Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia
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 tre...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
University of Belgrade, University of Novi Sad
2017-01-01
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| Series: | Archives of Biological Sciences |
| Subjects: | |
| Online Access: | http://www.doiserbia.nb.rs/img/doi/0354-4664/2017/0354-46641600091L.pdf |
| _version_ | 1819230991174074368 |
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| author | Lazić Jelena Kotur Nikola Krstovski Nada Dokmanović Lidija Zukić Branka Predojević-Samardžić Jelica Životić Maja Milošević Goran Đorić Milica Janić Dragana Pavlović Sonja |
| author_facet | Lazić Jelena Kotur Nikola Krstovski Nada Dokmanović Lidija Zukić Branka Predojević-Samardžić Jelica Životić Maja Milošević Goran Đorić Milica Janić Dragana Pavlović Sonja |
| author_sort | Lazić Jelena |
| collection | DOAJ |
| description | 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>T and MTHFR c.1298A>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 PCRRFLP and
allele-specific PCR assays. Our results revealed similar distributions of
MTHFR c.677C>T and MTHFR c.1298A>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>C
genotypes were not associated with MTX toxicity. Carriers of any MTHFR
c.677C>T and MTHFR c.1298A>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>T nor MTHFR c.1298A>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. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 41004] |
| first_indexed | 2024-12-23T11:37:51Z |
| format | Article |
| id | doaj.art-072f18078def4165bb887796f9ca28ed |
| institution | Directory Open Access Journal |
| issn | 0354-4664 1821-4339 |
| language | English |
| last_indexed | 2024-12-23T11:37:51Z |
| publishDate | 2017-01-01 |
| publisher | University of Belgrade, University of Novi Sad |
| record_format | Article |
| series | Archives of Biological Sciences |
| spelling | doaj.art-072f18078def4165bb887796f9ca28ed2022-12-21T17:48:34ZengUniversity of Belgrade, University of Novi SadArchives of Biological Sciences0354-46641821-43392017-01-0169223924610.2298/ABS160325091L0354-46641600091LImportance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemiaLazić Jelena0Kotur Nikola1Krstovski Nada2Dokmanović Lidija3Zukić Branka4Predojević-Samardžić Jelica5Životić Maja6Milošević Goran7Đorić Milica8Janić Dragana9Pavlović Sonja10University Children`s Hospital, Department of Hematology and Oncology, Belgrade + School of Medicine, BelgradeInstitute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Biomedicine, BelgradeUniversity Children`s Hospital, Department of Hematology and Oncology, Belgrade + School of Medicine, BelgradeUniversity Children`s Hospital, Department of Hematology and Oncology, Belgrade + School of Medicine, BelgradeInstitute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Biomedicine, BelgradeChildren’s Hospital, University Clinic of Banja Luka, Republic of Srpska, Bosnia and HercegovinaSchool of Medicine, Institute of Pathology, Belgrade + School of Medicine, BelgradeUniversity Children`s Hospital, Department of Hematology and Oncology, BelgradeSchool of Medicine, BelgradeUniversity Children`s Hospital, Department of Hematology and Oncology, Belgrade + School of Medicine, BelgradeInstitute of Molecular Genetics and Genetic Engineering, Laboratory for Molecular Biomedicine, BelgradeDespite 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>T and MTHFR c.1298A>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 PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>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>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>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>T nor MTHFR c.1298A>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. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III 41004]http://www.doiserbia.nb.rs/img/doi/0354-4664/2017/0354-46641600091L.pdfpharmacogenetic markerspediatric lymphoblastic leukemiaMTHFR c.677MTHFR c.1298 |
| spellingShingle | Lazić Jelena Kotur Nikola Krstovski Nada Dokmanović Lidija Zukić Branka Predojević-Samardžić Jelica Životić Maja Milošević Goran Đorić Milica Janić Dragana Pavlović Sonja Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia Archives of Biological Sciences pharmacogenetic markers pediatric lymphoblastic leukemia MTHFR c.677 MTHFR c.1298 |
| title | Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| title_full | Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| title_fullStr | Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| title_full_unstemmed | Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| title_short | Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| title_sort | importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia |
| topic | pharmacogenetic markers pediatric lymphoblastic leukemia MTHFR c.677 MTHFR c.1298 |
| url | http://www.doiserbia.nb.rs/img/doi/0354-4664/2017/0354-46641600091L.pdf |
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