Identification and Utilization of Donor and Recipient Genetic Variants to Predict Survival After HCT: Are We Ready for Primetime?

Abstract

Overall survival following hematopoietic cell transplantation (HCT) has improved over the past two decades through better patient selection and advances in HLA typing, supportive care, and infection prophylaxis. Nonetheless, mortality rates are still unsatisfactory and transplant-related mortality remains a major cause of death after unrelated allogeneic HCT. Since there are no known pre-HCT, non-HLA biologic predictors of survival following transplant, for over a decade, scientists have been investigating the role of non-HLA germline genetic variation in survival and treatment-related mortality after HCT. Variation in single nucleotide polymorphisms (SNPs) has the potential to impact chemotherapy, radiation, and immune responses, leading to different post-HCT survival outcomes. In this paper, we address the current knowledge of the contribution of genetic variation to survival following HCT and discuss study design and methodology for investigating HCT survival on a genomic scale.

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant

“…Score descriptions are given below the image. 1b indicates eQTL 1 transcription factor (TF) 71 however, we did not reproduce these findings, similar to 2 other recent studies attempting to replicate previous candidate gene associations with GVHD after BMT. 73,97 Other reports have also concluded that a substantial amount of the published candidate gene literature has presented false-positive associations.…”

“…We conducted the first adequately powered evaluation of these candidate single-nucleotide polymorphism (SNP) and gene hypotheses using typed and imputed data from an existing genome-wide association study (GWAS) named DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT) to replicate or validate these published associations. 71,72 In addition, we leveraged the available genome-wide data from DISCOVeRY-BMT and measured the aggregate association of all SNPs in the candidate genes with survival outcomes to determine how many of these candidate genes play a significant role in survival after transplant. Lastly, using publicly available data, we characterized the potential functionality of each candidate SNP in relation to the gene of interest.…”

Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex

“…The cases and controls were selected from an ongoing parent study: Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVeRY-BMT). [35][36][37][38] Briefly, the parent study was designed to find common germ line genetic variation associated with survival after an URD-BMT. DISCOVeRY-BMT consists of 2 cohorts of ALL, acute myeloid leukemia, and myelodysplastic syndrome patients and their HLA-matched unrelated healthy donors 35 (supplemental Methods).…”

Non-HLA genetic mismatches and BMT outcome

“…4,5 Another approach would be a so-called candidate gene study. However, as the authors noted, candidate gene studies of BMT outcome have yield mixed results, 6 which is true for multiple outcomes. 5 This study contributes importantly to our understanding of the role of non-HLA genetic variants on BMT outcomes.…”