Multi-class biological tissue classification based on a multi-classifier: Preliminary study of an automatic output power control for ultrasonic surgical units.

Ultrasonic surgical units (USUs) have the advantage of minimizing tissue damage during surgeries that require tissue dissection by reducing problems such as coagulation and unwanted carbonization, but the disadvantage of requiring manual adjustment of power output according to the target tissue. In order to overcome this limitation, it is necessary to determine the properties of in vivo tissues automatically. We propose a multi-classifier that can accurately classify tissues based on the unique impedance of each tissue. For this purpose, a multi-classifier was built based on single classifiers with high classification rates, and the classification accuracy of the proposed model was compared with that of single classifiers for various electrode types (Type-I: 6 mm invasive; Type-II: 3 mm invasive; Type-III: surface). The sensitivity and positive predictive value (PPV) of the multi-classifier by cross checks were determined. According to the 10-fold cross validation results, the classification accuracy of the proposed model was significantly higher (p<0.05 or <0.01) than that of existing single classifiers for all electrode types. In particular, the classification accuracy of the proposed model was highest when the 3mm invasive electrode (Type-II) was used (sensitivity=97.33-100.00%; PPV=96.71-100.00%). The results of this study are an important contribution to achieving automatic optimal output power adjustment of USUs according to the properties of individual tissues.

Selective transfection with osmotically active sorbitol modified PEI nanoparticles for enhanced anti-cancer gene therapy.

Polysorbitol-mediated transporter (PSMT) has been previously shown to achieve high transfection efficiency with minimal cytotoxicity. Polysorbitol backbone possesses osmotic properties and leads to enhanced cellular uptake. The PSMT/pDNA nanoparticles were prepared and the particle size, surface charge of the nanoparticles was determined for the study. PSMT delivers genes into cells by the caveolae mediated endocytic pathway. Caveolae expression is usually altered in transformed cancer cells. Transfection through the caveolae may help PSMT to selectively transfect cancer cells rather than normal cells. Transfection of the luciferase gene by PSMT was tested in various cell types including cancer cell lines, primary cells, and immortalized cells. Luciferase transgene expression mediated by PSMT was remarkably increased in HeLa cells compared to expression using the control carrier Lipofectamine. Moreover, the toxicity of PSMT was comparable to the control carrier (Lipofectamine) in the same cells. Selective transfection of cancer cells using PSMT was further confirmed by co-culture of cancer and normal cells, which showed that transgene expression was pre-dominantly achieved in cancer cells. A functional p53 gene was also delivered into HeLa cells using PSMT and the selective transgene expression of p53 protein in cancer cells was analyzed through western blotting and confocal microscopy. HeLa cells transfected with PSMT/p53 plasmid nanoparticles showed cellular damage and apoptosis, which was confirmed through propidium iodide staining.

Polymorphisms in DNA repair genes and MDR1 and the risk for non-Hodgkin lymphoma.

The damage caused by oxidative stress and exposure to cigarette smoke and alcohol necessitate DNA damage repair and transport by multidrug resistance-1 (MDR1). To explore the association between polymorphisms in these genes and non-Hodgkin lymphoma risk, we analyzed 15 polymorphisms of 12 genes in a population-based study in Korea (694 cases and 1700 controls). Four genotypes of DNA repair pathway genes (XRCC1 399 GA, OGG1 326 GG, BRCA1 871 TT, and WRN 787 TT) were associated with a decreased risk for NHL [odds ratio (OR)XRCC1 GA=0.80, p=0.02; OROGG1 GG=0.70, p=0.008; ORBRCA1 TT=0.71, p=0.048; ORWRN TT=0.68, p=0.01]. Conversely, the MGMT 115 CT genotype was associated with an increased risk for NHL (OR=1.25, p=0.04). In the MDR1 gene, the 1236 CC genotype was associated with a decreased risk for NHL (OR=0.74, p=0.04), and the 3435 CT and TT genotypes were associated with an increased risk (OR3435CT=1.50, p<0.0001; OR3435TT=1.43, p=0.02). These results suggest that polymorphisms in the DNA repair genes XRCC1, OGG1, BRCA1, WRN1, and MGMT and in the MDR1 gene may affect the risk for NHL in Korean patients.

