Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GSTM1, GSTT1 and GSTP1 Ile105Val that are members of the GST gene family encode for Phase II drug/xenobiotic metabolizing enzymes, primarily with detoxifying function, and are polymorphic in humans. GSTM1 and GSTT1 homozygous deletion genotypes do not express the enzymes. It has been hypothesised that individuals with homozygous deletion of the GSTM1 and/or GSTT1 gene may have lower detoxification capacity towards genotoxic agents therefore those individuals may be at increased risk of myelodysplastic syndrome which is a preleukemic condition. Genetic polymorphism of GSTM1, GSTT1 and GSTP1 Ile105Val was investigated in a case-control study in a Hungarian patient population comprising 86 patients with myelodysplastic syndrome and 99 hospital-based controls. There were no statistically significant differences between cases and controls for the GSTM1, GSTT1 and GSTP1 Ile105Val genotype frequencies for any of the three genes separately and in various combinations. This suggests that these genetic polymorphisms may not be strong risk factors, if any, for myelodysplastic syndrome.
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PMID:Glutathione S-transferase enzyme polymorphisms in a Hungarian myelodysplasia study population. 1849 76

DNA methylation levels are affected by numerous environmental influences, including diet and xenobiotic exposure, and neoplasia has been firmly associated with genomic hypomethylation and localized hypermethylation of tumor suppressor genes. To reverse methylation-induced gene repression, DNA hypomethylating agents are currently in clinical trials for various malignancies, with two of these now approved for the therapy of myelodysplastic syndrome, and the efficacy of these drugs can be assessed by the monitoring of global DNA methylation levels. Herein, we outline a simple, well-established method for the evaluation of genomic DNA methylation levels, based on the ability of isolated DNA to "accept" radiolabeled methyl groups from S-[3H-methyl] adenosylmethionine, using the bacterial CpG methyltransferase SssI. As this enzyme methylates all unmethylated CpG dinucleotides in the genome, radiolabeled methyl group acceptance is inversely proportional to the level of preexisting methylation. This assay is applicable to a number of translational and basic research questions.
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PMID:Methyl group acceptance assay for the determination of global DNA methylation levels. 1898 4

DNA methylation is one of the major epigenetic changes in human cancers, leading to silencing of tumor suppressor genes, with a pathogenetic role in tumor development and progression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Methylation of key promoter regions, induced by cytotoxic therapy together with complex genetic changes, is important in the biology of therapy-related myeloid neoplasms (t-MN). We were interested in the characterization of the methylation pattern of AML and MDS de novo and therapy-related. We studied 385 patients (179 females, 206 males), of a median age of 66 years (range 16-98 years). There were 105 MDS, 208 de novo AML and 72 t-MN (45 MDS and 27 AML). Using a methylation-specific PCR, we studied the promoter methylation status of E-cadherin (CDH1), TSP1 and DAP-Kinase 1. These genes have been shown to be involved in the malignant transformation, interfering with angiogenesis, interaction with micro-environment, apoptosis and xenobiotic detoxification. We found no associations between promoter hypermethylation and gender or age at the time of initial diagnosis. In patients with MDS, there were no associations between hypermethylation and clinical characteristics, including IPSS score, WHO classification and cytogenetics. DAPK1 was more frequently methylated in t-MDS/AML when compared to de novo MDS and AML (39% vs 15.3% and 24.4%, p=0.0001), while methylation of CDH1 was similar in t-MDS/AML and AML (51% and 53.4%), but less frequent in de novo MDS (29%) (p=0.003). In the t-MDS/AML group, we found that the methylation pattern appeared to be related to the primary tumor, with DAPK1 more frequently methylated in patients with a previous lymphoproliferative disease (75% vs 32%, p=0.006). On the other hand, methylation of CDH1 was associated to radiotherapy for the primary malignancy (84.5% vs 38%, p=0.003). TSP1 hypermethylation was rare and not characteristic of t-MDS/AML. In 177 patients studied for concurrent methylation of several promoters, t-MN and AML de novo were significantly more frequently hypermethylated in 2 or more promoter regions than de novo MDS (20% vs 12.4%, p<0.001). Chemotherapy and individual genetic predisposition have a role in t-MDS/AML development, the identification of specific epigenetic modifications may explain complexity and genomic instability of these diseases and give the basis for targeted-therapy. The significant association with previous malignancy subtypes may underlie a likely susceptibility to methylation of specific targets and a role for constitutional epimutations as predisposing factors for the development of therapy-related myeloid neoplasm.
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PMID:Promoter methylation of DAPK1, E-cadherin and thrombospondin-1 in de novo and therapy-related myeloid neoplasms. 2065 75

Therapy-related myeloid neoplasms (t-MNs) are an increasingly recognized complication in patients previously treated with radiotherapy and/or chemotherapy for cancer or autoimmune disease. Single nucleotide variants (SNVs) in genes involved in the cellular pathways of detoxification, DNA repair and apoptosis may modify the individual risk of developing a t-MN. We studied the frequency of the SNVs of six genes involved in xenobiotic detoxification (CYP3A4, NQO1, GSTA1, GSTM1, GSTP1 and GSTT1), two DNA repair genes (RAD51 and XRCC3) and one key regulator of apoptosis (BCL2L10) in a case-control study including 111 cases of t-MN and 259 controls. This is the first report on the prevalence of BCL2L10 Leu21Arg polymorphism in myeloid malignancies. In this line, we also tested 146 cases of de novo myelodysplastic syndrome (MDS) and 109 cases of de novo acute myeloid leukemia (AML). Our results showed a significantly lower frequency of the BCL2L10-21Arg allele in patients with t-MN and de novo MDS compared to controls (Leu/Arg + Arg/Arg: 50.6% vs. 65.9%, p = 0.017 and 45.8% vs. 65.9%, p = 0.0003, respectively). Carriers of the BCL2L10-21Arg variant have a reduced risk of developing t-MN and de novo MDS.
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PMID:The BCL2L10 Leu21Arg variant and risk of therapy-related myeloid neoplasms and de novo myelodysplastic syndromes. 2404 76

The myelodysplastic syndromes (MDS) are morphologically and genetically heterogeneous, and as such a single etiological factor is implausible. Therapy-related MDS has a clear etiology but the predisposition factors remain unclear. Most MDS (>90%) is not therapy-related and an etiology for this majority of patients, and indeed of better defined (morphological or genetic) subgroups cannot yet be ascertained. Exposure to occupational and environmental toxins is not obviously a major etiological contributor. The exceptions may be exposure to low concentrations of benzene and to tobacco smoke (which contains benzene amongst other carcinogens), but even these xenobiotics produce only modestly increased Hazard ratios for the development of MDS. It seems likely that low penetrance genetic variants may influence predisposition, and these may include pathways for xenobiotic metabolism, DNA repair and other quantitative trait loci.
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PMID:Occupational and environmental etiology of MDS. 2450 9

Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members.
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PMID:Applying molecular epidemiology in pediatric leukemia. 2597 90