ABSTRACT
Background: allogeneic hematopoietic stem cell transplantation [HSCT] is widely used to treat various hematological malignant and non-malignant diseases. The occurrence of complications following HSCTas graft versus host disease[GVHD], hepatic veno-occlusive disease [VOD], oral mucositis [OM], drug induced hepatic and renal adverse events- is highly variable and dependent on a multitude of host, donor, and treatment factors. Identifying important genetic variables will allow for better prediction of HSCTrelated outcomes, and in the process of identifiing these susceptibilities, that could help to develop targeted interventions
Objectives: to evaluate impact of the C677T polymorphism of 5,10-methylenetetrahydrofolate reductase [MTNFR] on the clinical outcomes of patients treated using human leukocyte antigen-matched sibling stem cell transplantation as acute gruff versus host disease [GVHD],oral mucositis ,drug induced hepatic and renal toxicity, transplant related mortality[TRM] and overall survival[OS]
Patients and Methods: we examined the association of a single nucleotide polymorphism [SNP] at position 677 in the MTHFR gene of patients with outcomes of allogeneic HSCT. MTHFR genotyping was performed by po2ymerase chain reaction-restriction fiagment length polymorphism [PCR-RFLP]
Results: 46 Patients with complete clinical records were recruited. Median age at the time of HSCT was 22 years [range 3-42 years]; 32 patients [69.6%] above >/=18 years, and the median follow-up period of survivors was 21 months. 212efrequencies of the MTHFR C677T genotypes in patients were 43.5% [20 patients] for 677CC, 50% [23 patients] for 677CX and 6.5% [3 patients] for 677TT; the allelic frequency of the 677T was 31.5%. Recipient MTHFR677 in CT or TT versus CC showed non-statistically significant higher incidence of acute GVHD [7/26] 26.9% versus [2/20] 10%; p=0.15, hepatic toxicity [11/26] 42.3% versus [5/20] 25%, p= 0.22 and TRM [5/26] 19.2% versus [2/20] 10%; p=0.45. Recipients with variant allele MTHFR 677T were associated with lower non statistically signijicant overall survival; p=0.281. Conclusion: Genofyping for WHFR C677T before HSCT could have clinical significance, not statistically proven in our study, in prediction of patients at high risk of developing poor outcomes. Larger studies with homogeneous HSCT cohort are needed to identifi such potential phar]nacogenetic markers with suflciently strong evidence to be used in clinical practice
ABSTRACT
ALL is the most common pediatric cancer. The causes of the majority of pediatric acute leukemia are unknown and are likely to involve an interaction between genetic and environmental factors. Therefore, unfavourable gene-environmental interactions might be involved in the genesis of ALL. The aim of this work was to evaluate, in a case-control study, whether the common polymorphisms in 5, 10-methylenetetrahydro-folate reductase [MTHFR] namely [C677T and A1298C] and methionine synthase [MS] [A2756G] genes may play a role in altering susceptibility to pediatric ALL as individual genes and in combination. DNA of 88 ALL patients [age <18 years] and 311 healthy control subjects was analyzed for the polymorphisms of MTHFR and MS genes using PCR-RFLP method. The frequencies of the wild types of MTHFR 677CC, MTHFR 1298AA and MS 2756AA, the homozygous genotypes of MTHFR 677TT, MTHFR 1298CC and MS 2756GG and heterozygous genotypes of MTHFR 677CT and MS 2756AG showed no statistically significant differences between patients and controls. The frequency of the MTHFR 1298AC heterozygous genotype was 25% among patients compared to 45.0% among controls; the difference was found to be statistically significant [p value =0.001, O.R=0.382 and 95% C.1=0.222-0.658]. The frequency of the MTHFR 1298AC heterozygous genotype plus 1298CC homozygous genotype was 34% among patients compared to 54.3% among controls and the difference was statistically significant [p value=0.001]. A synergistic effect of 677CT and 298AC [CTAC] was observed, [p value=0.002] with 3.65 fold protection [OR 0.273 and 95% C.1=0.155-0.9] compared to 2.6 folds for MTHFR 1298AC alone. This protective effect of CTAC polymorphism was abolished when combined with MS 2756AA or AG. The present study provided further evidence for the protective role of MTHFR 1298AC mutant alleles in acute lymphoblastic leukemia in children [2.6 fold protection]. This suggests that folate and methionine metabolism play an important role in the pathogenesis of pediatric ALL. In contrast to the main bulk of literature, we did not find any protective role of either MTHFR C677T or MS A2756G polymorphisms. This may reflect the ethnic variation in both the polymorphism frequencies, variation in plasma level of folate in addition to the possible role of gene-environment interaction mainly dietary availability of folate. The synergistic effect of MTHFR 1298AC and 677CT and its abolishment by MS 2756AA or AG further emphasizes that the interaction of genes, rather than the polymorphism in any single one, determines risk susceptibility to disease