Improved therapeutic effect against leukemia by a combination of the histone methyltransferase inhibitor chaetocin and the histone deacetylase inhibitor trichostatin A.

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.

Association of GSTT1 polymorphism with acute myeloid leukemia risk is dependent on smoking status.

Genetic polymorphisms in drug-metabolizing, DNA repair and multidrug resistance genes affect the risks for many cancers. We analyzed 21 polymorphisms in 17 genes in these pathways to evaluate their association with the risk of acute myeloid leukemia (AML) and to examine whether smoking modifies these associations in a population-based study in Korea (415 cases, 1700 controls). We found marginal associations between the risk of AML and CYP1A1 1188, and XRCC1 194, ERCC1 IVS5 + 33 and WRN 787 polymorphisms. However, when we performed the analysis according to smoking exposure, we found a stronger association for ERCC1 only in the non-smoking population (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.60-0.91, p = 0.004), while we found the GSTT1-null genotype to be associated with an increased risk of AML in ever-smokers (OR = 1.51; 95% CI = 1.06-2.15, p = 0.02). These results indicate that ERCC1 and GSTT1-null polymorphisms may have an effect on AML risk that is dependent on smoking exposure.

H2AFX polymorphisms are associated with decreased risk of diffuse large B cell lymphoma in Koreans.

Polymorphisms of the H2A histone family member X (H2AFX) gene have been associated with decreased non-Hodgkin lymphoma (NHL, -417AA) risk and increased breast cancer (1654AG/GG, and -1420GA/AA) risk. We investigated whether H2AFX polymorphisms are associated with the risk of NHL and its subtypes in 573 NHL Korean patients and 721 cancer-free control subjects, using high resolution melting polymerase chain reaction and an automatic sequencer. There was no association between polymorphisms and the risk of overall NHL, all B cell lymphoma, or all T cell lymphoma. However, the -1420 AA genotype was associated with decreased diffuse large B cell lymphoma (DLBCL) risk (OR, 0.65; 95% CI, 0.43-0.97), and there was a trend for allele dose-effect (p-trend=0.03). The -1187 CC genotype was associated with decreased DLBCL risk with borderline significance (OR, 0.70; 95% CI, 0.48-1.02). There was a trend for an allele dose-effect with borderline significance (p-trend=0.06). These results suggest that the -1420 AA genotype of H2AFX may be associated with reduced DLBCL risks in the Korean population.

Treatment outcome of all-trans retinoic acid/anthracycline combination chemotherapy and the prognostic impact of FLT3/ITD mutation in acute promyelocytic leukemia patients.

BACKGROUND: All-trans retinoic acid (ATRA)/anthracycline chemotherapy is beneficial in newly diagnosed acute promyelocytic leukemia (APL); however, it is important to identify patients with high-risk disease to increase the cure rate. We investigated the outcome of ATRA/anthracycline chemotherapy and clinicobiological correlations of FLT3/ITD and NPM1 mutations in APL patients. METHODS: Induction therapy included oral ATRA (45 mg/m(2)/day) and idarubicin (12 mg/m(2)/day, intravenous, on days 2, 4, and 6). Patients achieving complete remission (CR) received 3 courses of ATRA combined with reinforced consolidation therapy. Mutations were analyzed using GeneScan and polymerasae chain reaction assays of bone marrow samples obtained from patients at diagnosis. RESULTS: Forty-five (84.9%) of 53 eligible patients achieved CR. The overall relapse rate was 8.9%, and the 3-year overall survival (OS) and leukemia-free survival (LFS) were 84.9±4.9% and 77.5±6.0%, respectively. The NPM1 mutation was not found in any patient, while the FLT3/ITD mutation was found in 10 (20.0%) patients. Of the FLT3/ITD+ patients, 80% belonged to the high-risk group, defined according to the presenting WBC and platelet counts. Among the patients who achieved CR, those who were FLT3/ITD+ had a higher relapse rate than those FLT3/ITD-. FLT3/ITD+ patients also had a significantly lower 3-year LFS than FLT3/ITD- patients. Multivariate analysis of the LFS showed that the FLT3/ITD mutation was independently associated with a shorter overall LFS, after adjusting for pretreatment risk stratification. CONCLUSION: This study investigated the clinical outcome of newly diagnosed APL patients treated with ATRA/anthracycline chemotherapy. Patients carrying the FLT3/ITD mutation had more aggressive clinical features and a poorer clinical outcome.

Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D6*10/*10.

BACKGROUND AND PURPOSE: The objective of this study was to investigate the combined influence of genetic polymorphisms in ABCB1 and CYP2D6 genes on risperidone pharmacokinetics. EXPERIMENTAL APPROACH: Seventy-two healthy Korean volunteers receiving a single oral dose of 2 mg risperidone were included in this study. KEY RESULTS: Significant differences were observed between the ABCB1 3435C>T genotypes for the pharmacokinetic parameters (peak serum concentration) of risperidone and the active moiety (risperidone and its main metabolite, 9-hydroxyrisperidone). There were no significant differences in the area under the serum concentration-time curves of risperidone and the active moiety among the ABCB1 2677G>T/A and 3435C>T genotypes. However, the peak serum concentration and area under the serum concentration-time curves were significantly different among the ABCB1 3435C>T genotypes in CYP2D6*10/*10. CONCLUSIONS AND IMPLICATIONS: These findings indicate that polymorphisms of ABCB1 3435C>T in individuals with CYP2D6*10/*10, which has low metabolic activity, could play an important role in the potential adverse effects or toxicity of risperidone.

DNA methylation changes following 5-azacitidine treatment in patients with myelodysplastic syndrome.

DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments.

A genome-wide study of moyamoya-type cerebrovascular disease in the korean population.

OBJECTIVE: Structural genetic variation, including copy-number variation (CNV), constitutes a substantial fraction of total genetic variability, and the importance of structural variants in modulating susceptibility is increasingly being recognized. CNV can change biological function and contribute to pathophysiological conditions of human disease. Its relationship with common, complex human disease in particular is not fully understood. Here, we searched the human genome to identify copy number variants that predispose to moya-moya type cerebrovascular disease. METHODS: We retrospectively analyzed patients who had unilateral or bilateral steno-occlusive lesions at the cerebral artery from March, 2007, to September, 2009. For the 20 subjects, including patients with moyamoya type pathologies and three normal healthy controls, we divided the subjects into 4 groups : typical moyamoya (n=6), unilateral moyamoya (n=9), progression unilateral to typical moyamoya (n=2) and non-moyamoya (n=3). Fragmented DNA was hybridized on Human610Quad v1.0 DNA analysis BeadChips (Illumina). Data analysis was performed with GenomeStudio v2009.1, Genotyping 1.1.9, cnvPartition_v2.3.4 software. Overall call rates were more than 99.8%. RESULTS: In total, 1258 CNVs were identified across the whole genome. The average number of CNV was 45.55 per subject (CNV region was 45.4). The gain/loss of CNV was 52/249, having 4.7 fold higher frequencies in loss calls. The total CNV size was 904,657,868, and average size was 993,038. The largest portion of CNVs (613 calls) were 1M-10M in length. Interestingly, significant association between unilateral moyamoya disease (MMD) and progression of unilateral to typical moyamoya was observed. CONCLUSION: Significant association between unilateral MMD and progression of unilateral to typical moyamoya was observed. The finding was confirmed again with clustering analysis. These data demonstrate that certain CNV associate with moyamoya-type cerebrovascular disease.

The role of peroxiredoxin V in (-)-epigallocatechin 3-gallate-induced multiple myeloma cell death.

