THYMIDILATE SYNTHASE POLYMORPHISMS IN INDONESIAN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA
ABSTRACT: The enzyme
thymidylate synthase (TS) converts dUMP into dTMP and requires folates as
co-factors. Since dTMP is necessary for DNA synthesis, TS is an important
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 leukaemia (ALL). A
triple repeat is associated with a higher TS gene expression than a double
repeat, resulting in poorer outcome of ALL patients treated with the
anti-folate methotrexate (MTX). In addition, the association of TS expression
and MTX resistance appears to be even more pronounced in combination with an accumulation
of folates. This latter event can occur when methylenetetrahydrofolate
reductase (MTHFR) has impaired enzyme activity due to a C667T mutation. In this
study, we determined the ethnic variations of the TS and MTHFR genotype between
Caucasian an Indonesian in ALL cells obtained at diagnosis from 157 Caucasian
and 101 Indonesian children with MTX-treatment in prospective. Furthermore, we
determined the involvement of TS polymorphisms in MTX sensitivity, by using a
TS inhibition assay (TSIA). 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. These results demonstrate significant ethnic variation in a
TS gene regulatory element in leukemic cells. A difference was found between
the MTX sensitivity and the presence of a double or triple repeat in the
Caucasian ALL group. Interestingly, according to these data it seems that the
samples with a triple repeat show a shift in their distribution towards
hypersensitivity to MTX, in contrast to previously described results. However four
of the samples (16.0%) did show resistance to MTX, which may suggest an additional
role for other enzymes, such as MTHFR. Further investigation in the Indonesian
samples may give insight in the role of the polymorphisms in MTX sensitivity.
Keywords: thymidylate
synthase, acute lymphoblastic leukaemia, polymorphism, ethnic variations,
childhood, Indonesia
Author: IDG Ugrasena, Bambang
Permono, Edy Supriadi, Laura Vroling
Journal Code: jpkedokterangg050051
