SummaryPolymorphisms in the genes coding folate-metabolizing enzymes affect the risk of some forms of cancer. We investigated the association between these polymorphisms and non-Hodgkin lymphoma (NHL) risk in a populationbased study (583 cases and 1700 controls). The MTHFR 677TT and CT genotypes were associated with reduced risk for NHL [odds ratios (OR) = 0AE79; 95% confidence intervals (CI) = 0AE65-0AE98 for 677CT and 0AE61; 0AE45-0AE82 for 677TT] and diffuse large B-cell lymphoma (DLBCL) (OR = 0AE68; 0AE51-0AE88 for 677CT; OR = 0AE56; 0AE38-0AE83 for 677TT). The MTHFR 1298CC genotype was associated with increased risk for NHL (OR = 1AE71; 1AE07-2AE75) and T-cell lymphoma (OR = 3AE05; 1AE53-6AE11). The MTRR 66GG genotype was associated with increased risk for DLBCL (OR = 1AE56; 1AE03-2AE38) and the TYMS 2R2R genotype was associated with increased risk for T-cell lymphoma (OR = 2AE83; 1AE33-6AE01). Using subjects with 3RG3RG as a reference group, TYMS 2R2R was associated with increased risk for T-cell lymphoma (OR = 2AE46; 1AE04-5AE79). Interestingly, we observed a reduced association between the TYMS 2R3RG genotype and DLBCL (OR = 0AE61; 0AE38-0AE99). These results suggest that MTHFR, MTRR and TYMS polymorphisms may play a significant role in the risk for NHL.

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.

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.

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.

No abstract