Immunogenetics of Outcomes Disparities After Allogeneic HCT

项目总结/摘要 没有任何地方的癌症存活率的种族差异像造血细胞移植（HCT）那样引人注目 因为病人和捐献者都对存活率有贡献。HLA基因特征是祖先- 信息量大。当考虑到祖先特有的特征时，生存差异会减少，但主要是 在非洲人、西班牙人、亚洲人和高加索美国人的移植患者之间仍然存在差距。的复发 血癌仍然是移植失败的主要原因;然而，NKG 2轴的作用，主要的抗- 肿瘤途径，在HCT后复发和存活率是不明确的。未满足的需求是确定NKG 2 配体/受体免疫遗传因素参与复发，并解释生存差异。如果这些 因素是已知的，然后对患者的生殖系进行前瞻性风险评估，并优化供体选择 可以减少甚至消除美国人口之间的生存差异。我们已经阐明了 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， 确定了影响基因表达的关键祖先信息NKG 2配体和受体变体， 生存我们建议确定祖先特异性NKG 2配体和受体错义和调控变异 这说明了每个种族的生存，并检查了跨种族的最佳特征的影响，以最小化或 消除HCT中的生存差异。具体目标是：1）确定支持NKG的机制2 不同种族中配体/受体表达的差异; 2）定义NKG 2配体/受体祖先信息 每个种族的生存差异，以及3）用祖先特异性“理想”定义生存差异 免疫遗传学特征这些目标将通过对NKG 2的系统分析实现 配体/受体变异以鉴定功能变体，然后对相关供体进行大规模基因分型， 无关的供体和脐带血移植患者和供体，并确定理想的特征， 每个种族的生存。通过以下措施可以减少甚至消除生存差距的程度 将定义具有理想特征的患者和供体的移植。从这个信息 该项目将增加所有需要这种挽救生命的治疗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.