TPMT

Gene Summary

Gene:TPMT; thiopurine S-methyltransferase
Aliases: TPMTD
Location:6p22.3
Summary:This gene encodes the enzyme that metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals, causing thiopurine S-methyltransferase deficiency. Related pseudogenes have been identified on chromosomes 3, 18 and X. [provided by RefSeq, Aug 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:thiopurine S-methyltransferase
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TPMT (cancer-related)

Cascorbi I, Werk AN
Advances and challenges in hereditary cancer pharmacogenetics.
Expert Opin Drug Metab Toxicol. 2017; 13(1):73-82 [PubMed] Related Publications
INTRODUCTION: Cancer pharmacogenetics usually considers tumor-specific targets. However, hereditary genetic variants may interfere with the pharmacokinetics of antimetabolites and other anti-cancer drugs, which may lead to severe adverse events. Areas covered: Here, the impact of hereditary genes considered in drug labels such as thiopurine S-methyltransferase (TPMT), UDP-glucuronosyltransferase 1A1 (UTG1A1) and dihydropyrimidine dehydrogenase (DPYD) are discussed with respect to guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Moreover, the association between genetic variants of drug transporters with the clinical outcome is comprehensively discussed. Expert opinion: Precision therapy in the field of oncology is developing tremendously. There are a number of somatic tumor genetic markers that are indicative for treatment with anti-cancer drugs. By contrast, for some hereditary variants, recommendations have been developed. Although we have vast knowledge on the association between drug transporter variants and clinical outcome, the overall data is inconsistent and the predictability of the related phenotype is low. Further developments in research may lead to the discovery of rare, but functionally relevant single nucleotide polymorphisms and a better understanding of multiple genomic, epigenomic as well as phenotypic factors, contributing to drug response in malignancies.

Kimura S, Hasegawa D, Yoshimoto Y, et al.
Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants.
Rinsho Ketsueki. 2016; 57(6):748-53 [PubMed] Related Publications
Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days. The 6MP dose was subsequently adjusted based on the white blood cell count. The ratios of the prescribed 6MP dose over the protocol dose in early consolidation, central nervous system (CNS) prophylaxis, re-induction, interim maintenance and maintenance therapy were 63%, 27%, 4%, 26% and 7%, respectively. Suspension of therapy was required during early consolidation, CNS prophylaxis and interim maintenance therapy. We investigated candidate genes for 6MP-associated myelotoxicity and found homozygous NUDT15 variant alleles and a heterozygous inosine triphosphate pyrophosphatase (ITPA) variant allele. In patients with homozygous NUDT15 variants, drastic reduction (less than 10%) of the 6MP dose from the protocol dose might be required not only during maintenance therapy, but also during other treatment courses containing 6MP. Screening of candidate genes at diagnosis is recommended in order to avoid serious adverse events.

Hagleitner MM, Coenen MJ, Patino-Garcia A, et al.
Influence of genetic variants in TPMT and COMT associated with cisplatin induced hearing loss in patients with cancer: two new cohorts and a meta-analysis reveal significant heterogeneity between cohorts.
PLoS One. 2014; 9(12):e115869 [PubMed] Free Access to Full Article Related Publications
Treatment with cisplatin-containing chemotherapy regimens causes hearing loss in 40-60% of cancer patients. It has been suggested that genetic variants in the genes encoding thiopurine S-methyltransferase (TPMT) and catechol O-methyltransferase (COMT) can predict the development of cisplatin-induced ototoxicity and may explain interindividual variability in sensitivity to cisplatin-induced hearing loss. Two recently published studies however, sought to validate these findings and showed inconsistent results. The aim of this study was to evaluate the role of polymorphisms in the TPMT and COMT genes in cisplatin-induced ototoxicity. Therefore we investigated two independent cohorts of 110 Dutch and 38 Spanish patients with osteosarcoma and performed a meta-analysis including all previously published studies resulting in a total population of 664 patients with cancer. With this largest meta-analysis performed to date, we show that the influence of TPMT and COMT on the development of cisplatin-induced hearing loss may be less important than previously suggested.

