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非亲属供血或骨髓移植（BMT）后与移植相关的死亡率。BMT包括化疗放射治疗，然后输注供体血液干细胞，用于成功治愈其他致命的血液疾病。3名符合条件的患者中约有2名没有匹配的兄弟姐妹供体，因此需要非亲属供体BMT。移植相关死亡率（因任何治疗相关原因导致的死亡）在移植后1年内发生在3个匹配良好的非亲属供体BMT患者中有1个，这是向更多患者提供这种治疗性治疗的主要限制因素。这项研究将使用全基因组扫描来检测2800名因急性白血病或骨髓增生异常综合征而在2000- 2008年期间在美国150家BMT中心接受移植的患者及其匹配良好的非亲属供体对移植相关死亡率的遗传易感。化疗辐射的类型和使用高剂量与低剂量化疗将被测试与患者和/或供体的基因组成的相互作用，以确定是否由于这种相互作用而增加或减少了移植相关死亡率的风险。随后，研究人员将在2009年至2011年期间接受治疗的1,000对患者-供体对的后续队列中测试结果的有效性。这项研究的意义在于，如果成功的话，额外的基因检测可以迅速转化为常规临床实践，从而提高非亲属供体BMT后患者的生存率。迄今为止，遗传和移植相关死亡率之间的关系只在少数基因中进行了研究，并没有考虑到药物或剂量的暴露。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的遗传原因的能力，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项目结束时与科学界和医学界公开共享，为进一步的科学发现提供独特而强大的资源。这项建议的研究解决了美国血液和骨髓移植协会对预后指标和监测工具的优先研究领域。

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.