Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate

Abstract

Osteosarcoma patients are commonly treated with high doses of methotrexate (MTX). MTX is an analog of folate, which is essential for DNA synthesis. Genetic polymorphism at single nucleotide can be indicative to the prognostic outcome in patients. Germ-line variants in candidate genes, coding for enzymes active in the metabolism of MTX, were studied in 62 osteosarcoma patients. Patients harboring the GG genotype in reduced folate carrier 1 (RFC1) rs1051266 had significantly better survival in comparison with patients having the AA genotype (P=0.046). These patients also had a lower frequency of metastasis (15%, P=0.029). Also patients homozygous for the G allele of rs1053129 in the dihydrofolate reductase (DHFR) gene were more likely to have a metastasis (45%, P= 0.005), and the methylenetetetrahydrofolate reductase (MTHFR) 677C allele was associated with higher degree of liver toxicity (88%, P=0.007). The study suggests that germ-line variants in the MTX metabolic pathway are associated with survival and side effects in patients treated with MTX.

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

“…Nearly half literatures reported a significant correlation between the C677T variant genotype and an increased risk of developing adverse events (grades 3 and 4 hematologic and non-hematologic toxicity) after treatment with MTX alone or in combination with other agents, in patients with hematologic malignancies [ 30 ], ovarian [ 31 ] and breast cancers [ 32 ] and even patients with rheumatoid arthritis or juvenile idiopathic arthritis [ 33 ]. While other reports shared opposite results [ 14 , 34 – 36 ]. There are few reports discussing MTHFR polymorphisms in osteosarcoma [ 36 ] (summarized in Table 3 ).…”

“…While other reports shared opposite results [ 14 , 34 – 36 ]. There are few reports discussing MTHFR polymorphisms in osteosarcoma [ 36 ] (summarized in Table 3 ). From 2009 to 2015, three literatures [ 14 , 35 , 36 ] investigated the potential effects of MTHFR on osteosarcoma patients and were all focused on Caucasian origin.…”

“…There are few reports discussing MTHFR polymorphisms in osteosarcoma [ 36 ] (summarized in Table 3 ). From 2009 to 2015, three literatures [ 14 , 35 , 36 ] investigated the potential effects of MTHFR on osteosarcoma patients and were all focused on Caucasian origin. It seemed this MTHFR indeed had some impact on the toxicity of MTX but not on the disease outcomes and histological responses.…”

“…While there was only one study presented with different oncologic prognosis [ 42 ]. From the available data, the most evident association emerging is between the C677T variant form and increased MTX toxicity [ 29 , 32 , 36 , 41 ]. Converse correlations between C677T and MTX efficacy presented a pool of heterogeneous and sometimes contrasting results that provided equivocal conclusions [ 1 , 19 , 36 , 43 ].…”

Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

“…Recently, several genes were found to play important roles in the pharmacokinetics or pharmacodynamics of chemotherapy agents, such as the role of polymorphism of reduced folate carrier 1 and methylenetetetrahydrofolate reductase in high-dose methotrexate treatment (13). Therefore, the effect of MGMT status on the survival of patients with …”