(-)-Epigallocatechin 3-gallate (EGCG) is a potent antioxidant polyphenol in green tea that acts as an anticancer agent via both direct and indirect pathways. Although the relationship between EGCG's anticancer effects and its antioxidant activity is not fully understood, it is known that EGCG stimulates production of reactive oxygen species (ROS), which induce oxidative stress leading to cell death. In IM9 multiple myeloma cells, EGCG acted in a dose- and time-dependent manner to induce apoptotic cell death. Among the antioxidant enzymes expressed in IM9 cells, levels of peroxiredoxin V (PrdxV) were selectively and significantly reduced by EGCG. Moreover, the ROS scavenger NAC completely inhibited EGCG-induced apoptosis and PrdxV reduction, while overexpression of PrdxV, but not a Prdx(VC48S) mutant, protected IM9 cells from EGCG-induced apoptosis. EGCG-induced reductions in cell viability and PrdxV levels were also observed in primary CD138+ multiple myeloma cells from patients. These results suggest that PrdxV is a key target via which EGCG mediates its anticancer effects.

Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia.

BACKGROUND: Nucleophosmin (NPM1) gene and fms-like tyrosine kinase 3 gene-internal tandem duplication (FLT3-ITD) mutations are the most frequent mutations in patients with cytogenetically normal (CN)-AML. We analyzed the prognostic impact of these mutations and their interactions in adults with CN-AML. METHODS: NPM1 mutation (NPM1mut) and FLT3-ITD mutation (FLT3-ITD+) were analyzed by GeneScan and PCR assays of bone marrow samples obtained from 121 adult patients with CN-AML (age≤60 years at diagnosis). RESULTS: The incidence of FLT3-ITD+ was higher in the NPM1mut group than in the wild-type NPM1 gene (NPM1wt) group. The patients were divided according to their mutation status into the NPM1mut/FLT3-ITD (isolated NPM1mut), NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-, and NPM1wt/FLT3-ITD+ (isolated FLT3-ITD+) groups. The isolated NPM1mut group showed significantly better clinical outcomes in terms of relapse rate, 5-year relapse-free survival (RFS), and overall survival (OS) than the other groups. In contrast, the isolated FLT3-ITD+ group had a higher relapse rate and shorter RFS and OS than the other groups. The 5-year RFS rate was much higher among the patients who underwent allogeneic stem cell transplantation (alloSCT) than among those treated with high-dose cytarabine chemotherapy (HDAC) only as consolidation therapy in the isolated NPM1mut group and the NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD- group. CONCLUSION: Adult patients with CN-AML carrying isolated NPM1mut and isolated FLT3-ITD+ exhibit different clinical outcomes than those with NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-. Although isolated NPM1mut leads to favorable clinical outcomes of CN-AML, the role of alloSCT in such patients remains to be considered.

Association with TP53 codon 72 polymorphism and the risk of non-Hodgkin lymphoma.

Polymorphism of TP53 Arg72Pro is associated with many different cancers[1-4]. Few studies have investigated its role in the susceptibility to non-Hodgkin lymphoma (NHL) [5,6]. To examine the association between this polymorphism and NHL risk, we conducted a Korean large-scale, population-based case-control study (945 cases and 1,700 controls). The TP53 72CC genotype was associated with increased risk of NHL (P 5 0.04) and diffuse large B-cell lymphoma (P 5 0.04). Our findings provide evidence that the TP53 Arg72Pro is associated with an increased risk of NHL in Korea.

Fas and FasL polymorphisms are not associated with acute myeloid leukemia risk in Koreans.

Fas and Fas ligand (FasL) polymorphisms in the promoter regions influence transcriptional activities. The interaction of these two genes plays a crucial role in apoptotic cell death regulation. They have been associated with esophageal, lung, uterine cervical, and urinary bladder cancers in human. We performed a case-control study to investigate the association between Fas and FasL polymorphisms and acute myeloid leukemia (AML) risk. Fas−1377G>A (rs2234767), −670T>C (rs1800682), and FasL−844T>C (rs763110) polymorphisms in 592 AML patients and 858 healthy controls were genotyped and tested for associations between polymorphisms and AML risk. There were no significant differences in genotypic and haplotypic distributions and gene-gene interaction between patients and controls in the overall analysis (p>0.05). These results suggested that polymorphisms of Fas and FasL genes were not associated with AML risk in the Korean population.

