Thiopurine methyltransferase (TPMT) risk alleles (mainly *2,*3B,
*3C and *3A) are the major determinants of interindividual differences in
the severe toxicity or efficacy of 6-mercaptopurine (6MP) during the
treatment of childhood acute lymphoblastic leukemia (ALL). The
frequencies of these risk alleles, known to functionally impair TPMT
activity, were investigated among 167children with ALL and 206 healthy
adult controls in Turkish population by using allele specific PCR and PCRRFLP
methods. TPMT*3A and TPMT*3C were the only deficiency alleles
detected in Turkish population with an allele frequency of 0.5% for both.
The total frequency of mutant TPMT alleles in Turkish population (1.0%)
was found to be significantly lower than those of other Caucasian
populations (5.3-7.0%), but it was found to be very similar to Kazak
population (1.2%) which is also Caucasian in ethnic origin.
v
In the patient group, two individuals were found to be heterozygote
for *3C and *3A allele. One individual was homozygous mutant (*3B/*3C).
In this study, the clinical histories of the patients with TPMT defects were
examined retrospectively from hospital records. The patients with
heterozygous or homozygous mutant genotypes had systematically
developed severe neutropenia, infection and some other specific
conditions (like lesions around mouth, oral herpes and high fever) when
they were administered with 6MP during the therapy. This study provides
the first data on the frequency of common TPMT risk alleles in the Turkish
population, based on analysis of pediatric patients with ALL. The results
would contribute valuable information to the public health, as more
clinicians and patients become aware of the importance of TPMT
polymorphisms, less patients will suffer from 6MP related adverse effects.
In addition, in this study two genes EPHX1-microsomal epoxide
hydrolase (exon 3 and exon 4 polymorphisms) and SULT1A1*2 variant &ndash / sulfotransferase 1A1, either alone or in combination were investigated as
risk modifiers in the development of childhood acute lymphoblastic
leukemia due to their dual role (activation/detoxification) in the metabolism
of various carcinogens. Also interactions of these polymorphisms with
non-genetic risk factors (parental smoking exposure and parental age at
conception) were investigated. The conclusion inferred from results was
that only genetically reduced EPHX1 activity (homozygous mutant
genotype for EPHX1 exon 3 polymorphism and some specific genotype
combinations with exon 4 polymorphism) was found to be significantly
associated with the risk of childhood ALL.
| Identifer | oai:union.ndltd.org:METU/oai:etd.lib.metu.edu.tr:http://etd.lib.metu.edu.tr/upload/3/12610520/index.pdf |
| Date | 01 April 2009 |
| Creators | Tumer, Tugba |
| Contributors | Arinc, Emel |
| Publisher | METU |
| Source Sets | Middle East Technical Univ. |
| Language | English |
| Detected Language | English |
| Type | Ph.D. Thesis |
| Format | text/pdf |
| Rights | To liberate the content for public access |
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