Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis

Abstract

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) share common features: elevated oxidative stress, DNA repair deficiency, and aberrant DNA methylation. We performed a hospital-based case-control study to evaluate the association in variants of genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation with susceptibility and prognosis of these malignancies. To that end, 16 SNPs (one per gene: CAT, CYBA, DNMT1, DNMT3A, DNMT3B, GPX1, KEAP1, MPO, MTRR, NEIL1, NFE2F2, OGG1, SLC19A1, SOD1, SOD2, and XRCC1) were genotyped in 191 patients (101 MDS and 90 AML) and 261 controls. We also measured oxidative stress (reactive oxygen species/total antioxidant status ratio), DNA damage (8-hydroxy-2'-deoxyguanosine), and DNA methylation (5-methylcytosine) in 50 subjects (40 MDS and 10 controls). Results showed that five genes (GPX1, NEIL1, NFE2L2, OGG1, and SOD2) were associated with MDS, two (DNMT3B and SLC19A1) with AML, and two (CYBA and DNMT1) with both diseases. We observed a correlation of CYBA TT, GPX1 TT, and SOD2 CC genotypes with increased oxidative stress levels, as well as NEIL1 TT and OGG1 GG genotypes with higher DNA damage. The 5-methylcytosine levels were negatively associated with DNMT1 CC, DNMT3A CC, and MTRR AA genotypes, and positively with DNMT3B CC genotype. Furthermore, DNMT3A, MTRR, NEIL1, and OGG1 variants modulated AML transformation in MDS patients. Additionally, DNMT3A, OGG1, GPX1, and KEAP1 variants influenced survival of MDS and AML patients. Altogether, data suggest that genetic variability influence predisposition and prognosis of MDS and AML patients, as well AML transformation rate in MDS patients. © 2016 Wiley Periodicals, Inc.

DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome

“…Limitations due to sample size are common in scientific publications, as stated by Danjou et al 39 and Gonçalves et al 40. We found significant associations and correlations, but the number of cases evaluated was low and we cannot exclude the possibility that the absence of associations related to other genes might be explained by this factor.…”

Integrated bioinformatic analysis of microarray data reveals shared gene signature between MDS and AML

“…TEC, a non-receptor type protein-tyrosine kinase, was revealed to be highly expressed in MDS patients (31). GPX1 , which encodes a glutathione peroxidase and helps to reduce organic hydroperoxides and hydrogen peroxide (H 2 O 2 ) by glutathione, has been reported to be dramatically upregulated in AML and relate with MDS by SNPs assay and DNA methylation (32,33). ASS1 (Argininosuccinate synthetase 1) gene product is responsible for the process of arginine biosynthesis; however, Miraki-Moud et al (34), reported that most AML lacked ASS1 expression, which may be due to small sample size and the different detection methods.…”

Single nucleotide polymorphisms in DNA glycosylases: From function to disease

“…Other studies associate hOGG1 Ser326Cys polymorphism with risk of other types of cancer such as hepatocellular carcinoma (HCC), [153], cholangiocarcinoma (CCA) [154], upper aerodigestive tract cancer (UADT, [155]), nasopharyngeal carcinoma [156][157][158][159] and prostate cancer [160] but they rely on a small sample size which leads to a considerable lack of statistical power and ethnic and geographic differences that may account for the discrepancies observed. This polymorphism seems also to associate with myelodysplastic syndrome (MDS) and modulate acute myeloid leukemia (AML) transformation in MDS patients influencing survival of MDS and AML patients [161]. [162].…”

“…Two PSC patients with CCA were found to be heterozygotic for NEIL1 Gly83Asp SNP [200], however the small number of individuals analysed does not allow drawing any conclusion on the association with CCA. The NEIL1 rs4462560 SNP was reported to be associated with MDS [161].…”