Increased risk for treatment-related mortality after bone marrow transplantation in GSTM1-positive recipients

Abstract

Treatment-related mortality (TRM) is a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). A variety of drugs are used in allogeneic HSCT, and a genetic polymorphism in metabolic enzymes could affect the metabolism of drugs and potentially influence TRM. Here, we focused attention on GSTM1 and GSTT1 enzymes, which metabolize chemotherapeutic agents, chemical carcinogens and by-products of oxidative stress and are absent from more than 50% of some populations. To assess the significance of homozygous GSTM1 and GSTT1 gene deletion in HSCT, we analyzed DNA from 373 patients with hematological disease and their HLA-identical unrelated bone marrow donors using PCR. Homozygous GSTM1 and GSTT1 gene deletions were observed in 56 and 45% of patients, respectively, and 57 and 46% of donors, respectively. There was no significant association between GSTT1 polymorphism and any outcome. However, a GSTM1-positive genotype in recipients was significantly associated with higher TRM and lower survival. These results suggest that a GSTM1-null genotype in recipients protects against TRM after allogeneic HSCT. Further studies are needed to elucidate a mechanism of increased risk for TRM in GSTM1-positive recipients.

Inactivation by UDP-glucuronosyltransferase enzymes: The end of androgen signaling

“…The second androgen-conjugating enzymes expressed in the prostate, UGT2B17, have also attracted attention. Interestingly, the complete deletion of the human UGT2B17 gene has been reported in humans, and this polymorphism is associated to a risk factor for high transplant related mortality because the UGT2B17 enzyme can be immunogenic in the recipient with homozygous UGT2B17 deletion [61,62]. Wilson et al, reported that DNA spanning the UGT2B17 gene is absent in 9 of the 40 DNA human samples examined and that the allele frequency varies between the two ethnic groups African Americans (allele frequency 0.21) and Caucasians (allele frequency 0.33) [63].…”

Decreased risk of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation in patients with the 5,10-methylenetetrahydrofolate reductase 677TT genotype

“…Non-HLA genetic polymorphisms that can predict the risk and severity of GVHD are found in genes encoding minor histocompatibility antigens, pro-and anti-inflammatory cytokines, non-cytokine immunoregulators, and drug-metabolizing enzymes [4][5][6][7]. In a previous study, we analyzed the association between homozygous glutathione S-transferase M1 and T1 gene deletions in the recipient and donor with various outcomes of HSCT, and we found a significant association between the presence of the glutathione S-transferase M1 enzyme in the recipients and higher treatment-related mortality (TRM) as well as a lower rate of survival [8]. In another study, we reported that a homozygous gene deletion leading to a null phenotype for the UDP-glycosyltransferase 2 family, polypeptide B17 enzyme [9], is an independent risk factor for higher TRM and lower survival after HSCT [10].…”

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation

“…The same group reported similar findings when they investigated 2 additional genes, GSTM1 and GSTT1, in 373 HLA-matched unrelated HSCT pairs. 43 GSTM1 and GSTT1 were also identified as homozygous null at appreciable frequency in the Hapmap population. 9 GSTT1 has been identified as a potential alloantigen mediating de novo immune hepatitis in liver transplant recipients who are homozygous null for the gene, but receive a GSTT1 ϩ graft.…”