title: 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.
authors.affiliation: Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal.|Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Coimbra, Portugal.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Gonçalves
authors.affiliation: Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal.|Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Coimbra, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alves
authors.affiliation: Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Coimbra, Portugal.|Department of Neurology, Laboratory of Neurochemistry, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Baldeiras
authors.affiliation: Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal.|Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra, EPE (CHUC, EPE), Coimbra, Portugal.
authors.forename: Emília
authors.initials: E
authors.lastname: Cortesão
authors.affiliation: Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.|Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra, EPE (CHUC, EPE), Coimbra, Portugal.
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Carda
authors.affiliation: Molecular Genetics and Pathology Unit, Hospital of Divino Espírito Santo of Ponta Delgada, EPE, Ponta Delgada, São Miguel Island, Azores, Portugal.|Azores Genetics Research Group, Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Faculty of Sciences, BioISI-Biosystems and Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Branco
authors.affiliation: Laboratory for Biostatistics and Medical Informatics, FMUC, Coimbra, Portugal.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Oliveiros
authors.affiliation: Department of Medicine, Hospital Distrital da Figueira da Foz, EPE (HDFF, EPE), Figueira da Foz, Portugal.
authors.forename: Luísa
authors.initials: L
authors.lastname: Loureiro
authors.affiliation: Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal.|Department of Medicine, Hospital Distrital da Figueira da Foz, EPE (HDFF, EPE), Figueira da Foz, Portugal.
authors.forename: Amélia
authors.initials: A
authors.lastname: Pereira
authors.affiliation: Department of Oncology, Centro Hospitalar e Universitário de Coimbra, EPE (CHUC, EPE), Coimbra, Portugal.|Faculty of Medicine, University Clinic of Oncology, University of Coimbra-FMUC, Coimbra, Portugal.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Nascimento Costa
authors.affiliation: Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, Faculty of Medicine, University of Coimbra-FMUC, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), FMUC, Coimbra, Portugal.|Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences (CNC.IBILI), Coimbra, Portugal.|Clinical Hematology Department, Centro Hospitalar e Universitário de Coimbra, EPE (CHUC, EPE), Coimbra, Portugal.
authors.forename: Ana Bela
authors.initials: AB
authors.lastname: Sarmento-Ribeiro
authors.affiliation: Molecular Genetics and Pathology Unit, Hospital of Divino Espírito Santo of Ponta Delgada, EPE, Ponta Delgada, São Miguel Island, Azores, Portugal.|Azores Genetics Research Group, Instituto Gulbenkian de Ciência, Oeiras, Portugal.|Faculty of Sciences, BioISI-Biosystems and Integrative Sciences Institute, University of Lisboa, Lisbon, Portugal.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mota-Vieira
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D019175:DNA Methylation; D004260:DNA Repair; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D005492:Folic Acid
keywords: acute myeloid leukemia; genetic predisposition; myelodysplastic syndrome; single nucleotide polymorphism; survival