Associations between polymorphisms in the thymidylate synthase gene, the expression of thymidylate synthase mRNA and the microsatellite instability phenotype of colorectal cancer

Merkelbach‐Bruse, Sabine; Hans, Volkmar; Mathiak, Micaela; Sanguedolce, R; Alessandro, Riccardo; Rüschoff, Josef; Büttner, Reinhard; Houshdaran, Farzad; Gullotti, Lucia

doi:10.3892/or.11.4.839

Cited by 15 publications

(17 citation statements)

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“…Studies have also shown lack of association between TS enhancer polymorphism and mRNA expression. 4,5 However, an association between TS polymorphism and protein expression has been shown. 4,6 The study did not apply IHC but rather an FdUMP binding assay for quantification of TS protein.…”

Section: Discussionmentioning

confidence: 99%

Expression of Thymidylate Synthase in Primary Colorectal Adenocarcinoma

Lindebjerg

Nielsen

Hoeffding

et al. 2006

Applied Immunohistochemistry &Amp; Molecular Morphology

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Thymidylate synthase (TS) is a key regulatory enzyme in the cellular pathway of de novo pyrimidine synthesis and a target enzyme for 5-fluorouracil (5-FU). Most clinical studies have shown that high levels of TS in tumors are associated with decreased sensitivity to 5-FU treatment. In this study TS expression was assessed at DNA, RNA, and protein levels. The study included 69 tumors from patients with primary colorectal adenocarcinoma. At the DNA level TS enhancer polymorphism was measured on whole blood by PCR. At the RNA level TS mRNA expression was measured on formalin-fixed paraffin-embedded tumor tissue and on fresh-frozen tumor tissue by real-time RT-PCR. Protein expression was assessed by IHC. Correlation was found between TS mRNA expression in fresh-frozen tumor tissue and formalin-fixed paraffin-embedded tissue (R=0.71). TS enhancer 3/3 had significantly higher protein levels as assessed by IHC than the TS enhancer 2/2 (P=0.02), although there was no statistically significant correlation between TS enhancer polymorphism and TS mRNA expression. An interesting observation not previously reported is that the predominant IHC reaction pattern in tumors from patients with the TS enhancer genotype 3/3 is different in tumors from patients with genotypes 2/2 and 2/3. The results indicate that clinical studies of the significance of TS with regard to 5-FU-based chemotherapy should be based on assessment of TS activity at DNA, RNA, and protein levels.

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Section: Discussionmentioning

confidence: 99%

Expression of Thymidylate Synthase in Primary Colorectal Adenocarcinoma

Lindebjerg

Nielsen

Hoeffding

et al. 2006

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…The triple tandem genotype is associated with higher TS mRNA and TS protein levels compared to the double tandem genotype. [20][21][22][23] The effect of higher numbers of repeats is not yet clear. The allele frequency of TSER*3 appears almost similar in Asians, Africans and Caucasians (about 50%), but the frequency of homozygous TSER*3 was reported to be significantly higher in Asians (67%) compared to Caucasians (38%).…”

Section: -Fluorouracilmentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…Polymorphism of the TS gene is known to occur at a 28 bp nucleotide fragment of the 5¢-untranslated region (5¢-UTR), or with the presence or absence of a 6 bp nucleotide fragment in the 3¢-untranslated region (3¢-UTR; Ulrich et al 2000). These two kinds of polymorphism can influence TS expression by influencing the stability of the TS mRNA, and thus affect the drug sensitivity of cancer patients (Calascibetta et al 2004;Mandola et al 2004;Merkelbach-Bruse et al 2004). In the present work, we studied the relationship between polymorphism of the 3¢-UTR of the TS gene and drug sensitivity of gastric cancer to 5-FUbased chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy

Gao

et al. 2006

J Hum Genet

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Polymorphism in the 3¢-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy Abstract To investigate the relationship between polymorphism in the 3¢-untranslated region (3¢-UTR) of the thymidylate synthase (TS) gene and sensitivity of gastric cancer to 5-fluorouracil (5-FU)-based chemotherapy, 106 cases of advanced gastric cancer were analyzed. All patients were treated with 5-FU-based chemotherapy; DNA from peripheral blood leukocytes was obtained before therapy. TS 3¢-UTR genotypes were detected by PCR-RFLP. Polymorphism in the TS 3¢-UTR can be classified into three groups according to the presence or absence of a 6 bp nucleotide fragment: the À6/À6 bp, À6/+6 bp and +6/+6 bp groups. The response rate of the À6/À6 bp and À6/+6 bp groups was found to be significantly higher than the +6/+6 bp group. These results show that the presence of the TS 3¢-UTR 6 bp nucleotide fragment can be correlated with the sensitivity of gastric cancer to 5-FU-based chemotherapy, and that the TS 3¢-UTR polymorphism profile can be used to guide the choice of 5-FU-based chemotherapy in advanced gastric cancer.

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Associations between polymorphisms in the thymidylate synthase gene, the expression of thymidylate synthase mRNA and the microsatellite instability phenotype of colorectal cancer

Cited by 15 publications

References 0 publications

Expression of Thymidylate Synthase in Primary Colorectal Adenocarcinoma

Expression of Thymidylate Synthase in Primary Colorectal Adenocarcinoma

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Polymorphism in the 3′-untranslated region of the thymidylate synthase gene and sensitivity of stomach cancer to fluoropyrimidine-based chemotherapy

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