Genetic Allelic Variation in the p53 DNA Repair Pathway Constitute a Risk Factor for Long-Term Survival in Hematopoietic Stem Cell Transplantation

Abstract

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-matched related and unrelated donors is well recognized as a potentially curative treatment for patients with high-risk leukemia and myelodysplastic syndrome (MDS), however, transplant-related morbidity and mortality limit the success of HSCT. Evidence from population-based studies suggests a role of genetic variation in the tumor suppressor gene p53 in health. P53 is a transcription factor that responds to cellular stress by regulating cell-cycle arrest, DNA repair and apoptosis. Studies in vitro indicate that the p53 codon 72Arg allele gene product predominantly increases apoptotic events, while 72Pro mediates cell-cycle arrest and DNA repair. We sought to define the role of germline allelic variations of the p53 Arg72Pro single nucleotide polymorphism (SNP) (rs1042522) in post-transplantation outcome. We determined the p53 Arg72Pro genotype in 1067 Caucasian unrelated donor-recipient pair samples obtained from the National Marrow Donor Program Research Repository and analyzed clinical outcome data from the Center for International Blood and Marrow Transplantation. Patients received myeloablative conditioning and marrow (n =1025 ) or peripheral blood stem cells (n = 42 ) from HLA-A, B, C, DRB1 and DQB1 10 of 10 allele-matched unrelated donors between 1985 and 2002 (50.9% were transplanted during the years 1992–1997) for the treatment of acute lymphoblastic leukemia (ALL) (15.9%), acute myelogenous leukemia (AML) (25.9%), chronic myelogenous leukemia (CML) (57.6%) or MDS (0.6%). 457 (42.8%) of the recipients were female. The allele frequency for the minor p53 72Pro allele was 0.255 (donors) and 0.249 (recipients) corresponding to the expected allele frequency for Caucasian individuals of mixed European origin. Presence of 1 or 2 minor p53 codon 72Pro alleles in patients was associated with an increased hazard of mortality: HR=1.12 (1.00–1.26, p=0.05). There was no statistically significant effect of donor genotype for SNP Arg72Pro on mortality, and no such effect of donor or recipient genotype on severity of acute graft-versus-host disease (GVHD) or disease recurrence. We further investigated the role of genetic variation in the MDM2 oncogene, a well-recognized central node in the p53 pathway that binds and inhibits p53 by regulating location, stability and activity. The minor G allele at position -309 (rs2279444) of the MDM2 promoter increases transcription of MDM2. We determined the genotype of the -309 SNP in the MDM2 promoter in the donors and recipients. Patients with 2 p53 72Proalleles and at least one copy of the -309 G allele had a 1.41-fold increase in mortality risk (95% CI, 1.00–1.98, p=0.05) compared to patients with 0–1 p53 72Pro alleles and zero G alleles at -309 (reference group), while patients with 2 p53 72Pro alleles and zero -309 G alleles had a similar outcome to that in the reference group (hazard ratio 1.00 (95% CI 0.65–1.56, p=.99)). In summary, our results are consistent with the hypothesis that p53 codon 72Pro is associated with increased post-transplant mortality, but with the increase due primarily to recipients that also have at least one G allele in MDM2 SNP -309. Inspection of Kaplan-Meier curves for patients with different genotypes of SNP p53 codon 72 demonstrates the increase in mortality for recipients with the 72Pro/Progenotype 6–10 years post-transplantation. These results suggest that genotyping of HSCT recipients for SNP in p53 codon 72 and MDM2 -309 may have predictive value for late transplant outcome. If confirmed in additional studies, prospective genotyping of SNPs in p53 codon 72 and MDM2 -309 and possibly other significant genomic positions could be used to plan transplant regimens and aid in risk assessment.