PARP-1 Val762Ala polymorphism is associated with reduced risk of non-Hodgkin lymphoma in Korean males.

BACKGROUND: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a role in DNA repair, differentiation, proliferation, and cell death. The polymorphisms of PARP-1 have been associated with the risk of various carcinomas, including breast, lung, and prostate. We investigated whether PARP-1 polymorphisms are associated with the risk of non-Hodgkin lymphoma (NHL). METHODS: Subjects from a Korean population consisting of 573 NHL patients and 721 controls were genotyped for 5 PARP-1 polymorphisms (Asp81Asp, Ala284Ala, Lys352Lys, IVS13+118A>G, and Val762Ala) using High Resolution Melting polymerase chain reaction (PCR) and an automatic sequencer. RESULTS: None of the 5 polymorphisms were associated with overall risk for NHL. However, the Val762Ala polymorphism was associated with reduced risk for NHL in males [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.41-0.93 for CC genotype and OR, 0.84; 95% CI, 0.60-1.16 for TC genotype] with a trend toward a gene dose effect (p for trend, 0.02). The Asp81Asp (p for trend, 0.04) and Lys352Lys (p for trend, 0.03) polymorphisms revealed the same trend. In an association study of PARP-1 haplotypes, the haplotype-ACAAC was associated with decreased risk of NHL in males (OR, 0.75; 95% CI, 0.59-0.94). CONCLUSION: The present data suggest that Val762Ala, Asp81Asp, and Lys352Lys polymorphisms and the haplotype-ACAAC in PARP-1 are associated with reduced risk of NHL in Korean males.

Polymorphisms of drug-metabolizing genes and risk of non-Hodgkin lymphoma.

Drug metabolizing genes are involved in the detoxification of chemical carcinogens. Polymorphisms in drug-metabolizing genes affect the risk of some forms of cancer. We analyzed six polymorphisms to evaluate their association with risk for non-Hodgkin lymphoma (NHL), and to examine whether smoking modifies these associations in population-based study in Korea (713 cases and 1,700 controls). The GSTP1 rs1695 AG and the combined AG/GG genotypes were associated with decreased risk of NHL (odds ratio (OR)(AG) = 0.67, 95% confidence interval (CI) = 0.55-0.82; OR(AG/GG) = 0.66, 95% CI = 0.54-0.80) and DLBCL (OR(AG) = 0.63, 95% CI = 0.49-0.82; OR(AG/GG) = 0.64, 95% CI = 0.50-0.82). For T-cell lymphoma, only the combined AG/GG genotype was associated with decreased risk (OR(AG/GG) = 0.65, 95% CI = 0.44-0.96). The CYP1A1 rs1048943 AG genotype and the combined AG/GG genotypes were associated with increased risk of NHL (OR(AG) = 1.28, 95% CI = 1.07-1.54; OR(AG/GG) = 1.26, 95% CI = 1.06-1.51) and DLBCL (OR(AG) = 1.32, 95% CI = 1.04-1.66; OR(AG/GG) = 1.30, 95% CI = 1.03-1.63), but not T-cell lymphoma. Smoking does not modify the association between these polymorphisms and NHL risk. Our data provide evidence that the GSTP1 rs1695 and the CYP1A1 rs1048943 genotypes affect the risk of NHL in Korea.

The role of collagen type I alpha2 polymorphisms: intracranial aneurysms in Koreans.

