Methylenetetrahydrofolate reductase C677T polymorphism and toxicity in allogeneic hematopoietic cell transplantation

OpenAlex İngilizce

The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyses the conversion of 5-,10-methylenetetrahydrofolate (MEFH4) to 5- MEFH4, the principal form of folate in the blood stream (1). One of the MTHFR gene polymorphisms results in the heterozygous variant 677 CT or homozygous variant 677 TT with reduced specific activities compared with the wild-type 677 CC (2). Ulrich et al. (3) reported a relationship between MTHFR gene polymorphisms and methotrexate (MTX) toxicity. MTX exerts its cytotoxic effect by inhibiting dihydrofolate reductase and also other related enzymes of folate metabolism, including MTHFR. We evaluated whether the MTHFR genotype would affect the MTX toxicity in the allogeneic hematopoietic cell transplantation (HCT) setting. Fifty-three patients received allogeneic HCT (bone marrow 16, peripheral blood 37) as primary and unmanipulated transplantation for hematologic malignancies (Table 1). All donors were human leukocyte antigen-identical siblings. Busulphan and cyclophosphamide were mostly used as a preparative regimen. All patients received the same peritransplant infection prophylaxis and graft-versus-host disease prophylaxis. The latter consisted of cyclosporine and short-term MTX (intravenously at day 1, 15 mg/m2, and at days 3, 6, and 11, 10 mg/m2). Myelosuppression and gastrointestinal toxicity were evaluated by defining the severity of mucositis with monitoring of serum bilirubin levels. The severity of mucositis was assessed according to the most commonly used World Health Organization grading system (4,5). Patients were followed-up until engraftment was achieved or until the end of day 28. Genotype cells were collected from pretransplant bone-marrow samples and were stored until polymerase chain reaction–restriction fragment-length polymorphism analyses were performed. The frequencies of the CC, CT, and TT genotypes were found to be 47%, 43%, and 10%, respectively. Sixty-six percent of the patients developed grade III (24/53, 45%) and grade IV (11/53, 21%) oral mucositis. Among different genotypes, the distribution of grade IV mucositis was similar (P =0.14). The allelic frequency was found to be 31% (33/106) for the T allele and 69% (73/106) for the C allele. When the severity of mucositis (less than or equal to grade IV) was compared between C and T alleles, patients with the C allele had increased oral mucositis, and a statistically significant difference was found by the presence of the C allele (P <0.05). When the severity of mucositis (less than or equal to grade IV) was compared between each genotype, there was no statistically significant difference (CC vs. TT, P =0.15; CT vs. TT, P =0.40; CC vs. CT, P =0.12). The hematopoietic recovery time and the increment in bilirubin levels until the 28th day of transplantation were also similar among the different MTHFR genotypes. It has been reported that patients with the 677TT genotype have a tendency to experience higher MTX toxicity, but our data showed no statistically significant difference (3). The study cohort included a small sample size that limited our ability to draw conclusions, but we believe that our results can lead to conclusions about MTHFR677 polymorphism in Turkish HCT recipients. We believe that studies performed with different ethnic populations and with a greater number of patients are needed to clarify this issue.Table 1: Baseline characteristics of patients and comparison of common adverse effects of methotrexate among different genotypes of methylene tetrahydrofolate reductase (MTHFR) C677TSevgi Kalayoglu-Besisik Yasar Caliskan Deniz Sargin Nuray Gurses Ugur Ozbek