Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment
Autori
Kotur, NikolaLazić, Jelena
Ristivojević, Bojan
Stanković, Biljana
Gašić, Vladimir
Dokmanović, Lidija
Krstovski, Nada
Milosević, Goran
Janić, Dragana
Zukić, Branka
Pavlović, Sonja
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a p...redictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.
Ključne reči:
pharmacokinetics / pharmacogenomics / pediatric ALL / methotrexate / drug-related toxicityIzvor:
Genes, 2020, 11, 4Izdavač:
- MDPI, Basel
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200042 (Univerzitet u Beogradu, Institut za molekularnu genetiku i genetičko inženjerstvo) (RS-MESTD-inst-2020-200042)
DOI: 10.3390/genes11040468
ISSN: 2073-4425
PubMed: 32344632
WoS: 000537224600070
Scopus: 2-s2.0-85083846605
Institucija/grupa
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Kotur, Nikola AU - Lazić, Jelena AU - Ristivojević, Bojan AU - Stanković, Biljana AU - Gašić, Vladimir AU - Dokmanović, Lidija AU - Krstovski, Nada AU - Milosević, Goran AU - Janić, Dragana AU - Zukić, Branka AU - Pavlović, Sonja PY - 2020 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1322 AB - Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients. PB - MDPI, Basel T2 - Genes T1 - Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment IS - 4 VL - 11 DO - 10.3390/genes11040468 ER -
@article{ author = "Kotur, Nikola and Lazić, Jelena and Ristivojević, Bojan and Stanković, Biljana and Gašić, Vladimir and Dokmanović, Lidija and Krstovski, Nada and Milosević, Goran and Janić, Dragana and Zukić, Branka and Pavlović, Sonja", year = "2020", abstract = "Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.", publisher = "MDPI, Basel", journal = "Genes", title = "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment", number = "4", volume = "11", doi = "10.3390/genes11040468" }
Kotur, N., Lazić, J., Ristivojević, B., Stanković, B., Gašić, V., Dokmanović, L., Krstovski, N., Milosević, G., Janić, D., Zukić, B.,& Pavlović, S.. (2020). Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes MDPI, Basel., 11(4). https://doi.org/10.3390/genes11040468
Kotur N, Lazić J, Ristivojević B, Stanković B, Gašić V, Dokmanović L, Krstovski N, Milosević G, Janić D, Zukić B, Pavlović S. Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment. in Genes. 2020;11(4). doi:10.3390/genes11040468 .
Kotur, Nikola, Lazić, Jelena, Ristivojević, Bojan, Stanković, Biljana, Gašić, Vladimir, Dokmanović, Lidija, Krstovski, Nada, Milosević, Goran, Janić, Dragana, Zukić, Branka, Pavlović, Sonja, "Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment" in Genes, 11, no. 4 (2020), https://doi.org/10.3390/genes11040468 . .