Functional Genomic Markers in Stem Cell Transplantation

Fred Hutchinson Cancer Research Center, Seattle WA

Investigators

Linked publications & trials

Abstract

Description (provided by applicant): The success of hematopoietic cell transplantation (HCT) from unrelated volunteer donors for hematological malignancies has been limited by the extraordinary diversity of the HLA system and the challenge of identifying suitably matched donors. The importance of histocompatability matching for serologically defined HLA gene products has been well described. Molecular analysis has revealed that a family of unique alleles may encode a single serologically defined specificity. HLA allele disparity between a patient and unrelated donor has recently been found to influence engraftment, the development of graft- versus-host disease (GVHD) and overall survival after HCT; however, the relative importance of different locus, antigen, and allele mismatches and the impact of multiple allele disparities remains to be determined in transplants of diverse race and ethnicity. Although the selection of allele-matched donors may be desirable, the majority of patients in need of a transplant lack matched donors. Furthermore, if the international goal of worldwide sharing bone marrow donors is to benefit all patients, then it will be necessary to define well-tolerated mismatches. In putative matched transplants, identification of polymorphisms, which encode minor histocompatability determinants, are likely to be important in unrelated HCT. Project 9 seeks to identify genomic markers encoded within the MHC that have functional significance in stem cell transplantation. HLA-A, B, C, DRB, DQB I, DPB 1 alleles will be characterized in patients undergoing transplantation from unrelated and haploidentical related donors (Specific Aim I) for clinical outcome analysis and testing of microsatellite markers. HLA mismatches that are well tolerated by patients with respect to graft failure, GVHD and mortality will be defined (Specific Aim 2). We will characterize the frequency, heterozygosity and linkage disequilibria of microsatellite markers within the class I, II and III regions of the MHC (Specific Aim 3). Upon completion of the extensive high resolution HLA allele typing and microsatellite testing, Project 9 will work with Project 6 to build a genomic database of extended MHC haplotypes (Specific Aim 4). Finally, we will determine whether microsatellites, single nucleotide polymorphisms and NK genotypes have relevance to graft failure, GVHD and mortality, and the extent to which transplant outcome may be further optimized through donor matching for these markers (Specific Aim 5). The studies proposed in Project 4 will provide important new information on the diversity and function of MHC-encoded polymorph isms in clinical transplantation.