Burchard PR, Abou Tayoun AN, Lefferts JA, et al.
Development of a rapid clinical TPMT genotyping assay.
Clin Biochem. 2014; 47(15):126-9 [PubMed] Related Publications
OBJECTIVES: Thiopurine compounds are commonly used in the treatment of childhood acute lymphoblastic leukemia, and as immunosuppressants following organ transplantation or for treatment of various autoimmune disorders. Thiopurine S-methyltransferase (TPMT) is required for detoxification, through S-methylation, of 6-thioguanine nucleotides (TGNs), a byproduct of thiopurine metabolism. Single nucleotide polymorphisms (SNPs) in the TPMT gene have been shown to affect its function, with some variants associated with serious clinical manifestations including severe to fatal myelosuppression and organ transplant rejection following treatment with standard thiopurine doses. In this study, we describe a TaqMan real time PCR allelic discrimination assay requiring minimal DNA input for TPMT genotyping.
DESIGN AND METHODS: We designed controls for the homozygous wild type and allelic variants of TPMT*2, *3B, and *3C. Genomic DNA was extracted from an additional 412 human blood samples. The samples were tested for the TPMT*2, *3B, *3C, and *3A polymorphisms by TaqMan genotyping assays using the AB 7500 FAST Real-Time PCR instrument. Allelic discrimination plots were used to identify each mutation.
RESULTS: The TaqMan assay correctly genotyped all custom control DNA samples. Of the 412 tested samples, our assay identified 375 samples as wild-type *1/*1 (91.02%), 3 as *1/*2 (0.73%), 1 as *1/*3B (0.24%), 3 as *1/*3C (0.73%), 27 presumed to be *1/*3A (6.55%), and 3 as *3B/*3A (0.73%).
CONCLUSIONS: The clinical implications of TPMT genotyping, along with the simplicity and specificity of the TaqMan genotyping assays make this test highly suitable for use in a clinical laboratory.

Farfan MJ, Salas C, Canales C, et al.
Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia.
BMC Cancer. 2014; 14:299 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); however, interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. We determined the prevalence of the major genetic polymorphisms in 6-MP metabolizing enzymes in Chilean children with ALL.
METHODS: 103 Chilean pediatric patients with a confirmed diagnosis of ALL were enrolled. DNA was isolated from whole blood and genetic polymorphism in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) coding genes were detected by polymorphism chain reaction-restriction fragment length (PCR-RFLP) assay.
RESULTS: The total frequency of variant TPMT alleles was 8%. TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively. For ITPA, the frequency of P32T allele was 3%. We did not observe any homozygous variant for TPMT and ITPA alleles. We also analyzed a subgroup of 40 patients who completed the maintenance phase of ALL treatment, and we found that patients carrying a TPMT gene variant allele required a significantly lower median cumulative dosage and median daily dosage of 6-MP than patients carrying wild type alleles.
CONCLUSION: TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

Moreno-Guerrero SS, Ramírez-Pacheco A, Dorantes-Acosta EM, Medina-Sanson A
[Analysis of genetic polymorphisms of thiopurine S-methyltransferase (TPMT) in Mexican pediatric patients with cancer].
Rev Invest Clin. 2013 Mar-Apr; 65(2):156-64 [PubMed] Related Publications
BACKGROUND: Thiopurine S-Methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs, such as 6-mercaptopurine, 6-thioguanine and azathioprine, leading to their inactivation. Individuals who carry TPMT allele variants are more likely to experience life-threatening toxicity when these drugs are given at a standard dose. Wildtype phenotype TPMT*1 exhibits high level of catalytic activity, while all variants manifest with a decreased enzymatic activity. Ethnic-related differences in the distribution of TPMT variant alleles have been found. In Mexico, limited information is available; so far only two studies have been published and clear differences exist between them.
MATERIAL AND METHODS: Allelic variants and genotypes of the TPMT gene were determined in 240 Mexican children with leukemia and solid tumors using DNA extracted from peripheral blood. Polymorphisms G460A and A719G were identified by PCR-RFLP and G238C by the specific-allele PCR assay. The enzyme variants were detected by allelic discrimination.
RESULTS: Homozygous wild-type genotype TPMT*1/TPMT*1 was found in 173 patients (72.1%); 67 cases (27.9%) were heterozygous: 18 with genotype TPMT*1/TPMT*3B (7.5%), 17 TPMT*1/TPMT*3C (7.1%), 16 TPMT*1/TMPT*2 (6.7%), 14 TPMT*1/TPMT*3A (5.8%), and 2 (0.8%) were homozygous for two variants: TPMT*2/ TPMT*3B in both. The allele frequencies were TPMT*1 in 411 (85.62%), TPMT*3B in 20 (4.1%), TPMT*2 in 18 (3.75%), TPMT*3C in 17 (3.55%) and TPMT*3A in 14 (2.9%).
CONCLUSIONS: A high frequency and diversity of variant TPMT genotypes was found in this series with predominance of the TPMT*3B allele.

