Influence of MTHFR and RFC1 Polymorphisms on Toxicities During Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukemia or Lymphoma

Abstract

We investigated preliminarily whether methylenetetrahydrofolate reductase (MTHFR) 677C/T or reduced folate carrier 1 (RFC1) 80G/A polymorphisms were associated with toxicities during maintenance chemotherapy with mercaptopurine (6MP) and methotrexate (MTX) in children with acute lymphoblastic leukemia or lymphoblastic lymphoma. The clinical records of 20 children (2 to 15-y old) who had received maintenance chemotherapy were reviewed retrospectively and their genomic DNA was genotyped to identify polymorphisms at MTHFR 677C/T, RFC1 80G/A, and thiopurine methyltransferase 719A/G. Maintenance chemotherapy with 6MP and MTX was repeated on a weekly basis, and any week during which 6MP and/or MTX dosing was withheld was counted as an interrupted episode. Associations between the risk of interruptions and polymorphisms were studied using a generalized estimating equation analysis. Patients with an increasing number of T alleles at MTHFR 677C/T experienced interruptions in both 6MP (P<0.01) and MTX (P=0.03) more frequently. Patients with an increasing number of A alleles at RFC1 80G/A experienced interruptions in 6MP (P=0.04) more frequently. This preliminary study does not prove but suggests that MTHFR 677C/T and RFC1 80G/A polymorphisms may serve as predictors of toxicity during maintenance chemotherapy.

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

“…Pakakasama et al [28] studied RFC G80A polymorphism and MTX-induced toxicities and found no effect on the risk of oral mucositis, myelosuppression, or febrile neutropenia. And, these results were similar to Shimasaki et al [29]. However, Faganel Kotnik et al [30] found that patients with G allele have a protective effect on MTX-associated leucopenia [OR=0.15, 95 %CI=0.039-0.60, P<0.05].…”

Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival

“…2,11,12,14,15,26,27 Most of these studies did not find significant associations between the 677T allele and toxicity, 2,12,14,26,27 although one study reported a lower rate of episodes of toxicity among patients carrying the 677T allele 15 and another study showed that individuals with the 677T allele more frequently had to interrupt methotrexate treatment, suggesting that the MTHFR 677C>T serves as a predictor of toxicity during maintenance chemotherapy. 11 These different results are probably attributable to several factors including the methotrexate-dose, treatment protocol, ethnic background, and number of patients analyzed. In line with our findings, decreased hematologic toxicity associated with the 1298 AC/CC genotypes was previously described in children with ALL treated with high-dose methotrexate; nevertheless these studies did not find greater toxicity associated with the 677T allele.…”

“…MTHFR 677 C>T 9 and 1298 A>C) 10 can influence the effectiveness and the toxic effects of methotrexate. The relationship between polymorphisms affecting folate metabolism and methotrexate-related toxicity has been studied mainly in childhood ALL, 2,[11][12][13][14][15] while only a few studies have investigated this relationship in adult patients with hematologic diseases. 16,17 In particular, in adult ALL only MTHFR polymorphisms have been investigated and associated with increased methotrexaterelated toxicity.…”

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia

“…[18][19][20][21][22] rs1051266 in SLC19A1, resulting in a less efficient transporter, has been associated with more adverse events and worse overall prognosis. [23][24][25][26] A polymorphic tandem repeat in the 59UTR of the TYMS enhancer region (rs34743033) was associated with a significantly greater chance of response to treatment in 205 ALL patients treated with MTX. 27 A genome-wide association study implicated the intronic SNP rs11045879 in the SLCO1B1 transporter gene, which was in linkage disequilibrium (LD) with the functional SLCO1B1 SNP rs4149056, with MTX clearance and gastrointestinal toxicity in 640 ALL patients.…”