BACKGROUND: The COL1A2 is located on chromosome 7q22.1, and mutations in this gene have been associated with the development of IAs. In this study, we investigated whether the rs42524 and rs2621215 polymorphisms of the COL1A2 gene are associated with the development of cerebral aneurysms in the Korean population. METHODS: This was a hospital-based case control study conducted at Chonnam University Hospital, Gwangju, Korea. The study population consisted of 320 patients who had been treated for IA and 189 healthy hospital-based controls (angiographically negative for an IA). Two polymorphic loci were amplified by polymerase chain reaction, namely, rs42524 in exon 28 and rs2621215 in intron 46 of the COL1A2 gene, and analyzed by RFLP using HhaI or BfaI restriction enzymes, respectively. RESULTS: The genotype frequencies of rs42524 in cases were 88.0%, 11.4%, and 0.6% for the GG, GC, and CC genotypes, respectively, and in controls were 88.9%, 10.0%, and 1.1%, respectively. Similarly, the genotype frequencies of rs2621515 in cases were 88.0%, 10.1%, and 0.2% for the TT, TG, and GG genotypes, respectively, and among controls were 92.1%, 7.9%, and 0%, respectively. CONCLUSION: The rs2621215 SNP in intron 46 of the COL1A2 gene was found to be marginally associated with an increased risk of IA development in the Korean population examined. In contrast, rs42524 showed no association with an increased risk of IA development.

Enhanced invasiveness of drug-resistant acute myeloid leukemia cells through increased expression of matrix metalloproteinase-2.

The acquired drug resistance as well as extramedullary tissue infiltration of leukemic cells is a major obstacle in leukemia treatment. Excessive egress of leukemia cell blasts results in invasion into various organs or tissues, which is facilitated by the catalytic activities of matrix metalloproteinases (MMPs). However, the migration of chemoresistant leukemia cells remains unclear. Here, we generated drug-resistant variants of the human acute myeloid leukemia cell line (AML-2/WT) by stepwise exposure to anticancer drugs and evaluated the level of MMP-2 in the drug-resistant variants, along with their invasiveness. Each of the drug-resistant cell variants demonstrated predominant increases in the expression and gelatinolytic activity of MMP-2 as well as in invasiveness, which were significantly suppressed by both a MMP-2 inhibitor and a blocking antibody. Knockdown experiments using MMP-2 short hairpin RNA also indicated that its upregulation was strongly associated with the cells' increased invasive properties. Importantly, elevated levels of MMP-2 activity and invasiveness were observed in ex vivo mononuclear cell of bone marrow from patients with poor responses to chemotherapy. These findings suggest that advanced malignancy due to acquired drug resistance is responsible for the progressive invasiveness of leukemia cells via MMP-2.

Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies.

Several genetic polymorphisms in the genes coding folate-metabolizing enzymes have been associated with susceptibility to hematology malignancies. We conducted a Korean population-based case-control study to examine the relationship between the polymorphisms of folate-metabolizing enzymes and the risk of AML (acute myelogenous leukemia), CML (chronic myelogenous leukemia), MDS (myelodyspastic syndrome), and ALL (acute lymphoblastc leukemia). The MTHFR 677TT genotype was associated with an increased risk for ALL (odds ratios (OR)=1.77; 95% confidence intervals (CI)=1.02-3.09, p=.044). The MTRR 66 AG genotype was associated with an increased risk for MDS (OR=1.59; 1.06-2.38, p=.026) and the MTRR 66 GG genotype was associated with increased risk for AML (OR=1.51; 1.03-2.23, p=.037). The TYMS 2R3R genotype was associated with a decreased risk for AML (OR=0.76; 0.60-0.96, p=.022). The TYMS hap3 (2R-6bp) and hap4 (2R-0bp) were associated with decreased risk (OR=0.69; 0.53-0.90, p=.006) and increased risk (OR=1.65; 1.20-2.27, p=.002), respectively for AML. Hap C (677T-1298A) was associated with an increased risk (OR=1.40; 1.02-1.92, p=.04) for ALL. The risk for ALL appears to be associated with the MTHFR 677 polymorphism. The results are supportive of a risk modification by folate polymorphisms in several hematologic malignancies in Korea. The pattern of results suggests that MDS was associated with the DNA methylation status and the risk for AML was associated with both the DNA synthesis and DNA methylation status.