Cao L, Zhang ZX, Chai YH, et al.
[The effect of the adverse events with thiopurine S-methyltransferase gene mutation on outcome of childhood acute lymphoblastic leukemia].
Zhonghua Xue Ye Xue Za Zhi. 2013; 34(3):247-52 [PubMed] Related Publications
OBJECTIVE: To investigate thiopurine S-methyltransferase (TPMT) activity and gene promoter polymorphism to probe its significance of individual chemotherapy in acute lymphoblastic leukemia (ALL) children.
METHODS: HPLC method was carried out to determine TPMT activity (n=100), which activity at newly diagnosed. At the same time determination of TPMT activity in healthy children (n=180), these children come from the health care clinic. Using online primer3 software design primers, PCR products were purified. To sequence TPMT gene of the patients with clinical events(n=30). According to the method to analysis of correlation between TPMT activity and toxicity.
RESULTS: The average TPMT activities were (31.72±10.31) nmol·g⁻¹Hb·h⁻¹ and (30.70±9.67) nmol·g⁻¹Hb·h⁻¹ in ALL and healthy groups respectively, without gender differences of TPMT activities (P=0.45) in both groups. The TPMT activity with clinical events in newly diagnosed ALL patients (n=30) was (24.07±11.43) nmol·g⁻¹Hb·h⁻¹. There are significant differences of TPMT activities between severe bone marrow suppression [(20.96±7.24) nmol·g⁻¹Hb·h⁻¹] and ALL patients with clinical events groups (P<0.05). The TPMT activity of (40.46±8.18) nmol·g⁻¹Hb·h⁻¹ in recurrence children was also significantly different (P<0.05). TPMT activity in severe liver toxicity group was not significantly different (P=0. 930). Of TPMT gene sequencing in ALL patients with clinical events, only 3 children were heterozygosity mutations of TPMT*3C, while others homozygous genotype. There were significant differences of TPMT activities between heterozygosity genotype [(11.99±1.32) nmol·g⁻¹Hb·h⁻¹] and homozygous genotype groups [(24.95±11.32) nmol·g⁻¹Hb·h⁻¹] (P<0.05). There were five kinds of variations at the vicinity of the promoter region of -100 of tandem repeats (VNTR) polymorphism(*V3/*V3、*V3/*V4、*V4/*V4、*V5/*V5、*V4/*V6)without significant differences of TPMT activities among five kinds (P=0.186).
CONCLUSION: TPMT activity was related to the gene polymorphism. TPMT activity determination had prognostic value and guided individualized treatment.

Yang JJ, Bhojwani D
Thiopurine S-methyltransferase pharmacogenetics in childhood acute lymphoblastic leukemia.
Methods Mol Biol. 2013; 999:273-84 [PubMed] Related Publications
Pharmacogenetics is the growing field of study of genetic variations underlying interindividual differences in drug response. Inherited polymorphisms in genes coding for drug-metabolizing enzymes, transporters, and targets influence toxicity as well as efficacy associated with the medication. Thiopurines are agents widely used in hematologic malignancies, transplantation, and chronic inflammatory conditions. Myelosuppression is the commonly encountered dose-limiting toxicity. Polymorphisms in the thiopurine S-methyltransferase gene (TPMT), the predominant inactivating enzyme for thiopurines in hematopoietic tissue, are correlated with enzymatic activity of TPMT, thiopurine metabolism, and risk of clinical toxicity. In this chapter, we present TPMT genotype assessment that allows for prescribing pharmacogenetically guided doses to enhance patient safety and drug efficacy.

Wennerstrand P, Mårtensson LG, Söderhäll S, et al.
Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia.
Eur J Clin Pharmacol. 2013; 69(9):1641-9 [PubMed] Related Publications
PURPOSE: Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.
METHODS: Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.
RESULTS: Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (-9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).
CONCLUSIONS: Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

