Polymorphism of the thymidylate synthase gene and risk of relapse in childhood ALL

Pietrzyk, Jacek J; Bik-Multanowski, Mirosław; Skoczeń, Szymon; Kowalczyk, Jerzy; Balwierz, Walentyna; AlicjaChybicka,; Matysiak, Michał; Szczepański, Tomasz; Balcerska, Anna; Bodalski, Jerzy; Krawczuk‐Rybak, Maryna; Wysocki, Mariusz; Sobol, Grazyna; Wachowiak, Jacek

doi:10.1016/j.leukres.2011.04.007

Cited by 14 publications

(14 citation statements)

References 7 publications

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“…There are conflicting results regarding the roles of the TS, MTRR , and MTHFR gene polymorphisms in leukemia prognosis [5,8,9,15,18,23,24,25,26,27,28,32,33,38]. Some studies have indicated that these variants play protective roles [32,33,38], whereas others have shown that they are linked to increased rates of relapse and drug resistance [5,6,7,8,9,15,18,23,24,25,26,27,28].…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have indicated that these variants play protective roles [32,33,38], whereas others have shown that they are linked to increased rates of relapse and drug resistance [5,6,7,8,9,15,18,23,24,25,26,27,28]. Among these gene polymorphisms, the higher enzyme activity of the TS 3R/3R variant led to the diminished MTX effect and enhanced drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is no consensus on effective doses of HD-MTX in these patients. Recent research efforts have focused on determining the influence of different polymorphic enzyme variants on MTX toxicity and prognosis in children with ALL [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. Some have reported that several polymorphic variants of FRGs may be linked to relapse and HD-MTX-related toxicity in children with leukemia [5,6,7,8,9,10,11,12,13,14,15,16,17,21,22,23,24,25,26,27,28,29], whereas others have found that this treatment is protective against leukemia and there is no association between FRGs and toxicity [18,19,20,30,31,32,33].…”

Section: Introductionmentioning

confidence: 99%

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Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Yazıcıoğlu¹,

Kaya

S³

et al. 2017

Tjh

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Objective:High-dose methotrexate (HD-MTX) is widely used in the consolidation phase of childhood acute lymphoblastic leukemia (ALL), but the roles that polymorphisms in folate-related genes (FRGs) play in HD-MTX toxicity and prognosis in children with ALL are not understood. The aims of this study were to investigate the frequencies of polymorphisms in the genes for thymidylate synthase (TS), methionine synthase reductase (MTRR), and methylene tetrahydrofolate reductase (MTHFR) in Turkish children with ALL and to assess associations between these polymorphisms and HD-MTX-related toxicity and leukemia prognosis in this patient group.Materials and Methods:FRG polymorphisms were assessed by real-time polymerase chain reaction. Survival status, MTX levels, and toxicity data were retrieved from 106 patients’ charts.Results:The allele frequencies for the FRG polymorphisms were as follows: TS 2R 41.0%, 3R 57.0%, and 4R 2.0%; MTRR 66A 42.4% and 66G 57.6%; MTHFR 677C 59.3% and 677T 40.7%; and MTHFR 1298A 58.1% and 1298C 41.9%. At the 48th hour of HD-MTX infusion, serum MTX was significantly higher in patients who had TS 2R/3R/4R variants as compared to those with wild-type TS (p<0.05). No significant differences were detected with respect to event-free survival or toxicity between wild-type and other FRG variants.Conclusion:The frequencies of FRG polymorphisms in Turkish children with ALL are similar to those reported in other Caucasian populations. This is the first published finding of the TS 3R/4R variant in the Turkish population. The results indicate that HD-MTX can be tolerated by leukemic children with some polymorphic variants of FRG; thus, it may prevent future risk of leukemic relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Yazıcıoğlu¹,

Kaya

S³

et al. 2017

Tjh

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“…MTHFR 1298AC/TYMS 2R/2R genotypic combination is associated with reduced risk factor for DS in Italian population [8]. In another study, the 2R/2R genotype has been reported to be protective for coronary artery disease [35] and in drug response for certain cancer treatment [27,36,37] via interaction with folate intake. Further in a study of Artificial neural network analysis by Coppede et al, revealed TYMS 2R/3R genotype is closely connected with a condition of being mothers of DS and TYMS 3R/3R genotype connected with control mothers [38].…”

Section: Discussionmentioning

confidence: 99%

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Jaiswal¹,

Sukla²,

Mishra³

et al. 2016

J Mol Genet Med

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DNA methylation and nucleic acid biosynthesis are two crucial phenomena for normal chromosomes segregation. From our earlier studies, MTHFR 677T individually and in combination with other gene polymorphisms, micronutrient deficiency, hyperhomocysteinemia was shown to be associated with risk in Down syndrome (DS) mothers. Remethylation and nucleic acid biosynthesis pathways are dependent on the activity of Methylenetetrahydrofolate reductase (MTHFR) and Thymidylate synthase (TYMS) respectively, competing for common substrate molecule 5,10-methelenetetrahydrofolate (5,10-MTHF). The role of MTHFD1 1958 G>A (affecting synthesis of 5,10-MTHF), MTHFR 677 C>T (affecting methylation), TYMS 5'UTR 28 bp repeat polymorphism and TYMS 3'UTR 6bp deletion polymorphism (affecting nucleic acid biosynthesis) in a cohort of 200 case mothers and 187 control mothers (also 146 case triads: mother, father, and child) were studied in the present study. We observed a significant association of MTHFR 677 C>T in a co-dominant model (p=0.0428) and dominant model (0.0194) as well as TYMS 5'UTR 28 bp repeat polymorphism in a recessive model (p=0.0005) and dominant model (0.0161). The genotypic combination analysis revealed a significant additive effect of certain genotypic combinations (especially combination of MTHFR 677T and TYMS 2R alleles with other alleles or genotypes) in increasing risk. Weak linkage disequilibrium (LD) was observed between TYMS 5' and 3' UTR regions polymorphism in LD analysis. Transmission disequilibrium test (TDT) analysis revealed a consistent trend of preferential allele's transmission from parents. We concluded that genetic interaction of remethylation pathway and the nucleic acid metabolic pathway was significantly associated with risk factors for DS childbirth. However, replication studies are required to validate our observation in the population.

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“…Response to induction therapy for childhood ALL was slower in children with polymorphisms in quinone 1 (NQO1) and thymidylate synthase (TS) genes, and NQO1 genotype was associated with a lower 5-year event-free survival [95]. Furthermore, a recent study observed a strong association between promoter tandem repeat polymorphism of the TS gene and relapse frequency [96]. The authors suggested that genotyping for this variant should be performed in patients treated for ALL to enable further optimization of treatment protocols.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Pharmacokinetic and pharmacogenetic determinants and considerations in chemotherapy selection and dosing in infants

Hutson

Weitzman

Schechter

et al. 2012

Expert Opinion on Drug Metabolism & Toxicology

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Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.

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Polymorphism of the thymidylate synthase gene and risk of relapse in childhood ALL

Cited by 14 publications

References 7 publications

Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Influence of Folate-Related Gene Polymorphisms on High-Dose Methotrexate-Related Toxicity and Prognosis in Turkish Children with Acute Lymphoblastic Leukemia

Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remethylation with Down Syndrome Birth Risk: A Case-Control Study

Pharmacokinetic and pharmacogenetic determinants and considerations in chemotherapy selection and dosing in infants

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