Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes

描述（由申请人提供）：我们的项目与RC4领域“应用基因组学和其他高通量技术”和“利用科学促进医疗改革”相关。我们将全面询问基因组变异如何影响结果，结合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。项目已准备就绪，可以在应用程序的时间框架内进行分析；新员工符合ARRA的目标；利用COG和St. Jude的现有基础设施，该项目在资助期内是可持续的。ALL作为药物反应性肿瘤的模型：治愈率接近85%，但这些高治愈率的代价包括常见的严重药物不良反应。在这种疾病中，药物基因组学测试可以使药物个性化，从而进一步提高治愈率，并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一个模型。西班牙裔患者的复发风险高于其他种族。我们的研究小组最近发现，西班牙裔患者复发率较高与基因组有关，而这种差异似乎可以通过某些治疗方法消除。我们的知识差距在于，我们还不知道这些种族/民族差异背后的基因组机制，也不确定这些差异是否存在于大多数现代ALL方案中。在本应用中，我们利用了最新的儿童肿瘤组（COG） III期临床试验，并检验了与血统相关的遗传变异导致ALL治疗结果的种族差异的假设，部分原因是通过调节抗白血病药物的反应和处置。在Aim 1中，我们将确定全局遗传祖先组成对ALL复发风险的贡献，以及随机治疗干预对这一贡献的影响，研究了约2500名已经参加COG AALL0232高风险ALL试验的患者。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，并评估两种随机化治疗的影响。在目标2中，我们将使用混合作图来确定哪些特定的种系遗传变异导致了ALL结果的种族/民族差异。在Aim 3中，我们将在一项COG试验（AALL03N1, n ~ 720）中评估与祖先相关的复发风险相关的基因组祖先是否与抗白血病药物暴露（药物配置和依从性）相关，该试验专门设计用于评估种族和民族对这些表型的贡献，并确定哪些多态性通过影响硫嘌呤暴露导致了结果的种族差异。最终的目标将是实施药物基因组学测试来定制药物，以消除ALL结果的种族差异，并降低复发的风险，这是COG和St. Jude在过去的试验中已经使用的策略。这些发现适用于在成人恶性肿瘤和非癌症条件下使用类似药物。

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.