Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia
Authors
Lazić, JelenaKotur, Nikola
Krstovski, Nada
Dokmanović, Lidija
Zukić, Branka
Predojević-Samardzić, Jelica
Zivotić, Maja
Milosević, Goran
Dorić, Milica
Janić, Dragana
Pavlović, Sonja
Article (Published version)
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Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C gen...otypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.
Keywords:
pharmacogenetic markers / pediatric lymphoblastic leukemia / MTHFR c.677 / MTHFR c.1298Source:
Archives of Biological Sciences, 2017, 69, 2, 239-246Publisher:
- Srpsko biološko društvo, Beograd, i dr.
Funding / projects:
- Rare Diseases:Molecular Pathophysiology, Diagnostic and Therapeutic Modalities and Social, Ethical and Legal Aspects (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)
DOI: 10.2298/ABS160325091L
ISSN: 0354-4664
WoS: 000402556600005
Scopus: 2-s2.0-85019656420
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Lazić, Jelena AU - Kotur, Nikola AU - Krstovski, Nada AU - Dokmanović, Lidija AU - Zukić, Branka AU - Predojević-Samardzić, Jelica AU - Zivotić, Maja AU - Milosević, Goran AU - Dorić, Milica AU - Janić, Dragana AU - Pavlović, Sonja PY - 2017 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1080 AB - Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy. PB - Srpsko biološko društvo, Beograd, i dr. T2 - Archives of Biological Sciences T1 - Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia EP - 246 IS - 2 SP - 239 VL - 69 DO - 10.2298/ABS160325091L ER -
@article{ author = "Lazić, Jelena and Kotur, Nikola and Krstovski, Nada and Dokmanović, Lidija and Zukić, Branka and Predojević-Samardzić, Jelica and Zivotić, Maja and Milosević, Goran and Dorić, Milica and Janić, Dragana and Pavlović, Sonja", year = "2017", abstract = "Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C gt T and MTHFR c.1298A gt C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCR-RFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A gt C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C gt T and MTHFR c.1298A gt C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C gt T nor MTHFR c.1298A gt C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.", publisher = "Srpsko biološko društvo, Beograd, i dr.", journal = "Archives of Biological Sciences", title = "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia", pages = "246-239", number = "2", volume = "69", doi = "10.2298/ABS160325091L" }
Lazić, J., Kotur, N., Krstovski, N., Dokmanović, L., Zukić, B., Predojević-Samardzić, J., Zivotić, M., Milosević, G., Dorić, M., Janić, D.,& Pavlović, S.. (2017). Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences Srpsko biološko društvo, Beograd, i dr.., 69(2), 239-246. https://doi.org/10.2298/ABS160325091L
Lazić J, Kotur N, Krstovski N, Dokmanović L, Zukić B, Predojević-Samardzić J, Zivotić M, Milosević G, Dorić M, Janić D, Pavlović S. Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia. in Archives of Biological Sciences. 2017;69(2):239-246. doi:10.2298/ABS160325091L .
Lazić, Jelena, Kotur, Nikola, Krstovski, Nada, Dokmanović, Lidija, Zukić, Branka, Predojević-Samardzić, Jelica, Zivotić, Maja, Milosević, Goran, Dorić, Milica, Janić, Dragana, Pavlović, Sonja, "Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia" in Archives of Biological Sciences, 69, no. 2 (2017):239-246, https://doi.org/10.2298/ABS160325091L . .