Garrido C, Santizo VG, Müllers P, et al.
Frequency of thiopurine S-methyltransferase mutant alleles in indigenous and admixed Guatemalan patients with acute lymphoblastic leukemia.
Med Oncol. 2013; 30(1):474 [PubMed] Free Access to Full Article Related Publications
Thiopurine S-methyltransferase (TPMT) polymorphisms affect the enzyme's activity and are predictive for the efficacy and toxicity of thiopurine treatment of acute lymphoblastic leukemia (ALL), autoimmune diseases and organ transplants. Because inter-ethnic differences in the distribution of these polymorphisms have been documented, we sequenced the TMPT gene in 95 Guatemalans, yet identified no new alleles. We also determined the frequency of the TPMT 2, 3A, 3B and 3C alleles in 270 admixed and 177 indigenous pediatric patients with ALL and healthy subjects from Guatemala using TaqMan assays and DNA sequencing. Among the 447 subjects genotyped, 10.0 % of the ALL cases and 13.6 % of the healthy controls were heterozygous for one of the four TPMT variants screened. The genotype frequencies in ALL and control populations were 0.7 and 1.7 % for TPMT 1/ 2, 7.4 and 10 % for TPMT 1/3A, 0.3 and 0 % for TPMT 1/B, and 1.5 and 1.1 % for TPMT 1/C, respectively (p = 0.30). No statistically significant differences between admixed and indigenous ALL (p = 0.67) or controls (p = 0.41) groups were detected; however, 17 % of the admixed healthy group bore one TPMT mutant allele, and they have one of the highest reported frequencies of TPMT mutant allele carriers. Because of the clinical implications of these variants for therapeutic response, TPMT allele testing should be considered in all Guatemalan patients to reduce adverse side-effects from thiopurine drug treatments.

Ma XL, Li WJ, Zheng J, et al.
[Thiopurine S-methyltransferase gene sequence analysis of ALL children severely intolerant to 6-mercaptopurine].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012; 20(4):876-9 [PubMed] Related Publications
This study was aimed to analyze the thiopurine S-methyltransferase (TPMT) gene sequence in acute lymphoblastic leukemia (ALL) children severely intolerant to 6-mercaptopurine (6-MP) and to investigate the causes resulting in tolerance difference to 6-MP in ALL children so as to provide evidence for safe and rational use of 6-MP. The adverse reactions of drug was evaluated in ALL children treated with BCH-2003-ALL chemotherapeutic protocol during 2004-10-1 to 2007-9-30 according to NCI-CTC V2.0. The TPMT gene sequences of ALL children with 3-4 grade of severe toxicity during the maintenance therapy were analyzed by PCR and direct DNA sequencing. To assure the accuracy of sequencing, the 738 bp fragment of coding region in TPMT gene (NM_000367) was divided into 3 subfragments and bidirectionally sequenced. The results indicated that among 133 ALL children, 61 were severely intolerant to 6-MP. The direct DNA sequencing showed that among 59 patients (excluding 2 cases without RNA samples), the simple myelotoxicity was found in 37 cases, hepato-myelotoxicity was observed in 9 cases, hepatotoxicity along appeared in 12 cases, 1 case showed skin rash. Out of 59 ALL children, the C474T mutation was found in 57 cases, with mutation rate 96.6%, including 21 cases with heterozygous mutation and 36 cases with homozygosis mutation. The TPMT gene sequencing of 10 cases tolerant to 6-MP indicated that C474T mutation was detected in 8 cases which was homozygous mutation. It is concluded that the C474T mutation in 738 bp fragment of coding region in TPMT gene is very frequent, but it is not related with tolerance to 6-MP, suggesting that severe intolerance to 6-MP in ALL children may be not related with the mutation of coding region in TPMT gene.

Stocco G, Yang W, Crews KR, et al.
PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity.
Hum Mol Genet. 2012; 21(21):4793-804 [PubMed] Free Access to Full Article Related Publications
Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with mercaptopurine therapy.

Adam de Beaumais T, Jacqz-Aigrain E
Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia.
Eur J Clin Pharmacol. 2012; 68(9):1233-42 [PubMed] Related Publications
BACKGROUND: The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.
AIM: This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.

Mladosievicova B, Dzurenkova A, Sufliarska S, Carter A
Clinical relevance of thiopurine S-methyltransferase gene polymorphisms.
Neoplasma. 2011; 58(4):277-82 [PubMed] Related Publications
The therapeutic response to thiopurines may result in either severe toxic or inadequate effect based on the interindividual genetic variability. Same drug doses of various anticancer drugs cause considerable interindividual differences in the therapeutic response. Genetic factors have a major impact on effectiveness of several anticancer drugs such as mercaptopurine, 5-fluorouracil, platinum agents, and cyclophosphamide. Heredity related differences in interindividual response to thiopurine therapy represent perhaps the most compelling evidence of pharmacogenomics' usefulness in identification of patients in risk for adverse drug reactions. A number of variations in the gene for thiopurine methyltransferase (TPMT) have been associated with the low activity of this enzyme. Patients with intermediate and low activity of TPMT have a greater incidence of thiopurine toxicity. This minireview summarizes results of studies assessing the role of genetic polymorphisms in the gene encoding TPMT and their relationship to the toxicity of thiopurines.

