proposes a genome-wide association study (GWAS) of pediatric AML treatment response. Two hypotheses underlie this application. First, somatic genetic variation will modify AML relapse and treatment related infection risk. Second, clinical trial simulations (CTS) may define how genetic variation data may be used to modify AML treatment. These hypotheses will be tested in three specific aims. Aim 1 will use the Illumina Human 610 HH Bead Chip to perform a GWAS with 840 patients to identify genotypes associated with AML relapse and infectious complication risk. Aim 2 will use the Illumina Infinium" Chip to validate 4% of SNPs found in Aim 1 in 1,160 Caucasian patients and 750 non-Caucasian patients. Aim 3 will use CTS to test the clinical applicability of infection susceptibility genotypes discovered and validated in the first two aims. This application has significance both as the first GWAS in AML and as a novel step towards translating genetic variability data into the clinical care of patients. Furthermore, since pediatric and adult AML share common molecular pathologies and treatment strategies, this research may inform the care of both adult and pediatric AML patients.