Immunogenetics of Outcomes Disparities After Allogeneic HCT

项目摘要/摘要 在任何地方，癌症存活率的种族差异都不像造血细胞移植(Hct)那样显著。 因为患者和捐赠者都对生存结果做出了贡献。人类白细胞抗原基因特征是祖先- 见多识广。当考虑到祖先特有的特征时，生存差距会缩小，但主要是 非洲人、西班牙人、亚洲人和高加索美国人之间的移植患者之间仍然存在差距。旧病复发 血癌仍然是移植失败的主要原因；然而，NKG2轴的作用是主要的抗肿瘤作用。 HCT后复发和存活的肿瘤途径尚不清楚。尚未满足的需求是确定NKG2 配体/受体免疫遗传因子参与复发，并解释生存差异。如果这些 因素是已知的，然后是患者生殖系的前瞻性风险评估和优化的供体选择 可能会缩小甚至消除美国人口之间的生存差距。我们已经阐明了生存 非洲人、西班牙人、亚洲人和高加索美国人血统的HCT患者之间的差异，以及 确定了影响基因表达和基因表达的关键祖先-信息性NKG2配体和受体变体 生死存亡。我们建议鉴定祖先特异性的NKG2配体和受体的错义和调节变异 这说明了每个种族的存活率，并检查了跨种族的最佳特征的影响，以最大限度地减少或 消除高血压病患者的生存差距。具体目标是1)确定支持NKG2的机制 配体/受体在不同种族中的表达差异；2)定义NKG2配体/受体祖先-信息性 每个种族的生存差异，以及3)用特定于祖先的“理想”来定义生存差异。 免疫遗传特性。这些目标将通过对NKG2的系统分析来实现 配基/受体变异以确定功能变异，随后对相关供体进行大规模基因分型， 无血缘关系的捐献者和脐带血移植患者和捐赠者以及理想特征的识别 在每个种族中生存。生存差距可能被缩小甚至消除的程度 具有理想特征的患者和捐赠者的移植将被定义。从这里得到的信息 该项目将提高所有需要这种救命疗法的患者的移植成功率。

Project Summary/Abstract Nowhere are racial disparities in cancer survival rates as striking as in hematopoietic cell transplantation (HCT) because both the patient and the donor contribute to survival outcomes. HLA genetic features are ancestry- informative. When ancestry-specific features are accounted for, survival disparities are diminished but major gaps still exist between African, Hispanic, Asian and Caucasian American transplant patients. Relapse of the blood cancer remains the chief cause of transplant failure; however, the role for the NKG2 axis, the major anti- tumor pathway, in relapse and survival after HCT is ill-defined. The unmet need is to identify the NKG2 ligand/receptor immunogenetic factors involved in relapse and which account for disparities in survival. If these factors were known, then prospective risk-assessment of the patient’s germline and optimized donor selection could diminish or even abolish survival disparities across US populations. We have elucidated the survival disparities between HCT patients of African, Hispanic, Asian and Caucasian American ancestry, and have identified key ancestry-informative NKG2 ligand and receptor variants that impact gene expression and survival. We propose to identify ancestry-specific NKG2 ligand and receptor missense and regulatory variation that account for survival in each race, and examine the impact of optimal features across races to minimize or abolish survival disparities in HCT. The specific aims are to 1) identify mechanisms that underpin NKG2 ligand/receptor expression variation in diverse races; 2) define NKG2 ligand/receptor ancestry-informative variation for survival in each race, and 3) define survivorship disparities with ancestry-specific “ideal” immunogenetic characteristics. The goals will be achieved through systematic analysis of NKG2 ligand/receptor variation to identify functional variants, followed by large-scale genotyping of related donor, unrelated donor and cord blood transplant patients and donors and identification of ideal features that inform survival within each race. The extent to which survival disparities may be diminished or even abolished through transplantation of patients and donors with ideal characteristics will be defined. The information from this project will increase the success of transplantation for all patients in need of this life-saving therapy.