Peregud-Pogorzelski J, Tetera-Rudnicka E, Kurzawski M, et al.
Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: the Polish multicenter analysis.
Pediatr Blood Cancer. 2011; 57(4):578-82 [PubMed] Related Publications
BACKGROUND: 6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients.
PROCEDURE: A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers.
RESULTS: The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A, 1 TPMT*3A/*3A) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A, TPMT*1 (wild-type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004).
CONCLUSIONS: The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy.

Wang L, Pelleymounter L, Weinshilboum R, et al.
Very important pharmacogene summary: thiopurine S-methyltransferase.
Pharmacogenet Genomics. 2010; 20(6):401-5 [PubMed] Free Access to Full Article Related Publications

Kapoor G, Sinha R, Naithani R, Chandgothia M
Thiopurine S-methyltransferase gene polymorphism and 6-mercaptopurine dose intensity in Indian children with acute lymphoblastic leukemia.
Leuk Res. 2010; 34(8):1023-6 [PubMed] Related Publications
The prevalence of thiopurine S-methyltransferase (TPMT) polymorphism and its association with clinical and hematological toxicities was retrospectively analyzed in 71 Indian children with acute lymphoblastic leukemia (ALL). Only heterozygous TPMT alleles were observed (10%, 7/71) with relative frequencies being *1/*3C (4.2%), *1/*2 (4.2%) and *1/*3A (1.4%). The median 6-mercaptopurine dose administered during the maintenance therapy was 31% lower among patients with heterozygous TPMT alleles versus the rest (32.1mg/m(2)/day and 46.2mg/m(2)/day, p=0.005), though the myelosuppression and toxicities were similar in both the groups. Identification of TPMT genotype appears to be important in making the ALL treatment more effective and less toxic.

Chen XW, Yue LJ, Li CR, et al.
[Studies on the mutation and polymorphism of the TPMT gene in Chinese children with acute leukemia].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2009; 26(4):457-60 [PubMed] Related Publications
OBJECTIVE: To investigate the allelic frequencies and distribution of single-nucleotide polymorphisms within the coding region (cSNPs) of thiopurine S-methyltransferase gene (TPMT) in Chinese children with acute leukemia (AL) and healthy controls, in order to provide genetic references for individual chemotherapy for AL patients by studying the relationship between the cSNP in human TPMT and chemotherapeutic effect of thiopurine drugs.
METHODS: The bone marrow samples from 53 children with AL and peripheral blood samples from 115 healthy children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for the polymorphisms in the TPMT gene by reverse transcriptase-polymerase chain reaction (RT-PCR)-denaturing gradient gel electrophoresis (DGGE) and DNA sequencing. The distribution of each genotype was evaluated.
RESULTS: Two novel heterozygote mutations, 210C>T (C70C, silent) and 622T>C (F208L), were identified in the coding region of the TPMT in a single sample, respectively. The mother of the child with mutation 622T>C was confirmed as the same genotype by DGGE and sequencing (NCBI_ss accession numbers 107796292 and 107795933). Two known polymorphisms, 474T>C (silent) and 719A>G (T240C), were identified. The allelic frequencies were 14.2%, 2.83% and 17.0%, 3.04% in the AL children and control children respectively, with the total allelic frequencies of 16.2% (first reported in the Chinese Han population) and 2.99% respectively. No association with susceptibility to disease was observed.
CONCLUSION: Two novel mutations and two known polymorphisms were identified in Chinese children by RT-PCR-DGGE combined with DNA sequencing, which provides the first step to identify genetic markers for predicting variability in response to and toxicity of thiopurine drugs.

