Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes

描述（由申请人提供）：我们的项目与RC 4领域的“应用基因组学和其他高通量技术”和“利用科学实现卫生保健改革”有关。“我们将全面研究基因组变异如何影响结果，再加上对大型临床数据集的综合分析，以了解与祖先背景相关的多态性如何影响急性淋巴细胞白血病（ALL）复发风险。该项目已准备就绪，可以在申请的时间范围内进行分析;新员工与ARRA的目标一致;利用COG和St. Jude的现有基础设施，该项目在资助期后可持续发展。ALL作为药物反应性肿瘤的模型：治愈率接近85%，但这些高治愈率的成本涉及常见的严重药物不良反应。这是一种疾病，其中药物基因组学测试可以允许个体化的药物治疗，以进一步提高治愈率和最大限度地减少药物不良反应。ALL也是研究健康结果中种族和民族差异的模型。西班牙裔患者的复发风险高于其他种族群体。我们的研究小组最近表明，西班牙裔美国人的这种较高复发率存在基因组成分，并且这种结果的差异似乎可以通过某些疗法消除。我们知识上的差距是，我们还不知道这些种族/民族差异的基因组机制，也不确定这些差异是否存在于最现代的ALL治疗方案中。在本申请中，我们利用最新的儿童肿瘤学组（COG）III期临床试验，并测试的假设，即祖先相关的遗传变异有助于种族差异的治疗结果的ALL，部分通过调节反应和处置的抗白血病药物。在目标1中，我们将确定全球遗传祖先组成对ALL复发风险的贡献，以及随机治疗干预对该贡献的影响，研究已经入组COG AALL 0232高风险ALL试验的约2500例患者。我们将使用基因组工具来研究美国人口的主要遗传祖先群体，并评估两种治疗随机化的影响。在目标2中，我们将使用混合物图谱来确定哪些特定的生殖系遗传变异导致ALL结局的种族/民族差异。在目标3中，我们将在一项专门设计用于评估人种和种族对这些表型的贡献的COG试验（AALL 03 N1，n ~ 720）中评估与祖先相关复发风险相关的基因组祖先是否与抗白血病药物暴露（药物处置和依从性）相关，并确定哪些多态性通过影响巯基嘌呤暴露导致结局的种族差异。最终的目标将是实施药物基因组学测试，以定制药物，消除所有结果中的种族差异，并减轻复发的风险，这是COG和St. Jude在过去的试验中已经使用的策略。这些发现适用于成人恶性肿瘤和非癌症疾病中使用类似药物。 公共卫生相关性：对于某些疾病，种族/族裔群体之间的治愈率存在差异。随着基因组学的新工具，我们建议确定基因组变异在多大程度上解释了种族/民族群体之间儿童白血病治愈率的差异，涉及哪些基因，以及这些基因变异是否解释了种族/民族群体之间接触抗白血病药物的差异。从长远来看，我们的目标是消除治愈率的种族/民族差异。

DESCRIPTION (provided by applicant): Our project is relevant to the RC4 areas of "Applying Genomics and Other High Throughput Technologies" and to "Using Science to Enable Health Care Reform." We will comprehensively interrogate how genomic variation affects outcome, coupled with an integrated analysis of large clinical datasets, to understand how polymorphisms that are related to ancestral background affect acute lymphoblastic leukemia (ALL) relapse risk. The project is ready to go and can be analyzed within the time frame of the application; new hires are consistent with the goals of ARRA; using the existing infrastructure of the COG and St. Jude, the project is sustainable beyond the period of funding. ALL serves as a model for drug-responsive tumors: cure rates approach ~85%, but the cost of these high cure rates involves common serious adverse reactions to medications. This is a disease in which pharmacogenomic testing may allow for individualization of medications to further improve cure rates and minimize adverse drug effects. ALL is also a model for the study of racial and ethnic disparities in health outcomes. Patients of Hispanic ethnicity have a higher risk of relapse than other race groups. Our group has recently shown that there is a genomic component to this higher relapse rate in Hispanics, and this disparity in outcome appears to be abrogated by certain therapies. The gap in our knowledge is that we do not yet know the genomic mechanisms that underlie these racial/ethnic disparities, nor is it defined whether these disparities are present in the most modern ALL regimens. In this application, we capitalize on the most recent Children's Oncology Group (COG) phase III clinical trials, and test the hypothesis that ancestry-related genetic variation contributes to racial disparities in treatment outcome of ALL, partly through modulating response to and disposition of anti-leukemic agents. In Aim 1, we will determine the contribution of global genetic ancestral composition to relapse risk in ALL, and the impact of randomized treatment interventions on that contribution, studying the ~ 2500 patients already enrolled on the COG AALL0232 trial for high risk ALL. We will use genomic tools to study the major genetic ancestral groups of the U.S. population and assess the impact of two treatment randomizations. In Aim 2, we will use admixture mapping to identify which specific germ-line genetic variations contribute to racial/ethnic disparities in outcome of ALL. In Aim 3, we will assess whether genomic ancestry associated with ancestry-related relapse risk is associated with anti-leukemic drug exposure (drug disposition and adherence) in a COG trial (AALL03N1, n ~ 720) that has been specifically designed to assess the contribution of race and ethnicity to these phenotypes, and identify which polymorphisms contribute to racial differences in outcome via influencing thiopurine exposure. The eventual goal will be to implement pharmacogenomic testing to tailor medications to eliminate racial disparities in ALL outcomes and to mitigate the risk of relapse, a strategy that the COG and St. Jude have already used in past trials. These findings have applicability for use of similar drugs in adult malignancies and in non-cancer conditions. PUBLIC HEALTH RELEVANCE: For some diseases, there are differences among racial/ethnic groups in cure rates. With the new tools of genomics, we propose to identify the extent to which genomic variation explains the differences among race/ethnicity groups in cure rates for childhood leukemia, what genes are involved, and whether those gene variations explain differences among race/ethnic groups in exposure to anti-leukemic medications. Long term, we aim to eradicate race/ethnicity differences in cure rates.