Genetic susceptibility to unrelated donor stem cell transplant-related mortality

描述（由申请人提供）：本研究的总体目的是更好地了解遗传学如何影响无关供体血液或骨髓移植（BMT）后的移植相关死亡率。骨髓移植包括化疗和放射治疗，然后输注供体的造血干细胞，用于成功治愈其他致命的血液疾病。大约三分之二的合格患者没有匹配的同胞供体，因此需要无关供体BMT。移植相关死亡（由于任何治疗相关原因导致的死亡）发生在BMT后1年内的3例匹配良好的无关供体BMT患者中的1例，并且是向更多患者提供这种治愈性治疗的主要限制因素。这项拟议的研究将使用全基因组扫描来测试2，800名患者及其匹配良好的无关供体对移植相关死亡率的遗传易感性，这些患者在>150个美国国家中的任何一个接受了急性白血病或骨髓增生异常综合征移植。2000年至2008年期间的BMT中心。将测试化疗辐射的类型以及使用高剂量与减少剂量的化疗与患者和/或供体基因组成的相互作用，以确定由于这种相互作用，移植相关死亡率的风险是否增加或降低。然后将在2009-2011年接受治疗的1，000名患者-供体对的后续队列中测试结果的有效性。这项研究的意义，如果成功的话，是额外的基因检测可以迅速转化为常规的临床实践，这可以提高无关供体BMT后患者的生存率。迄今为止，遗传学和移植相关死亡率之间的关系仅在少数基因中进行了研究，并且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，该项目将提高研究移植相关死亡率遗传原因的能力，并为更有针对性的个性化方法提供初步支持，以选择使用哪种化疗药物和剂量。本研究产生的数据将在本项目结束时与科学和医学界公开共享，为更多的科学发现提供独特而强大的资源。这项拟议的研究涉及美国血液和骨髓移植学会的预后指标和监测工具的优先研究领域。 公共卫生相关性：该项目将研究受体和供体基因对无关供体血液或骨髓移植（BMT）相关死亡率的贡献，并为更有针对性的个性化方法提供初步支持，以选择使用哪种化疗药物以及剂量。目标是提高无关供体骨髓移植用于治疗血液病后的生存率，这将使更多的患者接受这种挽救生命的疗法。本研究产生的数据将在本项目结束时与科学和医学界公开共享，为更多的科学发现提供独特而强大的资源。

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.