Karas-Kuzelicki N, Mlinaric-Rascan I
Individualization of thiopurine therapy: thiopurine S-methyltransferase and beyond.
Pharmacogenomics. 2009; 10(8):1309-22 [PubMed] Related Publications
The metabolism of a given drug depends, not solely on a particular enzyme, but rather on a complex metabolic network. Thiopurine S-methyltransferase (TPMT) catalyzes the methylation, and thus deactivation, of 6-mercaptopurine, a thiopurine used in the treatment of acute lymphoblastic leukemia. Low TPMT activity has been associated with severe toxicity of 6-mercaptopurine. Determination of mutations in the TPMT gene before starting 6-mercaptopurine therapy constitutes a quick, simple and cost-effective strategy to individualize thiopurine dosing. However, TPMT phenotype-to-genotype correlation is not complete, indicating a need for identification of novel biomarkers. Based on our recent findings and reviewing seemingly unrelated literature reports we present a synthesis of the current understanding of factors that influence TPMT activity and consequently modulate responsiveness to thiopurine treatment. Identification and understanding of these factors is crucial for improving the efficacy and safety of acute lymphoblastic leukemia treatment.

Dokmanović L, Janić D, Krstovski N, et al.
[Importance of genotyping of thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy].
Srp Arh Celok Lek. 2008 Nov-Dec; 136(11-12):609-16 [PubMed] Related Publications
INTRODUCTION: Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients.
OBJECTIVES: To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene.To establish if variable number of tandem repeats (VNTR) genotype influences the treatment effects of MP.
METHOD: Fifty randomly selected patients treated according to ALL IC-BFM 2002 protocol were tested for most frequent TPMT gene mutations using PCR based methods. VNTR genotype was determined in 20 children by PCR methods. During the maintenance phase, we recorded the number of weeks when therapy was applied in either full doses, reduced doses or when patients were without any therapy.
RESULTS: Fifty children were examined, 29 boys (58%) and 21 girls (42%); age ranged from 1.8-17.3 years (median 6.2 years). Four patients (8%) were heterozygous for TPMT mutations, all of them carrying the TPMT*3A variant. After 12, 14, 16 and 19 weeks of therapy with reduced doses of MP, the patients switched to full doses due to good tolerance.There was no therapy omission. Cumulative dose of MP was reduced for 7.8%, 7.4%, 11.2% and 16.6%, respectively, in patients with TPMT mutations. No significant difference was found between children with no mutations and TPMT heterozygotes regarding full dose therapy (53.6 vs. 55.7 weeks, respectively) and reduced dose therapy (19.9 vs. 15.2 weeks respectively). The number of detected VNTRs ranged from four to seven. The majority of patients had different number of VNTRs on homologous chromosomes. Most frequently detected polymorphism was VNTR*5. No correlation was found between TPMT and VNTR genotype inheritance.
CONCLUSION: Obeying pharmacogenetic principles in the treatment of childhood ALL may improve the tolerance of therapy with MP.

Silva MR, de Oliveira BM, Viana MB, et al.
Thiopurine S-methyltransferase (TPMT) gene polymorphism in Brazilian children with acute lymphoblastic leukemia: association with clinical and laboratory data.
Ther Drug Monit. 2008; 30(6):700-4 [PubMed] Related Publications
The frequency of allele variants of gene TPMT*2, *3A, *3B, and *3C was estimated in a population of 116 Brazilian children with acute lymphoblastic leukemia. The association between genotype and clinical and laboratory data obtained during chemotherapy maintenance phase and the correlation of intraerythrocyte concentration of 6-mercaptopurine metabolites (6-tioguanine nucleotide nucleotides and methylmercaptopurine) were analyzed. A multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used in DNA amplification. Twelve patients presented TPMT gene mutation, all in heterozygous form. The most frequent allele variation was TPMT*3A (3.9%), followed by *3C (0.9%), *2 (0.4%), and *3B (0%). There was no significant association between clinical and laboratory data and the presence of mutation in TPMT gene. Of the 36 patients who were monitored for 6-mercaptopurine metabolite levels, only 1 had the mutation. In this patient, high 6-tioguanine nucleotide and low methylmercaptopurine concentrations were found. Event-free survival (EFS) for the whole group was 73.4%. There was no significant difference in event-free survival in the comparison between the groups with and without mutation (P = 0.06).

