More severe toxicity of genetic polymorphisms on MTHFR activity in osteosarcoma patients treated with high-dose methotrexate

Abstract

5,10-Methylenetrahydrofolate reductase (MTHFR), a key enzyme for folate metabolism, catalyses the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is located at the end of the short arm (1p36.3). Two common non-synonymous variants, the C677T (Ala222Val) and A1298C (Glu429Ala), were mainly described with decreased enzymatic activity and an alteration of intracellular folate distribution. Osteosarcomas are currently treated with high dose of methotrexate (MTX). The decreased enzyme activity of MTHFR theoretically could increase the drug action of MTX and at the same time increase toxic and side effect. Germline variants of C677T and A1298C were studied in 59 osteosarcoma patients, with whom the A1298C is detected with particularly low rate of mutant genotype (N = 1, 0.8%) and could not proceed with statistical calculations. 15 patients were wild type of C677T (CC, 25.4%), 20 were heterozygous mutant genotype (CT, 33.9%) and 24 were homozygous mutant genotype (TT, 40.7%). Patients harboring the TT/CT genotype had the same progression-free survival and tumor necrosis rate in comparison with patients having the CC genotype (P = 0.349 and P = 0.465 respectively). And the C677T polymorphisms had no significant correlation with MTX initial plasma concentration (P = 0.867; r = 0.024) and delayed elimination (P = 0.305; r = −0.136). However patients with mutant genotype of C677T were associated with higher degree of liver toxicity (P = 0.043) and fever reaction of MTX (P = 0.050) while G3/G4 hematologic toxicity were more likely to be noticed with TT than CT/CC (P = 0.095). The study suggests that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway seems to be associated with the trend for more side effects statistically, but has no obvious effect on histologic response and survival.

Influence of MTHFR C677T and A1298C polymorphisms on the survival of pediatric patients with non-Hodgkin lymphoma

“…39 Similarly, Xie et al suggested that genetic polymorphism of MTHFR C677T in the MTX metabolic pathway had no obvious effect on progression-free survival and tumor necrosis rate in sarcoma (age range, 5-52 years). 40 For hematological malignancy, early studies on childhood ALL have reported controversial results. [16][17][18] However, a recent review concluded that there was no association or opposite effects in the majority of published data, and that these two polymorphisms are not suitable predictors of outcome in pediatric ALL.…”

Pharmacogenomics and Pharmacogenetics in Osteosarcoma: Translational Studies and Clinical Impact

“…One study carried out in patients after high-dose MTX-therapy found a significant association between the T allele and liver toxicity in 49 patients with HGOS [ 111 ]. This association, however, was not confirmed in the subsequent meta-analysis, including seven studies with a total of 1044 patients (148 with HGOS), whereas a recent study on 59 Han Chinese patients with HGOS found the variant T allele of MTHFR rs1801133 being associated with higher degrees of liver toxicity [ 108 ].…”

“…The TT genotype was significantly associated with grade 3–4 hematologic toxicity in 96 pediatric HGOS patients [ 107 ]. In a recent study, the variant T allele of this polymorphism was reported to correlate with higher degrees of hematologic toxicities in 59 Han Chinese patients with HGOS [ 108 ].…”

“…Two studies reported polymorphisms in association with fever: the AC/AA genotypes of ERCC1 rs3212986 [ 54 ] and the T allele of MTHFR rs1801133 [ 108 ].…”

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

“…Among genes related to methotrexate metabolism, the most widely studied in HGOS has been the 5,10-methylenetetrahydrofolate reductase (MTHFR) [15,18]. The most remarkable information on the possible clinical impact about this gene consisted with the association of the variant allele (T) of MTHFR rs1801133 with higher degrees of liver and hematologic toxicities in a series of 59 Han Chinese HGOS patients [19].…”