Nan Young Kim

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

Abstract 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.

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; ORAG/GG = 0.66, 95% CI = 0.54–0.80) and DLBCL (ORAG = 0.63, 95% CI = 0.49–0.82; ORAG/GG = 0.64, 95% CI = 0.50–0.82). For T‐cell lymphoma, only the combined AG/GG genotype was associated with decreased risk (ORAG/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 (ORAG = 1.28, 95% CI = 1.07–1.54; ORAG/GG = 1.26, 95% CI = 1.06–1.51) and DLBCL (ORAG = 1.32, 95% CI = 1.04–1.66; ORAG/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. Am. J. Hematol. 2009.

Adverse prognostic effect of homozygous TET2 mutation on the relapse risk of acute myeloid leukemia in patients of normal karyotype.

Mutation in ten-eleven-translocation oncogene family member 2 ( TET2 ) has been extensively investigated in the context of several hematologic malignancies and occurs in 7%–23% of patients with acute myeloid leukemia (AML).[1][1]–[4][2] TET2 acts to demethylate DNA, and TET2 mutations are

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.

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.

Concentrative nucleoside transporter 3 as a prognostic indicator for favorable outcome of t(8;21)-positive acute myeloid leukemia patients after cytarabine-based chemotherapy

Although acute myeloid leukemia (AML) exhibits diverse responses to chemotherapy, patients harboring the t(8;21) translocation are part of a favorable risk group. However, the reason why this subgroup is more responsive to cytarabine-based therapy has not been elucidated. In the present study, we analyzed expression levels of cytarabine metabolism-related genes in patients diagnosed with AML with or without t(8;21) and investigated their correlation with clinical outcomes after cytarabine-based therapy. Among the 8 genes studied, expression of the concentrative nucleoside transporter 3 (CNT3) gene was significantly higher in t(8;21)-positive patients compared to the others in the test population and the validation cohort (P<0.001 in Mann-Whitney U test; P<0.002 in Pearsons correlation analysis). Additionally, in both multivariate and univariate analyses, t(8;21)-positive patients categorized in a higher CNT3 expression tertile had longer disease-free survival [hazard ratio (HR), 0.117; 95% confidence interval (CI), 0.025-0.557; P=0.008] and overall survival (HR, 0.062; 95% CI, 0.007-0.521; P=0.010) compared to t(8;21)-positive patients in a lower CNT3 expression tertile. Notably, these trends did not occur in t(8;21)-negative patients. Our results demonstrate that CNT3 expression is associated with overall favorable outcomes and is predictive of clinical outcomes in AML patients with t(8;21). This suggests that CNT3 expression can be used to optimize treatment strategies for AML patients.

Abstract 143: Global DNA methylation level in whole blood and risk of non-Hodgkin lymphoma

Global DNA hypomethylation may result in chromosomal instability and cancer risk. This study was performed to determine the association between DNA hypomethylation in derived from whole blood and non-Hodgkin lymphoma. We analyzed DNA of 506 NHL and 1680 control subjects at Chonnam National University Hwasun Hospital, Korea. Global DNA methylation levels were assessed using bisulfited-PCR pyrosequencing of long interspersed nuclear element-1 (LINE-1). All participants were subsequently categorized into quartiles by mean % in control. When the highest quartile was considered as a reference category (Q4), the following adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were observed for decreasing methylation quartiles OR (Q3) =2.36 (95% CI:1.40-3.97); OR (Q2) =4.67 (95% CI: 2.89-7.55) and OR (Q1) =17.56 (11.19-27.56). This is, to the best of our knowledge, the first study to show that global DNA hypomethylation was significantly associated with increased for NHL risk in a large case-control study. These findings suggest that global methylation levels in genomic DNA may be play important role in the NHL risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 143.