Uncovering the Genetics of Poor and Exceptional Survivorship after Unrelated Donor Allogeneic Hematopoietic Cell Transplantation (HCT)

Introduction: A previous genome-wide association study (GWAS) investigated joint and independent genetic factors in recipients and donors contributing to death in the first year after unrelated donor HCT (DISCOVeRY-BMT study, PMID: 34746714). The current study leveraged DISCOVeRY-BMT data to identify non-human leukocyte antigen (HLA) genetic factors related to poor and exceptional survivorship after allogeneic HCT.

Methods: DISCOVeRY-BMT, a collaboration with the Center for International Blood and Marrow Transplant Research (CIBMTR) consists of 2 cohorts of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) patients treated 2000-2011 and their ≥8/8 HLA-matched unrelated donors. Standard genotyping using the Illumina OmniExpress BeadChip and quality control were performed. Imputation used the Trans-Omics in Precision Medicine (TOPMed) Imputation Server (GRCh38). Given 80% of patients who survive 24 months post-HCT survive to 10 years (PMID: 28232372), we categorized patients who were alive with <120 but >24 months follow-up as exceptional survivors. Standard and poor survivors are those who died between 24-120 months post-HCT and <24 months post-HCT, respectively. GWAS was performed with additive multivariable logistic-Firth hybrid regression models adjusting for age at HCT, sex, cohort, disease (AML, ALL, MDS), disease status (early or advanced), year of HCT, and principal components. Summary statistics and median survival in months were calculated in R.4.4.1. P < 5 × 10⁻⁸ denoted genome-wide significance.

Results: Study sample consisted of 2886 European ancestry recipients, with survivors comprising 32% exceptional (N=937, median survival=142 months), 15% standard (N=441, median survival=47 months), and 53% poor (N=1508, median survival=5 months). Distributions by disease (17-21% ALL, 60-62% AML, 18-21% MDS) were similar in exceptional, standard, and poor survivor cases. Exceptional survivor cases had slightly higher early and lower advanced disease status (82% early, 18% advanced) compared to standard (71% early, 29% advanced) and poor survivors (64% early, 36% advanced). Single nucleotide polymorphism (SNP) rs7375273 on chromosome 4 (RXFP1) showed marginal genome-wide significance (OR=1.49, 95% CI=1.29-1.72, P=8.93E-08), that allele A is associated with increased odds of poor survivorship compared to all others (exceptional+standard). Although marginally genome-wide significant, the A allele of rs7507979 on chromosome 19 (INSR) showed increased odds of exceptional survivorship compared to poor survivors (OR=1.40, 95% CI=1.23-1.59, P=2.49E-07).

Conclusions: Using GWAS approach, we identified marginally significant variants in recipients associated with poor and exceptional survivorship. Rs7375273 is located within the RXFP1 (relaxin family peptide receptor 1) gene and is implicated in pathways involving G protein-coupled receptor activity and hormone binding. Previous GWAS have associated SNPs in RXFP1 with ALL (ETV6-RUNX1 positive). RXFP1 is differentially expressed in non-small cell lung cancer and is associated with poor survival. OpenTarget and eQTLgen provide in silico evidence linking rs7375273 to eQTLs within FNIP2 and changes in gene expression of whole blood. FNIP2 may impact leukemia survival post-HCT by regulating the mTOR pathway, immune responses, cellular stress mechanisms, and leukemia cell biology. INSR (insulin receptor), through ligand binding, activates its receptor INSR, initiating the insulin signaling pathway which governs glucose uptake, release, and the synthesis/storage of carbohydrates, lipids, and proteins. INSR has been implicated in GWAS traits such as triglyceride levels, blood pressure, body height, and cardiovascular disease. INSR plays a crucial role in cancer, particularly in the tumor vasculature of colorectal carcinoma, renal cell cancer, and gastric adenocarcinoma, where its elevated expression levels are associated with shorter survival. Further research is necessary to elucidate these mechanisms. Our future directions include expansion into larger, more diverse populations and replication in independent cohorts. This work strives to further delineate genomic predictors for HCT outcomes to better understand recipient inherited predisposition and identify novel mechanisms of survivorship post-HCT.