Pharmacogenetics of childhood acute lymphoblastic leukemia: investigation of frequency of tpmt risk alleles for thiopurine toxicity and the role of sult1a1, ephx1 polymorphisms as risk factors for development of the disease

Tümer, Tuğba
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 – 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.


Güray, Nülüfer Tülün (Elsevier BV, 1991-01-01)
1. Lung NADH-cytochrome b5 reductase was saturated with its artificial substrate, potassium ferricyanide at approximately 0.1 mM ferricyanide concentration, and the activity of the lung enzyme was inhibited by the higher concentrations of potassium ferricyanide. Ferricyanide at 0.5 and 1.0 mM inhibited the activity of the enzyme by about 20 and 61% respectively. The apparent K(m) value was calculated as 13.7-mu-M potassium ferricyanide and 4.3-mu-M NADH.
Interactions of cholesterol reducing agent simvastatin with phospholipid model membranes
Koçak, Mustafa; Severcan, Feride; Department of Biochemistry (2007)
Interactions of simvastatin with zwitterionic dipalmitoyl phosphotidylcholine (DPPC) multilamellar liposomes were investigated as a function of temperature and simvastatin concentration. And acyl chain length effect on the simvastatin-model membrane interactions was monitored with DPPC and dimyristoyl phosphotidylcholine (DMPC) lipids. All studies were carried out by two non-invasive techniques, namely Fourier transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC). The results s...
The serum immunoglobulin G glycosylation signature of gastric cancer
Ruhaak, L. Renee; Barkauskas, Donald A.; Torres, Javier; Cooke, Cara L.; Wu, Lauren D.; Stroble, Carol; Özcan Kabasakal, Süreyya; Williams, Cynthia C.; Camorlinga, Margarita; Rocke, David M.; Lebrilla, Carlito B.; Solnick, Jay V. (Elsevier BV, 2015-03-01)
Biomarkers may facilitate detection of gastric cancer at an earlier stage and reduce mortality. Here we sought to determine if the glycosylation profile of serum immunoglobulin G (IgG) could distinguish patients with non-atrophic gastritis (NAG), duodenal ulcer (DU) and gastric cancer (GC). Serum IgG was released and analyzed using nano-LC–TOF mass spectrometry. Statistically significant false discovery rate (FDR)-adjusted p-values were observed for 18 glycans, eight that differed significantly between NAG ...
Characterization of proteome alterations in Phanerochaete chrysosporium in response to lead exposure
Yildirim, Volkan; ÖZCAN, Servet; Becher, Doerte; Buettner, Knut; Hecker, Michael; Özcengiz, Gülay (Springer Science and Business Media LLC, 2011-03-09)
Background: Total soluble proteome alterations of white rot fungus Phanerochaete chrysosporium in response to different doses (25, 50 and 100 mu M) of Pb (II) were characterized by 2DE in combination with MALDI-TOF-MS.
The low frequency of defective TPMT alleles in Turkish population: A study on pediatric patients with acute lymphoblastic leukemia
Tumer, Tugba Boyunegmez; Ulusoy, Gulen; Adalı, Orhan; Sahin, Gurses; Gozdasoglu, Sevgi; Arinc, Ennel (Wiley, 2007-10-01)
6-Mercaptopurine (6MP) is an essential anticancer drug used in the treatment of childhood acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe toxicity or efficacy of 6MP Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C, are responsible over the 80% of low or undetectable enzyme activity. The frequencies of these variants were investigated among 106 children with ALL in Turkish population. TPM...
Citation Formats
T. Tümer, “Pharmacogenetics of childhood acute lymphoblastic leukemia: investigation of frequency of tpmt risk alleles for thiopurine toxicity and the role of sult1a1, ephx1 polymorphisms as risk factors for development of the disease,” Ph.D. - Doctoral Program, Middle East Technical University, 2009.