Dataset Information

DAC for Duke-NUS genomic sequencing projects

ABSTRACT: Data Access Committee EGAC00001000256

PROVIDER: EGAC00001000256 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Mutation signatures implicate aristolochic acid in bladder cancer development.

Poon Song Ling SL Huang Mi Ni MN Choo Yang Y McPherson John R JR Yu Willie W Heng Hong Lee HL Gan Anna A Myint Swe Swe SS Siew Ee Yan EY Ler Lian Dee LD Ng Lay Guat LG Weng Wen-Hui WH Chuang Cheng-Keng CK Yuen John Sp JS Pang See-Tong ST Tan Patrick P Teh Bin Tean BT Rozen Steven G SG

Genome medicine 20150428 1

<h4>Background</h4>Aristolochic acid (AA) is a natural compound found in many plants of the Aristolochia genus, and these plants are widely used in traditional medicines for numerous conditions and for weight loss. Previous work has connected AA-mutagenesis to upper-tract urothelial cell carcinomas and hepatocellular carcinomas. We hypothesize that AA may also contribute to bladder cancer.<h4>Methods</h4>Here, we investigated the involvement of AA-mutagenesis in bladder cancer by sequencing blad ...[more]

PMID: 26015808

Publication: 1/2

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Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.

Dataset Information

DAC for Duke-NUS genomic sequencing projects

Publications

Mutation signatures implicate aristolochic acid in bladder cancer development.

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