MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

Zhang, Wenchao; Liu, Zhongyue; Yang, Zhimin; Feng, Chengyao; Zhou, Xiaowen; Tu, Chao; Li, Zhihong

doi:10.3389/fonc.2021.781386

Cited by 9 publications

(4 citation statements)

References 42 publications

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“…In a meta-analysis by Zhu et al that included 14 studies with a sample size of 1714 children, the C677T mutant gene was significantly associated with hepatotoxicity ( 28 ). Additionally, several reports have confirmed a significantly higher risk of hepatic impairment in patients with mutant genotypes ( 29 - 32 ). El-Khodary et al also demonstrated significantly higher serum glutaminase levels in children with ALL who have CT and TT mutation compared to those with wild-type CC ( 33 ).…”

Section: Discussionmentioning

confidence: 92%

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

Tan¹,

Kong²,

Li³

et al. 2023

Transl Pediatr

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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.

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Section: Discussionmentioning

confidence: 92%

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

Tan¹,

Kong²,

Li³

et al. 2023

Transl Pediatr

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“…19 . Among them, genetic factors may be involved in the activities of MTX-associated enzymes, which may affect the metabolism and intracellular transport of the drug, thereby inducing the associated toxicity 20 . In the present study, the potential impact of MTX-related gene polymorphisms on MTX-related toxicity and clearance delay during HD-MTX treatment was analyzed in 189 Chinese children with ALL.…”

Section: Discussionmentioning

confidence: 99%

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Zhou,

He,

Ding

et al. 2023

Eur J Pediatr

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To assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. MethodsThe MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435C > T, and GSTP1 313A > G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). ResultsThe results of univariate and multivariate analyses showed that MTHFR 677C > T and ABCB1 3435 C T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No signi cant association was identi ed between MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435 C > T, and GSTP1 313A > G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by in uencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects. ConclusionMTHFR 677C > T and ABCB1 3435 C > T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were signi cantly elevated after HD-MTX treatment in children with the MTHFR 677C > T mutation gene. 1.Introduction Acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, characterized by the abnormal proliferation of lymphoblasts. Over the years, advancements in combination chemotherapy regimens have signi cantly improved the prognosis for children with ALL. The survival

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“…The incidence of osteosarcoma is bimodal with age, with an initial peak at 10–14 years of age, and a second peak after 60 years [ 99 ]. Primarily, osteosarcoma tends to occur in the metaphysis of the distal femur and proximal tibia [ 100 ], while metastasis is mainly detected in the lung [ 101 , 102 ]. With an annual incidence of approximately 3–4 patients per million, osteosarcoma is a relatively common malignant tumor in pediatric cancers, as well as one of the leading causes of cancer-related death in children and adolescents [ 103 , 104 ].…”

Section: Overview Of Pyroptosismentioning

confidence: 99%

The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy

Wang

Zhou

et al. 2022

J Hematol Oncol

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Pediatric cancers are the driving cause of death for children and adolescents. Due to safety requirements and considerations, treatment strategies and drugs for pediatric cancers have been so far scarcely studied. It is well known that tumor cells tend to progressively evade cell death pathways, which is known as apoptosis resistance, one of the hallmarks of cancer, dominating tumor drug resistance. Recently, treatments targeting nonapoptotic cell death have drawn great attention. Pyroptosis, a newly specialized form of cell death, acts as a critical physiological regulator in inflammatory reaction, cell development, tissue homeostasis and stress response. The action in different forms of pyroptosis is of great significance in the therapy of pediatric cancers. Pyroptosis could be induced and consequently modulate tumorigenesis, progression, and metastasis if treated with local or systemic therapies. However, excessive or uncontrolled cell death might lead to tissue damage, acute inflammation, or even cytokine release syndrome, which facilitates tumor progression or recurrence. Herein, we aimed to describe the molecular mechanisms of pyroptosis, to highlight and discuss the challenges and opportunities for activating pyroptosis pathways through various oncologic therapies in multiple pediatric neoplasms, including osteosarcoma, neuroblastoma, leukemia, lymphoma, and brain tumors.

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MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

Cited by 9 publications

References 42 publications

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

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

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

The emerging role of pyroptosis in pediatric cancers: from mechanism to therapy

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