Susceptibility to MDS: DNA Repair and Detoxification Genes

Seedhouse, Claire; Russell, Nigel H.

doi:10.1007/978-94-007-0440-4_2

Cited by 1 publication

(2 citation statements)

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“…Similar to other malignant diseases, myelodysplasia and its progression to AML is a genomic instability disorder, resulting from a stepwise accumulation of genetic abnormalities, probably because of an increased DNA damage burden and/or reduced ability to deal with the damage. 1,2 Folate is an important nutrient required for DNA synthesis and methylation because it provides one-carbon donor for the synthesis of de novo purines and pyrimidines, and remethylation of homocysteine for methylation reaction of protein, DNA and RNA. Its deficiency has been associated with various vascular and neurological diseases, as well as with diabetes, psoriasis and malignancies and acute lymphoblastic leukemia.…”

Section: Introductionmentioning

confidence: 99%

“…The base excision repair pathway is a multistep process that requires the activation of several proteins and the functional polymorphism in these genes may be responsible for an altered DNA repair capacity. 2,8 It is well known that the presence of functional polymorphisms in genes affects, in general, the respective enzyme activities. As an example, two known polymorphisms in the MTHFR gene, C677T and A1298C, lead to a 30-60% reduction in enzyme activity.…”

Section: Introductionmentioning

confidence: 99%

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MTHFR, TS and XRCC1 genetic variants may affect survival in patients with myelodysplastic syndromes treated with supportive care or azacitidine

Visani¹,

Loscocco²,

Ruzzo

et al. 2017

Pharmacogenomics J

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We evaluated the impact of genomic polymorphisms in folate-metabolizing, DNA synthesis and DNA repair enzymes on the clinical outcome of 108 patients with myelodysplastic syndromes (MDS) receiving best supportive care (BSC) or azacitidine. A statistically significant association between methylenetetrahydrofolate reductase (MTHFR) 677T/T, thymidylate synthase (TS) 5′-untranslated region (UTR) 3RG, TS 3′-UTR − 6 bp/ − 6 bp, XRCC1 399G/G genotypes and short survival was found in patients receiving BSC by multivariate analysis (P o0.001; P = 0.026; P = 0.058; P = 0.024). MTHFR 677T/T, TS 3′-UTR − 6 bp/ − 6 bp and XRCC1 399G/G genotypes were associated with short survival in patients receiving azacitidine by multivariate analysis (P o0.001; P = 0.004; P = 0.002). We then performed an exploratory analysis to evaluate the effect of the simultaneous presence of multiple adverse variant genotypes. Interestingly, patients with ⩾ 1 adverse genetic variants had a short survival, independently from their International Prognostic Scoring System (IPSS) and therapy received. To our knowledge, this is the first study showing that polymorphisms in folate-metabolizing pathway, DNA synthesis and DNA repair genes could influence survival of MDS patients.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%