Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia

Autor: Abrar Al-Sheikh, Mohammed Zawiah, Daniah Alshamaseen, Al-Motassem Yousef, Taha Kadi, Rand Farhad
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Antimetabolites
Antineoplastic
Cancer Research
medicine.medical_specialty
Adolescent
Genotype
Neutropenia
Toxicology
Thymidylate synthase
Gastroenterology
03 medical and health sciences
Folic Acid
0302 clinical medicine
Internal medicine
Dihydropyrimidine dehydrogenase
Humans
Medicine
Pharmacology (medical)
Prospective Studies
Allele
Child
Childhood Acute Lymphoblastic Leukemia
Methylenetetrahydrofolate Reductase (NADPH2)
Retrospective Studies
Pharmacology
Polymorphism
Genetic
biology
business.industry
Thymidylate Synthase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
Minor allele frequency
Tetrahydrofolate Dehydrogenase
Cross-Sectional Studies
Methotrexate
030104 developmental biology
Oncology
Child
Preschool
030220 oncology & carcinogenesis
Methylenetetrahydrofolate reductase
biology.protein
Female
business
medicine.drug
Zdroj: Cancer Chemotherapy and Pharmacology. 83:755-762
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-019-03776-8
Popis: Acute lymphoblastic leukemia (ALL) is one of the major malignancies affecting children in Jordan. Methotrexate (MTX) is the cornerstone of chemotherapy for ALL, and works by targeting enzymes involved in the folate pathway. We hypothesize that genetic polymorphisms of the folate pathway are associated with MTX toxicity in children with ALL. A total of 64 children with ALL were included in this study; 31 (48.4%) boys and 33 (51.6%) girls aged 2–16 years. The folate pathway genes were genotyped using polymerase chain reaction followed by sequencing and studying the association between genetic polymorphisms and MTX toxicity. The immunophenotype was B-lineage in 55 patients (85.9%) and T-lineage in nine patients (14.1%). All genetic polymorphisms, except for dihydropyrimidine dehydrogenase polymorphisms, were associated with hematological toxicities and did not appear to precipitate any non-hematological adverse events. Patients with ALL carrying dominant alleles of methylene tetrahydrofolate (MTHFR) C677T and dihydrofolate reductase 19 bp deletion were at a higher risk of developing severe leucopenia [OR (95% CI) = 4.5 (1.2–17), p = 0.03; 5.4 (1.6–17.8); p = 0.006] while minor allele carriers of MTHFR A1298C were more likely to develop neutropenia [OR (95% CI) = 6.1 (1.3–29.5); 0.04]. Furthermore, dominant allele carriers of thymidylate synthase 1494 del6 were at a higher risk of developing neutropenia [OR (95% CI) = 6 (1.2–31.1); p = 0.04]. Genetic polymorphisms of the folate pathway may modulate MTX-induced toxicity in childhood ALL.
Databáze: OpenAIRE
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