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Original Article

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Blood Res 2016; 51(1):

Published online March 31, 2016

https://doi.org/10.5045/br.2016.51.1.50

© The Korean Society of Hematology

Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma

Jeong A Park1, and Hee Young Shin2*

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1Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.

2Department of Pediatrics, Cancer Research Institute, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Correspondence to : Correspondence to Hee Young Shin, M.D., Ph.D. Department of Pediatrics, Cancer Research Institute, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. hyshin@snu.ac.kr

Received: January 29, 2016; Revised: March 14, 2016; Accepted: March 22, 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background

Methotrexate (MTX), one of the main drugs used to treat osteosarcoma, is a representative folic acid antagonist. Polymorphisms of various enzymes involved in the metabolism of MTX could contribute to differences in response to MTX in pediatric osteosarcoma patients.

Methods

Blood and tissue samples were obtained from 37 pediatric osteosarcoma patients who were treated with high-dose MTX therapy. The following 4 single nucleotide polymorphisms (SNPs) were analyzed: ATIC 347C>G, MTHFR 677C>T, MTHFR 1298A>C and SLC19A1 80G>A. Serial plasma MTX concentrations after high-dose MTX therapy and MTX-induced toxicities were evaluated. Correlations among polymorphisms, MTX concentrations and treatment-induced toxicities were assessed.

Results

Plasma MTX levels at 48 hours after high-dose MTX infusion were significantly associated with SLC19A1 80G>A (P=0.031). Higher plasma levels of MTX at 48 and 72 hours were significantly associated with MTX-induced mucositis (P=0.007 and P=0.046) and renal toxicity (P=0.002), respectively. SNP of SLC19A1 gene was associated with development of severe mucositis (P=0.026).

Conclusion

This study suggests that plasma levels of MTX are associated with GI and renal toxicities after high-dose MTX therapy, and genetic polymorphisms that affect the metabolism of MTX may influence drug concentrations and development of significant side effects in pediatric patients treated with high-dose MTX.

Keywords Pediatric, Osteosarcoma, Methotrexate, Toxicity, Single nucleotide polymorphism

Article

Original Article

Blood Res 2016; 51(1): 50-57

Published online March 31, 2016 https://doi.org/10.5045/br.2016.51.1.50

Copyright © The Korean Society of Hematology.

Influence of genetic polymorphisms in the folate pathway on toxicity after high-dose methotrexate treatment in pediatric osteosarcoma

Jeong A Park1, and Hee Young Shin2*

1Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.

2Department of Pediatrics, Cancer Research Institute, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.

Correspondence to:Correspondence to Hee Young Shin, M.D., Ph.D. Department of Pediatrics, Cancer Research Institute, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. hyshin@snu.ac.kr

Received: January 29, 2016; Revised: March 14, 2016; Accepted: March 22, 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Methotrexate (MTX), one of the main drugs used to treat osteosarcoma, is a representative folic acid antagonist. Polymorphisms of various enzymes involved in the metabolism of MTX could contribute to differences in response to MTX in pediatric osteosarcoma patients.

Methods

Blood and tissue samples were obtained from 37 pediatric osteosarcoma patients who were treated with high-dose MTX therapy. The following 4 single nucleotide polymorphisms (SNPs) were analyzed: ATIC 347C>G, MTHFR 677C>T, MTHFR 1298A>C and SLC19A1 80G>A. Serial plasma MTX concentrations after high-dose MTX therapy and MTX-induced toxicities were evaluated. Correlations among polymorphisms, MTX concentrations and treatment-induced toxicities were assessed.

Results

Plasma MTX levels at 48 hours after high-dose MTX infusion were significantly associated with SLC19A1 80G>A (P=0.031). Higher plasma levels of MTX at 48 and 72 hours were significantly associated with MTX-induced mucositis (P=0.007 and P=0.046) and renal toxicity (P=0.002), respectively. SNP of SLC19A1 gene was associated with development of severe mucositis (P=0.026).

Conclusion

This study suggests that plasma levels of MTX are associated with GI and renal toxicities after high-dose MTX therapy, and genetic polymorphisms that affect the metabolism of MTX may influence drug concentrations and development of significant side effects in pediatric patients treated with high-dose MTX.

Keywords: Pediatric, Osteosarcoma, Methotrexate, Toxicity, Single nucleotide polymorphism

Fig 1.

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Figure 1.

Plasma methotrexate levels at 48 hours after high-dose methotrexate infusion were significantly associated with the 80G>A variants of SLC19A1 (P=0.03).

Blood Research 2016; 51: 50-57https://doi.org/10.5045/br.2016.51.1.50

Fig 2.

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Figure 2.

Plasma methotrexate levels at 48 (A, B) and 72 hours (C, D) after high-dose methotrexate infusion were significantly associated with a development of grade 3 and 4 of mucositis and kidney toxicity.

Blood Research 2016; 51: 50-57https://doi.org/10.5045/br.2016.51.1.50
Sequencing by synthesis (SBS) primer sequences for multiple amplification of methotrexate related genes.
Allele-specific primer extension (ASPE) primer sequences.
Characteristics of patients.
Genotype frequencies of the patients.
Associations between SNPs and plasma methotrexate concentrations at 48 hours after high-dose methotrexate therapy.
Analysis of MTX-induced toxicity and MTX concentrations at 48 and 72 hours after high-dose MTX therapy.
Analysis of SNPs and methotrexate-induced toxicity.
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