Samochatova EV, Chupova NV, Rudneva A, et al.
TPMT genetic variations in populations of the Russian Federation.
Pediatr Blood Cancer. 2009; 52(2):203-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polymorphisms that reduce the activity of thiopurine S-methyltransferase (TPMT) cause adverse reactions to conventional doses of thiopurines, routinely used for antileukemic and immunosuppressive treatment. There are more than 20 variant alleles of TPMT that cause decreased enzymatic activity. We studied the most common variant alleles of TPMT and their frequency distribution in a large cohort of multiracial residents in the Russian Federation and compared their frequencies in children with and without malignancy to determine whether TPMT gene abnormality is associated with hematologic malignancy.
PROCEDURE: The TPMT biochip was used to detect 6 TPMT single nucleotide polymorphisms (SNPs) corresponding to 7 TPMT-deficiency alleles (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*3D, TPMT*7, and TPMT*8). We analyzed allele frequencies in the whole cohort, the childhood cancer group, and the non-cancer group. We also characterized disease features and outcome according to the presence of TPMT SNPs in children with acute lymphoblastic leukemia (ALL).
RESULTS: Fifty-five (5.5%) study participants overall had heterozygous TPMT genotypes (1 variant and 1 wild-type allele): TPMT*1/*3A (n = 45; 4.5%), TPMT*1/*3C (n = 8; 0.8%), and TPMT*1/*2 (n = 2; 0.2%). TPMT SNPs were more frequent in children with hematologic malignancy than in other participants (7.5% vs. 4.0%, P = 0.02). We found no significant association between TPMT SNPs and ALL treatment outcome (median follow-up, 31.3 months).
CONCLUSIONS: TPMT*3A is the most prevalent variant allele in the Russian Federation. The estimated frequency of variant alleles in the study cohort (5.5%) was similar to that observed in the White populations in the U.S. and Eastern Europe.

Krishnamurthy P, Schwab M, Takenaka K, et al.
Transporter-mediated protection against thiopurine-induced hematopoietic toxicity.
Cancer Res. 2008; 68(13):4983-9 [PubMed] Free Access to Full Article Related Publications
Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role of the Mrp4, an ATP transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage-dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (>18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP.

Kham SK, Soh CK, Liu TC, et al.
Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore.
Eur J Clin Pharmacol. 2008; 64(4):373-9 [PubMed] Related Publications
OBJECTIVE: The distribution of thiopurine methyltransferase (TPMT) activity in Asian populations has not been well documented. We studied the TPMT phenotype in three major Asian ethnic groups in Singapore, namely the Chinese (Ch), Malays (Mal) and Indians (Ind), with the aim of carrying out a comprehensive survey of the distribution of TPMT activity in Asians.
METHODS: A radiochemical assay was used to measure the enzymatic activity of TPMT in the red blood cells (RBCs) of 479 healthy adults (Ch=153, Mal=163 and Ind=163). Cut-off points for intermediate TPMT activity were validated using a receiver operating curve (ROC) analysis. PCR-based methods were used to screen for the TPMT*3C, TPMT*3A and TPMT*6 variants.
RESULTS: The histogram of the combined population cohort showed a bimodal distribution of TPMT activity, with no subject having low TPMT activity (<5 units). In total, TPMT variants were detected in 14 subjects (*1/*3C in 13 subjects; *1/*3A in one subject). We observed significant inter-ethnic differences in terms of TPMT activity (p<0.001), with the Malays showing a higher median activity than the Chinese or Indians (17.8 units vs 16.4 units). The Malays also showed a higher methylation rate--with a cut-off point for intermediate TPMT activity of 11.3 units--than the Chinese (9.9 units) or Indians (9.4 units). A high phenotype-genotype correlation of >97% was observed in all three races. We also genotyped 418 childhood leukaemias. The combined analysis of subjects participating in this and a previous study--1585 subjects--showed that 4.7% of Chinese (n=30/644), 4.4% of Malays (n=24/540) and 2.7% of Indians (n=11/401) were heterozygous at the TPMT gene locus.
CONCLUSION: This is the first comprehensive TPMT phenotype and genotype study in Asian populations, particularly in the Malays and Indians.

Taja-Chayeb L, Vidal-Millán S, Gutiérrez O, et al.
Thiopurine S-methyltransferase gene (TMPT) polymorphisms in a Mexican population of healthy individuals and leukemic patients.
Med Oncol. 2008; 25(1):56-62 [PubMed] Related Publications
Polymorphisms at the thiopurine S-methyltransferase coding gene (TPMT) determine enzyme activity and consequently, the development of toxicity secondary to thiopurines. Methods A total of 108 DNA samples from volunteer donors and 39 from patients with acute lymphoblastic leukemia (ALL) were analyzed. Genomic DNA from peripheral blood leukocytes was isolated by standard methods. TPMT gene fragments were amplified by PCR for exons 5, 7, and 10. Thereafter, these were analyzed by DHPLC for the most frequent mutant TPMT alleles. Results No elution profiles on DHPLC analysis, different from those previously reported, were documented. Frequency of functional allele polymorphisms was 17.6%, being the most frequent *3A (n = 13; 4.4%), followed by *3B (n = 5; 1.7%), *3C (n = 5; 1.7%), and *2 (n = 3; 1.0%). From 39 ALL patients, 22 were treated with thiopurines, and five from 10 with a functional polymorphism developed hematological toxicity (4 mild, 1 severe in a patient referred to our Hospital after developing pancytopenia while on treatment with thiopurine). Conclusions This is the first analysis of the polymorphisms at this gene in Mexican population. Since a direct relation has been documented within functional polymorphisms and enzyme activity, and DHPLC is a highly sensitive, rapid and efficient method, feasible to realize in any phase during the treatment of ALL patients, the routine typing of TPMT polymorphisms in the patients with ALL has been set in our Institution.

