Dataset Information

DAC for Tuebingen-Stuttgart cohort

ABSTRACT: Data Access Committee EGAC00001000317

PROVIDER: EGAC00001000317 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.

Winter Stefan S Fisel Pascale P Büttner Florian F Rausch Steffen S D'Amico Debora D Hennenlotter Jörg J Kruck Stephan S Nies Anne T AT Stenzl Arnulf A Junker Kerstin K Scharpf Marcus M Hofmann Ute U van der Kuip Heiko H Fend Falko F Ott German G Agaimy Abbas A Hartmann Arndt A Bedke Jens J Schwab Matthias M Schaeffeler Elke E

Scientific reports 20160720

Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigat ...[more]

PMID: 27435027

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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 Tuebingen-Stuttgart cohort

Publications

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.

Similar Datasets

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