Genetic Predictors of AML Treatment Response

描述（由申请人提供）：尽管急性髓性白血病（AML）在儿童和成人中都造成了巨大的治疗负担，但AML的治疗反应仍然不完全清楚。本申请提出了一项儿科AML治疗反应的全基因组关联研究（GWAS）。这一应用背后有两个假设。首先，体细胞遗传变异会改变AML复发和治疗相关感染风险。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中得到检验。Aim 1将使用Illumina Human 610 HH Bead芯片对840名患者进行GWAS，以确定与AML复发和感染并发症风险相关的基因型。Aim 2将使用Illumina Infinium芯片在1,160名高加索患者和750名非高加索患者中验证Aim 1中发现的4%的snp。目标3将使用CTS来测试前两个目标中发现和验证的感染易感基因型的临床适用性。这一应用具有重要意义，既是AML中的第一个GWAS，也是将遗传变异数据转化为患者临床护理的新一步。此外，由于儿童和成人AML具有共同的分子病理和治疗策略，本研究可能为成人和儿童AML患者的护理提供信息。

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. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) causes a substantial disease and treatment burden in both children and adults. This application will provide data on the role of somatic genetic variability in AML treatment response and will use clinical trial simulations to model the application of genotype data to clinical patient care. Thus, this application may not only inform the care of adult and pediatric AML patients, but may also provide important insights into the translation of genotype data into patient care.