Article ; Online: High frequency of the 3R/3R polymorphism in the thymidylate synthase enhancer region in Indonesian childhood acute lymphoblastic leukemia
Paediatrica Indonesiana, Vol 46, Iss 3, Pp 103-
2016 Volume 12
Abstract: Background Deoxyuridylate monophosphate (dTMP) is neces- sary for DNA synthesis and thymidylate synthase (TS) is an im- portant target of cancer chemotherapy. Ethnic variations of the polymorphic tandem repeat sequence in the enhancer region of the TS ... ...
| Abstract | Background Deoxyuridylate monophosphate (dTMP) is neces- sary for DNA synthesis and thymidylate synthase (TS) is an im- portant target of cancer chemotherapy. Ethnic variations of the polymorphic tandem repeat sequence in the enhancer region of the TS promoter has previously been described to influence the outcome of acute lymphoblastic leukemia (ALL). A triple repeat is associated with a higher TS gene expression than a double re- peat, resulting in poorer outcome of ALL patients treated with anti- folate methotrexate (MTX). Objective In this study, we determined the incidences of TS and methylenetetrahydrofolate reductase (MTHFR) polymorphism and ethnic variations between Indonesian and Caucasian ALL cell samples obtained at diagnosis. Furthermore, we determined the involvement of TS polymorphisms in MTX sensitivity using a thymidilate synthase inhibition assay (TSIA). Methods ALL cell samples were obtained at diagnosis from 101 Indonesian and 157 Caucasian children treated with MTX prospec- tively. Genotyping for TS and MTHFR was analyzed by Genescan and Lightcycler. TS polymorphism was determined by PCR assay and MTHFR polymorphism and was analyzed by melting curve analyses on lightcycler. Results Homozygous TS triple repeats were more than twice as common in Indonesian samples (76.3%) than in Caucasian samples (33.1%). Heterozygotes of the MTHFR mutations were seen in 15% of the screened Indonesian samples. Conclusion There are significant ethnic variations in TS gene regulatory elements of leukemic cells. A difference was found be- tween the MTX sensitivity and a double or triple repeat in the Cau- casian ALL group. The samples with a triple repeat show a shift in their distribution towards hypersensitivity to MTX. Further investi- gation on Indonesian samples may give insight in the role of poly- morphisms in MTX sensitivity |
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| Keywords | polymorphism ; acute lymphoblastic leukemia ; thymidilate synthase ; methotrexate ; children ; Medicine ; R ; Pediatrics ; RJ1-570 |
| Subject code | 616 |
| Language | English |
| Publishing date | 2016-10-01T00:00:00Z |
| Publisher | Indonesian Pediatric Society Publishing House |
| Document type | Article ; Online |
| Database | BASE - Bielefeld Academic Search Engine (life sciences selection) |
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