Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia

Autor: Amira Abdel Moneam Adly, Mohammed Abou El Asrar, Esmat E Abdulghaffar, Azza A.G. Tantawy, Eman A El-Bostany, Eman A El-Ghouroury
Rok vydání: 2010
Předmět:
Male
Genotype
medicine.drug_class
medicine.medical_treatment
Biology
Polymorphism
Single Nucleotide
Antimetabolite
chemistry.chemical_compound
Gene Frequency
Recurrence
hemic and lymphatic diseases
Acute lymphocytic leukemia
Antineoplastic Combined Chemotherapy Protocols
medicine
Asparaginase
Humans
Genetic Predisposition to Disease
Child
Cyclophosphamide
Alleles
Methylenetetrahydrofolate Reductase (NADPH2)
Stomatitis
Chemotherapy
Mercaptopurine
Daunorubicin
Cytarabine
Cancer
Hematology
General Medicine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
medicine.disease
Neoplasm Proteins
Methotrexate
chemistry
Vincristine
Child
Preschool
Methylenetetrahydrofolate reductase
Antifolate
Immunology
Cancer research
biology.protein
Prednisone
Egypt
Female
Gene polymorphism
Chemical and Drug Induced Liver Injury
Polymorphism
Restriction Fragment Length
medicine.drug
Zdroj: Blood Coagulation & Fibrinolysis. 21:28-34
ISSN: 0957-5235
Popis: Genetic variations of the enzymes involved in chemotherapy metabolism in cancer patients may play a role in determining relapse and toxicity risks. Methotrexate is a key drug in acute lymphoblastic leukemia (ALL) treatment; it inhibits DNA replication by blocking the conversion of 5,10 methylene tetrahydrofolate to 5-methylene tetrahydrofolate by methylene tetrahydrofolate reductase (MTHFR). MTHFR is central to folate metabolism and has two common functional polymorphisms (C677T and A1298C). The present study aimed to assess the prevalence of MTHFR polymorphisms C677T and A1298C in Egyptian children with ALL and the relation to the frequency of drug-induced complications and relapse rate. Forty ALL patients were included in the study. They were treated according to modified ALL-BFM 90 protocol, and were followed up for 3.1-6.5 years. The severity and duration of hepatic, mucosal and infectious complications during therapy were reported. MTHFR genotyping was done with a PCR-based restriction fragment length polymorphism assay. The MTHFR C677T polymorphic allele frequencies were 40, 27.5, and 32.5% for TT, CT, and CC genotypes, respectively among the studied ALL patients. The MTHFR A1298C polymorphic allele frequencies were 40, 35, and 25% for AA, AC, and CC genotypes, respectively. Methotrexate therapy was significantly associated with increased grade III/IV toxicity in TT genotype: diarrhea in 81.3%, oral mucositis in 81.3%, elevated transaminases in 87.5%, neutropenia in 78.7% compared to values of 7.7, 7.7, 15.3, and 7.7% in CC genotype, respectively (P0.0001, P0.0001, P0.0001, and P = 0.03). The 677 TT genotype was significantly associated with relapse in 5 years in 56.3%, compared to 18.2% in CT and 0% in CC alleles. The overall 5 years survival was significantly lower in 677 TT (50%) compared with CC genotypes (92.3%) (P = 0.001). No significant relation was found between MTHFR A1298C polymorphism and the risks of therapy induced complications or relapse rate in the studied ALL patients. MTHFR TT genotype is significantly associated with increased mucosal and hepatic toxicity during methotrexate therapy as well as increased relapse rate in childhood ALL. Because of the relatively high prevalence of the TT genotype in the studied Egyptian children with ALL, MTHFR gene polymorphisms should be studied in large multicenter studies; and dosage modification of methotrexate in the ALL treatment protocols should be considered based on the MTHFR gene pattern.
Databáze: OpenAIRE
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