RESUMO
Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.
Assuntos
Reparo do DNA/genética , Variação Genética , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Antineoplásicos Alquilantes/farmacocinética , Bussulfano/farmacocinética , Criança , Pré-Escolar , Estudos de Coortes , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Testes Genéticos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Heterozigoto , Humanos , Incidência , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Proteínas Supressoras de Tumor/genéticaRESUMO
Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence.