Daly AK
Individualized drug therapy.
Curr Opin Drug Discov Devel. 2007; 10(1):29-36 [PubMed] Related Publications
The pharmacogenetics of either individual patients or tumors has been used to aid the progress of personalized medicine to generate antitumor drugs (eg, trastuzamab and erlotinib) that are active against tumors expressing particular growth factor receptors. Outside the field of cancer therapeutics, pharmacogenetic tests have been introduced to detect patient genotypes with the aim of individualizing existing treatments. For example, the analysis of thiopurine S-methyltransferase genotypes enables the prediction of toxicity in patients to be treated with either 6-mercaptopurine or azathioprine, while the uridine 5'-diphosphoglucuronosyl-transferase 1A1 genotype may predict irinotecan toxicity. There is a large body of information concerning cytochrome P450 (CYP) polymorphisms and their relationship with drug toxicity and response; however, currently, there is limited use of CYP genotypes to individualize treatments. It is now well recognized that the CYP2C9 genotype, when combined with the genotype for vitamin K epoxide reductase complex subunit 1, is predictive of dose requirement for oral anticoagulants, a fact that is likely to have clinical utility. There is also potential to individualize treatments with certain drugs on the basis of CYP2D6, CYP2C19 and CYP3A5 genotypes. Studies on genes encoding drug receptors in relation to individualized prescription have been limited but there is increasing information on the relationship between response to beta2-adrenoceptor agonists and the genotype for the beta2-adrenoceptor gene. The introduction of pharmacogenetic tests into routine healthcare requires both a demonstration of cost-effectiveness and the availability of appropriate accessible testing systems.

Dokmanovic L, Urosevic J, Janic D, et al.
Analysis of thiopurine S-methyltransferase polymorphism in the population of Serbia and Montenegro and mercaptopurine therapy tolerance in childhood acute lymphoblastic leukemia.
Ther Drug Monit. 2006; 28(6):800-6 [PubMed] Related Publications
Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT*2, 3.2% for TPMT*3A, and 0.5% for TPMT*3B. A rare TPMT*3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P < 0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.

Deeken JF, Figg WD, Bates SE, Sparreboom A
Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics.
Anticancer Drugs. 2007; 18(2):111-26 [PubMed] Related Publications
A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.

Moloney FJ, Dicker P, Conlon PJ, et al.
The frequency and significance of thiopurine S-methyltransferase gene polymorphisms in azathioprine-treated renal transplant recipients.
Br J Dermatol. 2006; 154(6):1199-200 [PubMed] Related Publications

Allan JM, Rabkin CS
Genetic susceptibility to iatrogenic malignancy.
Pharmacogenomics. 2005; 6(6):615-28 [PubMed] Related Publications
Iatrogenic malignancies represent a devastating and often fatal long-term effect of therapy administered for a prior condition, usually a primary cancer. Earlier diagnosis and the development of more effective cancer treatments over the last 30 years have considerably improved the long-term survival of patients. However, the burgeoning number of cancer survivors has led to a parallel increase in the number of cases of iatrogenic malignancy. Consequently, understanding host susceptibility factors, such that high-risk patients can be identified, has become a priority. However, this task is made difficult by the heterogeneity of iatrogenic malignancies. Nevertheless, the identification of polymorphic loci and pathways predicted to modify dose (e.g., glutathione S-transferases, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase, cytochrome P450, and thiopurine S-methyltransferase) or determine cellular outcome (e.g., nucleotide excision DNA repair, base excision DNA repair, DNA mismatch repair, and cell death signaling) after therapy has provided insight into how host genetics may impact on the risk of developing iatrogenic malignancy.

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