Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome

Slama, Abdelhamid; Lacroix, Catherine; Planté‐Bordeneuve, Violaine; Lombès, Anne; Conti, Mary Anne; Reimund, Jean‐Marie; Auxenfants, É.; Crenn, Pascal; Laforêt, Pascal; Joannard, A; Séguy, D.; Pillant, H.; Joly, Philippe; Haut, Sandrine; Messing, Bernard; Saïd, Gérard; Legrand, Alain; Guiochon‐Mantel, Anne

doi:10.1016/j.ymgme.2004.12.004

Cited by 36 publications

(27 citation statements)

References 20 publications

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“…The estimated cumulative incidence of relapse by 3 years was 24% (95%CI, [20][21][22][23][24][25][26][27][28][29]. As found by the univariate (Table IIa) and multivariate (Table IVa) analyses, the only factor associated with the risk of relapse was disease stage at transplantationpatients transplanted in the advanced stage having a nearly two-fold higher risk of relapse than the rest (HR5 1.8, 95%CI 5 1.2-2.8; P 5 0.010).…”

Section: Relapse or Progressionmentioning

confidence: 99%

“…As found by the univariate (Table IIa) and multivariate (Table IVa) analyses, the only factor associated with the risk of relapse was disease stage at transplantationpatients transplanted in the advanced stage having a nearly two-fold higher risk of relapse than the rest (HR5 1.8, 95%CI 5 1.2-2.8; P 5 0.010). At 3 years after transplantation, the cumulative incidence of relapse in patients with advanced disease was 35% (95%CI, 27-45) as compared to 18% (95%CI, [14][15][16][17][18][19][20][21][22][23][24][25] in those with early stage disease.…”

Section: Relapse or Progressionmentioning

confidence: 99%

“…The cumulative incidence of GVHDRM at 3 years was 9% (95%CI, 6-13) in patients who received myeloablative conditioning, and 23% (95%CI, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] in those who received reduced-intensity regimens.…”

Section: American Journal Of Hematologymentioning

confidence: 99%

“…Specifically, TYMP catalyzes the reversible phosphorolysis of thymidine, thereby regulating the amount of nucleosides within the cells [19] in order to maintain a balanced deoxyribonucleoside triphosphate pool for DNA replication and repair [20][21][22][23]. The TYMP gene has a non-synonymous single nucleotide polymorphism (SNP) located in codon 465 of the coding sequence, in which a change of nucleotides (G to A) leads to an Ala-toThr substitution (rs112723255).…”

Section: Introductionmentioning

confidence: 99%

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A polymorphism in the TYMP gene is associated with the outcome of HLA‐identical sibling allogeneic stem cell transplantation

et al. 2013

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Thymidine phosphorylase (TYMP), an enzyme involved in nucleotide synthesis, has been implicated in critical biological processes such as DNA replication, protection against mutations, and tissue repair. In this work, we retrospectively evaluated the influence of a polymorphism in the TYMP gene (rs112723255; G/A) upon the outcome of 448 patients subjected to allogeneic stem cell transplantation (allo‐SCT) from an human leukocyte antigen (HLA)‐identical sibling donor. The TYMP genotype of patients correlated with overall survival—carriers of the minor allele (A) being at an increased risk of dying after transplantation (hazard ratio, HR = 1.9; P = 0.004). This effect was mostly due to differences in transplant toxicity‐related mortality (HR = 2.5; P = 0.029). In addition, the TYMP genotype of donors was associated with the risk of chronic graft‐versus‐host disease (GVHD)—carriers of the minor allele being at an increased risk of developing this complication ([HR] = 1.7; P = 0.039). The impact of such polymorphism on the risk of chronic GVHD is limited to patients transplanted in early stage disease (HR = 2.2; P = 0.019). The combination of a donor harboring the minor allele with a patient homozygous for the major allele was associated with the highest risk of chronic GVHD (HR = 2.8; P = 0.008). These findings provide the first evidence of the significant impact of the TYMP genotype upon the clinical outcome of patients treated with HLA‐identical sibling allo‐SCT. Am. J. Hematol. 88:883–889, 2013. © 2013 Wiley Periodicals, Inc.

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Section: Relapse or Progressionmentioning

confidence: 99%

Section: Relapse or Progressionmentioning

confidence: 99%

Section: American Journal Of Hematologymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A polymorphism in the TYMP gene is associated with the outcome of HLA‐identical sibling allogeneic stem cell transplantation

et al. 2013

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“…Although the nucleotide substitution c.261G4T has not been described previously, the resulting amino-acid replacement p.Glu87Asp has already been characterised. 14 The 175-kb deletion spans 12 genes and corresponds to known CNV-variation_5192, which occurs with almost 7% frequency in control samples. 12 In this Figure 1 Steady-state levels of SCO2 protein in muscle (a) and heart (b) mitochondria of patient 1.…”

Section: Resultsmentioning

confidence: 99%

Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders

et al. 2013

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Mitochondrial disorders are caused by defects in mitochondrial or nuclear DNA. Although the existence of large deletions in mitochondrial DNA (mtDNA) is well known, deletions affecting whole genes are not commonly described in patients with mitochondrial disorders. Based on the results of whole-genome analyses, copy number variations (CNVs) occur frequently in the human genome and may overlap with many genes associated with clinical phenotypes. We report the discovery of two large heterozygous CNVs on 22q13.33 in two patients with mitochondrial disorders. The first patient harboured a novel point mutation c.667G4A (p.D223N) in the SCO2 gene in combination with a paternally inherited 87-kb deletion. As hypertrophic cardiomyopathy (HCMP) was not documented in the patient, this observation prompted us to compare his clinical features with all 44 reported SCO2 patients in the literature. Surprisingly, the review shows that HCMP was present in only about 50% of the SCO2 patients with non-neonatal onset. In the second patient, who had mitochondrial neurogastrointestinal encephalopathy (MNGIE), a maternally inherited 175-kb deletion and the paternally inherited point mutation c.261G4T (p.E87D) in the TYMP gene were identified.

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Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early‐Onset Capecitabine‐Related Toxicity

Hamzic

Kummer

Milesi

et al. 2017

Clin Pharma and Therapeutics

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An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus associated with early-onset Cp-toxicity (Haplotype A3: OR = 2.2, 95% CI 1.2-4.0, P = 0.012; OR = 10.3, 95% CI 2.1-49.4, P = 0.0038). Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: OR = 4.3, 95% CI 1.3-14.2, P = 0.017; and c.1-92A>G: OR = 4.4, 95% CI 1.3-14.5, P = 0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact.

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Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome

Cited by 36 publications

References 20 publications

A polymorphism in the TYMP gene is associated with the outcome of HLA‐identical sibling allogeneic stem cell transplantation

A polymorphism in the TYMP gene is associated with the outcome of HLA‐identical sibling allogeneic stem cell transplantation

Large copy number variations in combination with point mutations in the TYMP and SCO2 genes found in two patients with mitochondrial disorders

Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early‐Onset Capecitabine‐Related Toxicity

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