Dataset Information

DAC University Hospital Cologne

ABSTRACT: Data Access Committee EGAC00001000361

PROVIDER: EGAC00001000361 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

Peifer Martin M Hertwig Falk F Roels Frederik F Dreidax Daniel D Gartlgruber Moritz M Menon Roopika R Krämer Andrea A Roncaioli Justin L JL Sand Frederik F Heuckmann Johannes M JM Ikram Fakhera F Schmidt Rene R Ackermann Sandra S Engesser Anne A Kahlert Yvonne Y Vogel Wenzel W Altmüller Janine J Nürnberg Peter P Thierry-Mieg Jean J Thierry-Mieg Danielle D Mariappan Aruljothi A Heynck Stefanie S Mariotti Erika E Henrich Kai-Oliver KO Gloeckner Christian C Bosco Graziella G Leuschner Ivo I Schweiger Michal R MR Savelyeva Larissa L Watkins Simon C SC Shao Chunxuan C Bell Emma E Höfer Thomas T Achter Viktor V Lang Ulrich U Theissen Jessica J Volland Ruth R Saadati Maral M Eggert Angelika A de Wilde Bram B Berthold Frank F Peng Zhiyu Z Zhao Chen C Shi Leming L Ortmann Monika M Büttner Reinhard R Perner Sven S Hero Barbara B Schramm Alexander A Schulte Johannes H JH Herrmann Carl C O'Sullivan Roderick J RJ Westermann Frank F Thomas Roman K RK Fischer Matthias M

Nature 20151014 7575

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affectin ...[more]

PMID: 26466568

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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 University Hospital Cologne

Publications

Telomerase activation by genomic rearrangements in high-risk neuroblastoma.

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