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.