Allelic Variation in TP53 and MDM2 DNA Repair Genes Constitute Genetic Risk Factors for Long-Term Survival in Allogeneic Stem Cell Transplantation

Field: Medicine (Health Sciences)

The p53 tumor suppressor pathway plays a major role in tumor development and cell survival. Germline single nucleotide polymorphisms (SNP)s in codon 72 of TP53 (Arg72Pro; rs1042522) and in the promoter region of the ubiquitin ligase MDM2 (-309; rs2279744) influence apoptotic activity in response to cellular stress. In vitro studies have demonstrated that cells homozygous for Arg72 in p53 have significantly increased apoptotic activity in response to cellular stress, while cells homozygous for Pro72 have increase in cell cycle arrest and DNA repair. We recently investigated the impact of these two SNPs on survival after transplantation from HLA 10/10 matched unrelated donors. In brief, analysis of samples and clinical outcome data contributed by the National Marrow Donor Program Research Sample Repository and by the Center for International Blood and Marrow Transplant Research, respectively, demonstrated that patients with two p53 72Pro alleles and at least one copy of the MDM2-309 G allele had an increase in mortality risk compared to patients with 2 p53 72Pro alleles and zero G alleles at -309 (HR = 1.41). We now report the results of a second independent cohort of donor-recipient pairs tested for the same p53 and MDM2 SNPs. All patients were treated at the Fred Hutchinson Cancer Research Center and represented 731 related and 669 unrelated pairs including HLA matched and mismatched cases. We find that patients with two p53 72Pro alleles and at least one copy of the MDM2-309 G allele had a significant increase in mortality risk compared to patients with 2 p53 72Pro alleles and zero G alleles at -309 (HR = 1.35). These results are consistent with our hypothesis that the combination of recipient genotypes for p53 Arg72/Pro and SNP -309 MDM2 affects post transplantation survival. Detailed analysis of other clinical outcome data are currently in progress. The p53 tumor suppressor pathway plays a major role in tumor development and cell survival. Germline single nucleotide polymorphisms (SNP)s in codon 72 of TP53 (Arg72Pro; rs1042522) and in the promoter region of the ubiquitin ligase MDM2 (-309; rs2279744) influence apoptotic activity in response to cellular stress. In vitro studies have demonstrated that cells homozygous for Arg72 in p53 have significantly increased apoptotic activity in response to cellular stress, while cells homozygous for Pro72 have increase in cell cycle arrest and DNA repair. We recently investigated the impact of these two SNPs on survival after transplantation from HLA 10/10 matched unrelated donors. In brief, analysis of samples and clinical outcome data contributed by the National Marrow Donor Program Research Sample Repository and by the Center for International Blood and Marrow Transplant Research, respectively, demonstrated that patients with two p53 72Pro alleles and at least one copy of the MDM2-309 G allele had an increase in mortality risk compared to patients with 2 p53 72Pro alleles and zero G alleles at -309 (HR = 1.41). We now report the results of a second independent cohort of donor-recipient pairs tested for the same p53 and MDM2 SNPs. All patients were treated at the Fred Hutchinson Cancer Research Center and represented 731 related and 669 unrelated pairs including HLA matched and mismatched cases. We find that patients with two p53 72Pro alleles and at least one copy of the MDM2-309 G allele had a significant increase in mortality risk compared to patients with 2 p53 72Pro alleles and zero G alleles at -309 (HR = 1.35). These results are consistent with our hypothesis that the combination of recipient genotypes for p53 Arg72/Pro and SNP -309 MDM2 affects post transplantation survival. Detailed analysis of other clinical outcome data are currently in progress.