Genetic Predictors of AML Treatment Response

描述（由申请人提供）：尽管急性髓性白血病（AML）在儿童和成人中造成了巨大的治疗负担，但AML治疗反应仍不完全清楚。该申请提出了一项儿科急性髓性白血病治疗反应的全基因组关联研究（GWAS）。这一应用基于两个假设。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）可以定义遗传变异数据如何用于修改AML治疗。这些假设将在三个具体目标中得到检验。目标1将使用Illumina Human 610 HH Bead Chip对840例患者进行GWAS，以确定与AML复发和感染并发症风险相关的基因型。目标2将使用Illumina Infinium”芯片验证目标1中发现的1,160名白人患者和750名非白人患者中4%的SNP。目的3将使用CTS来测试在前两个目的中发现和验证的感染易感基因型的临床适用性。该应用具有重要意义，既作为AML中的第一个GWAS，又作为将遗传变异性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，因此这项研究可以为成人和儿童AML患者的护理提供信息。 公共卫生相关性：急性髓性白血病（AML）在儿童和成人中均会造成巨大的疾病和治疗负担。该应用程序将提供关于AML治疗反应中体细胞遗传变异性作用的数据，并将使用临床试验模拟来模拟基因型数据在临床患者护理中的应用。因此，该应用程序不仅可以告知成人和儿童AML患者的护理，而且还可以提供将基因型数据转化为患者护理的重要见解。

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.