The Role of the
            <i>MTHFR</i>
            C677T Polymorphism in Methotrexate-Induced Toxicity in Pediatric Osteosarcoma Patients

Lambrecht, Loes; Sleurs, Charlotte; Labarque, Veerle; Dhooge, Catharina; Laenen, Annouschka; Sinnaeve, Friedl; Renard, Marleen; Uyttebroeck, Anne

doi:10.2217/pgs-2017-0013

Cited by 24 publications

(33 citation statements)

References 27 publications

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“…However, differential outcome was observed among patients receiving even the same therapeutic protocol. In previous studies, genetic polymorphisms have been shown to indicate patients’ response to chemotherapeutic agents which eventually could influence the final survival [10] , [11] , [12] , [13] . Herein, integration of such predictive genetic markers is crucial to optimize risk stratification and personalize chemotherapy strategy.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms of ERCC1 were reported to play important roles in the response to cisplatin mediated by the DNA repair pathway [10] . MTHFR C677T polymorphism was identified as a predictor of MTX toxicity in osteosarcoma patients [11] . The SNPs of ABCB1 and ABCC3 were found significantly associated with pharmacokinetic parameters and the occurrence of MTX toxicity [12] , [13] .…”

Section: Introductionmentioning

confidence: 99%

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Variants of FasL and ABCC5 are predictive of outcome after chemotherapy-based treatment in osteosarcoma

Xia

Sun

et al. 2018

Journal of Bone Oncology

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ObjectivesPrevious pharmacogenetics studies showed that genetic variants could be indicative of the response to chemotherapy. We aimed to investigate whether variants of FasL, MSH2, ABCC5, CASP3 and CYP3A4 are associated with the outcome after chemotherapy-based treatment in osteosarcoma.Methods132 osteosarcoma patients who had completed the neoadjuvant chemotherapy in our center were included. 5-year progression-free survival (PFS) was assessed from the initial treatment to the earliest sign of disease progression or death from any cause. 5 SNPs were genotyped using TaqMan SNP Genotyping Assay, including rs763110 of FasL, rs4638843 of MSH2, rs939338 of ABCC5, rs2720376 of CASP3 and rs4646437 of CYP3A4. Patients were classified into two groups according to the 5-year PFS (event/no event). The chi-square test was used to analyze difference of genotype frequency. Logistic regression analysis was used to determine the independent predictors of the PFS rate.ResultsThe overall 5-year PFS was 61.4% (81/132). Genotype TT/CT of rs763110 and genotype GG/AG of rs939338 were significantly associated with the event of 5-year PFS (p = 0.028 for rs763110; p = 0.039 for rs939338). Patients with no risk allele showed a 5-year PFS of 73.7% (42/57), which was significantly higher than a PFS of 54.2% (26/48) for patients with one risk allele and 48.1% (13/27) for patients with two different risk alleles (p = 0.03). Logistic regression analysis showed that allele T of FasL rs763110 and allele G of ABCC5 rs939338 were independent risk factors of the 5-year PFS. The ORs were 2.14 (95%CI = 1.13–3.35, p = 0.01) for rs763110 and 1.73 (95%CI = 1.05–2.52, p = 0.03) for rs939338, respectively.ConclusionsThe association of variants of FASL and ABCC5 with survival outcome after chemotherapy was validated in patients with osteosarcoma. Our findings may provide a new insight into a more personalized treatment for patients with osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variants of FasL and ABCC5 are predictive of outcome after chemotherapy-based treatment in osteosarcoma

Xia

Sun

et al. 2018

Journal of Bone Oncology

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“…These SNPs might be associated with decreased activity of methylenetetrahydrofolate reductase, elevated plasma homocysteine levels, and altered distribution of folate [ 41 ]. Thus patients with this genotype were more vulnerable to potential MTX induced toxicity since these reactions above may lead to slower folate metabolism and slower cell repair [ 42 ]. Weisman et al used univariate logistic regression to reveal that the MTHFR C677T also increases the occurrence of side effects in central nervous system, manifested as headache and lethargy [ 43 ].…”

Section: The Pharmacogenetics Of Mtxmentioning

confidence: 99%

“…Weisman et al used univariate logistic regression to reveal that the MTHFR C677T also increases the occurrence of side effects in central nervous system, manifested as headache and lethargy [ 43 ]. However, Lambrecht et al argued that MTHFR C667T was not a predictive factor for toxicity [ 42 ]. Berkani et al found no association between A1298C polymorphism and MTX toxicity [ 44 ].…”

Section: The Pharmacogenetics Of Mtxmentioning

confidence: 99%

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology

Wang

Peng

2020

Journal of Ophthalmology

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Methotrexate (MTX) is a folate analog widely used against a range of diseases including malignancies and autoimmune disorders. Its high effectiveness-price ratio also won extensive application in ophthalmology. On the other hand, although MTX has an excellent pharmacological efficacy, MTX associated side effects in clinical use, which vary from patient to patient, are nonnegligible. There is no comparatively systematic review on MTX associated side effects and its risk factors. This review aimed to reveal novel clinical approaches of MTX and its adverse effects in order to provide a reference for ophthalmic scholars in clinical application of MTX.

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“…Therefore, one needs to be precautious with direct generalization of pharmacogenetic associations found in other malignancies or other low dose MTX-treated traits such as autoimmune diseases to osteosarcoma. In osteosarcoma, only candidate gene studies have been performed to identify relevant pharmacogenetic variants, resulting in the identification of statistically significantly associations between variants in MTHFR , MTR and ABCB1 , and MTX pharmacokinetics, toxicities and survival rates ( Patino-Garcia et al., 2009 ; Windsor et al., 2012 ; Jabeen et al., 2015 ; Park and Shin, 2016 ; Lambrecht et al., 2017 ). Previously, our group investigated the role of a genetic variant in MTHFR (rs1801133) in MTX-induced liver toxicity in patients with osteosarcoma and ALL ( Hagleitner et al., 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of Drug Metabolizing Gene Panel in Osteosarcoma Patients Identifies Association Between Variants in SULT1E1, CYP2B6 and CYP4F8 and Methotrexate Levels and Toxicities

Hurkmans¹,

Klumpers

Vermeulen³

et al. 2020

Front. Pharmacol.

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High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5’-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 – -0.167); p = 2.60 × 10 -5 ]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 – -0.099); p = 3.04 × 10 -5 ] and rs4803419 [coef -0.186 (95% CI -0.278 – -0.093); p = 8.80 × 10 -5 ]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 – 0.287); p = 6.02 × 10 -5 ]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6 , and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.

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The Role of the MTHFR C677T Polymorphism in Methotrexate-Induced Toxicity in Pediatric Osteosarcoma Patients

Abstract: The MTHFR C667T polymorphism is not predictive for toxicity or overall survival, but could be used for relapse risk stratification.

Cited by 24 publications

References 27 publications

Variants of FasL and ABCC5 are predictive of outcome after chemotherapy-based treatment in osteosarcoma

Variants of FasL and ABCC5 are predictive of outcome after chemotherapy-based treatment in osteosarcoma

A Review of Clinical Applications and Side Effects of Methotrexate in Ophthalmology

Analysis of Drug Metabolizing Gene Panel in Osteosarcoma Patients Identifies Association Between Variants in SULT1E1, CYP2B6 and CYP4F8 and Methotrexate Levels and Toxicities

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