Genetic susceptibility to unrelated donor stem cell transplant-related mortality

描述(由申请人提供)：这项研究的总体目的是为了更好地了解在无血缘关系的供者血液或骨髓移植(BMT)后，遗传学如何导致移植相关的死亡率。骨髓移植包括化疗、放射治疗，然后输注捐献者的血液干细胞，用于成功治愈其他致命的血液疾病。大约3名符合条件的患者中有2名没有匹配的同胞捐赠者，因此需要无血缘关系的供者进行骨髓移植。移植相关死亡(因任何治疗相关原因死亡)发生在骨髓移植后1年内，每3例匹配良好的非亲缘供者BMT患者中就有1例死亡，这是向更多患者提供这种治疗方法的主要限制因素。这项拟议的研究将使用全基因组扫描来测试2800名患者及其匹配良好的非亲属捐赠者对移植相关死亡的遗传易感性，这些患者在2000-2008年间曾在美国150家骨髓移植中心中的任何一家接受过急性白血病或骨髓增生异常综合征的移植。化疗放射的类型以及大剂量和低剂量化疗的使用将被测试与患者和/或捐赠者的基因构成的相互作用，以确定这种相互作用是否增加或降低了与移植相关的死亡风险。然后，结果将在随后的2009-2011年间接受治疗的1000对患者-捐赠者对队列中进行有效性测试。这项研究的意义是，如果成功，额外的基因测试可以迅速转化为常规的临床实践，这可能会改善无关供者骨髓移植后患者的存活率。到目前为止，遗传学和移植相关死亡率之间的关系只在几个基因中进行了研究，没有考虑药物或剂量的暴露。通过进行第一次全面的全基因组扫描和计划的有效性测试，该项目将提高研究与移植相关的死亡的遗传原因的能力，并为选择使用哪些化疗药物和剂量提供更有针对性和个性化的方法提供初步支持。这项研究产生的数据将在该项目结束时与科学和医学界公开分享，为更多的科学发现提供独特和强大的资源。这项拟议的研究涉及美国血液和骨髓移植协会关于预后指标和监测工具的优先研究领域。 公共卫生相关性：该项目将研究受者和捐赠者的基因对无关供者血液或骨髓移植(BMT)相关死亡率的贡献，并为选择使用哪些化疗药物和剂量的更定制、个性化的方法提供初步支持。其目标是提高非血缘关系供者骨髓移植用于治疗血液疾病后的存活率，这将使更多的患者能够接受这种挽救生命的疗法。这项研究产生的数据将在该项目结束时与科学和医学界公开分享，为更多的科学发现提供独特和强大的资源。

DESCRIPTION (provided by applicant): The overall purpose of this study is to better understand how genetics contribute to transplant-related mortality after unrelated donor blood or bone marrow transplantation (BMT). BMT includes treatment with chemotherapy radiation followed by infusion of a donor's blood stem cells and is used to successfully cure otherwise fatal blood diseases. About 2 out of 3 eligible patients do not have a matched sibling donor and therefore require an unrelated donor BMT. Transplant related mortality (death due to any treatment related cause) occurs in 1 out of 3 well-matched unrelated donor BMT patients within 1-year after BMT and is a major limiting factor to offering this curative therapy to more patients. This proposed study will use a genome-wide scan to test for a genetic susceptibility to transplant related mortality in 2,800 patients, and their well-matched unrelated donors, who have received a transplant for acute leukemia or myelodysplastic syndrome at any of >150 U.S.-based BMT centers during the years 2000- 2008. The type of chemotherapy radiation and the use of high dose vs. reduced dose of chemotherapy will be tested for an interaction with the patient and/or donor's genetic makeup to determine if there is an increased or decreased risk of transplant-related mortality due to this interaction. The results will then be tested for validity in a subsequent cohort of 1,000 patient-donor pairs treated from 2009-2011. The significance of this study, if successful, is that additional genetic tests can be quickly translated to routine clinical practice which could improve patient survival after unrelated donor BMT. To date, a relationship between genetics and transplant related mortality has only been studied in a few genes and did not consider exposure to drug or dose. By performing the first comprehensive genome- wide scan with a planned test of validity, this project will improve the ability to study genetic causes for transplant-related mortality and provide preliminary support for a more tailored, individualized approach to selecting which chemotherapy drugs to use and at what dose. The data generated by this study will be shared publicly at the end of this project with the scientific and medical community to provide a unique and powerful resource for additional scientific discoveries. This proposed study addresses the American Society for Blood and Marrow Transplantation's Priority Research Area for Prognostic Indicators and Monitoring Tools. PUBLIC HEALTH RELEVANCE: This project will study the recipient and donor genetic contribution to unrelated donor blood or marrow transplant (BMT)-related mortality and provide initial support for a more tailored, individualized approach to selecting which chemotherapy drugs to use and at what dose. The goal is to improve survival after unrelated donor BMT used to treat blood diseases, which will enable more patients to receive this life- saving therapy. The data generated by this study will be shared publicly at the end of this project with the scientific and medical community to provide a unique and powerful resource for additional scientific discoveries.