Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes

儿童白血病结果的种族差异的药物基因组学

• 批准号: 8046829
• 负责人: MARY V RELLING
• 金额: $ 173.18万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046829
• 关键词: Acute Lymphocytic Leukemia; Adherence; Admixture; Adult; Adverse drug effect; Adverse reactions; Affect; African; Area; Asians; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Children' s Oncology Group; Clinical; Coupled; Data Set; Disease; Drug Exposure; Enrollment; Ethnic Origin; Ethnic group; European; Exposure to; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Glucocorticoids; Goals; Health; Health Care Reform; Hispanics; Intervention; Knowledge; Malignant Neoplasms; Maps; Methotrexate; Modeling; Native Americans; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phase III Clinical Trials; Phenotype; Population; Race; Randomized; Regimen; Relapse; Research Infrastructure; Resistance; Risk; Saint Jude Children' s Research Hospital; Science; Study models; Testing; Time; Treatment outcome; Variant; abstracting; antileukemic agent; base; chemotherapy; cohort; cost; design; genome wide association study; genome-wide; high risk; high throughput technology; improved; racial and ethnic; racial and ethnic disparities; racial difference; response; thiopurine; tool; tumor

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.

描述（由申请人提供）：我们的项目与“应用基因组学和其他高通量技术”的 RC4 领域以及“利用科学实现医疗保健改革”相关。我们将全面探讨基因组变异如何影响结果，并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，可以在申请的时间内进行分析；新员工与 ARRA 的目标一致；利用 COG 和 St. Jude 的现有基础设施，该项目在资助期结束后仍可持续。 ALL 是药物反应性肿瘤的模型：治愈率接近 85%，但高治愈率的代价是常见的严重药物不良反应。对于这种疾病，药物基因组学测试可以允许个体化用药，以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，西班牙裔患者较高的复发率与基因组因素有关，并且某些治疗方法似乎可以消除这种结果的差异。我们知识上的差距在于，我们还不知道这些种族/民族差异背后的基因组机制，也不清楚这些差异是否存在于最现代的 ALL 治疗方案中。在此应用中，我们利用最新的儿童肿瘤学组 (COG) III 期临床试验，并测试了以下假设：血统相关的遗传变异导致 ALL 治疗结果的种族差异，部分是通过调节抗白血病药物的反应和处置来实现的。在目标 1 中，我们将研究已入组 COG AALL0232 高风险 ALL 试验的约 2500 名患者，确定全球遗传祖先组成对 ALL 复发风险的影响，以及随机治疗干预措施对该贡献的影响。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，我们将使用混合图谱来确定哪些特定种系遗传变异会导致 ALL 结局中的种族/民族差异。在目标 3 中，我们将在 COG 试验 (AALL03N1，n ~ 720) 中评估与血统相关复发风险相关的基因组血统是否与抗白血病药物暴露（药物处置和依从性）相关，该试验专门设计用于评估种族和族裔对这些表型的贡献，并确定哪些多态性通过影响硫嘌呤暴露而导致结果中的种族差异。最终目标是实施药物基因组学测试来定制药物，以消除所有结果中的种族差异并降低复发风险，COG 和 St. Jude 已经在过去的试验中使用了这一策略。这些发现适用于在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，不同种族/族裔群体的治愈率存在差异。利用基因组学的新工具，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/民族群体之间在抗白血病药物暴露方面的差异。从长远来看，我们的目标是消除治愈率方面的种族/民族差异。