Relationship between methylenetetrahydrofolate reductase gene polymorphisms and methotrexate drug metabolism and toxicity

Abstract

Background Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX. Methods The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Results The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179–2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042–2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251–0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183–31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033–3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed. Conclusions Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China

“…Our study showed that ABCB1 C3435T was not associated with MTX elimination delay in HD-MTX treatment of children with ALL, which was consistent with some studies 1 , 33 , 34 that concluded that ABCB1 C3435T was not associated with MTX elimination delay, MTX plasma level or the MTX AUC in HD-MTX treatment of children with ALL. MTHFR C677T and MTHFR A1298C were also not associated with MTX elimination delay in HD-MTX treatment of children with ALL in our study, consistent with some studies on Chinese populations 6 , 29 , 35 and Korean populations. 18 However, other studies have indicated the opposite conclusions in HD-MTX treatment of children with ALL in Iran, 36 Poland 37 and Egypt.…”

“… 3 However, drug-related toxicities continue to limit its clinical use. 29 Response to MTX largely varies among patients receiving HD-MTX treatment. 2 , 30 Research on genetic predictors for MTX-induced toxicities would be helpful for selecting patients who may benefit from personalized treatment strategies.…”

“…Although the relationship between MTHFR C677T and MTHFR A1298C and HD-MTX toxicities has been extensively studied, definitive conclusions remain unavailable. 2 , 29 Nevertheless, the majority of published studies found no association between MTHFR polymorphisms and risk of HD-MTX toxicities. 39 , 40 This discrepancy might be attributed to the difference in racial groups, sample size, treatment regimens used and time points for evaluating HD-MTX toxicities between the present and previous studies.…”

“…Another important reason may be that there are many other enzymes or transporter proteins that have a combined impact on MTX pharmacokinetic variability in addition to MTHFR . 29 Therefore, MTHFR C677T and MTHFR A1298C gene polymorphisms may not be the main factors for HD-MTX toxicities in Chinese patients, though there may be a limited relationship between them. 6 …”

Genetic polymorphisms as predictors of methotrexate toxicity: literature review

“…Новые направления, возможности диагностики и успехи лечения к снижению стабильности и функции фермента MTHFR, тем самым влияя на метаболизм МТХ [47]. В 2012 г. E. LopezLopez и соавт.…”