Dataset Information

Molecular and Population Genetics (MPG) research at ICR DAC and POLA DAC

ABSTRACT: Data Access Committee EGAC00001000328

PROVIDER: EGAC00001000328 | EGA |

REPOSITORIES: EGA

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Publications

TCF12 is mutated in anaplastic oligodendroglioma.

Labreche Karim K Simeonova Iva I Kamoun Aurélie A Gleize Vincent V Chubb Daniel D Letouzé Eric E Riazalhosseini Yasser Y Dobbins Sara E SE Elarouci Nabila N Ducray Francois F de Reyniès Aurélien A Zelenika Diana D Wardell Christopher P CP Frampton Mathew M Saulnier Olivier O Pastinen Tomi T Hallout Sabrina S Figarella-Branger Dominique D Dehais Caroline C Idbaih Ahmed A Mokhtari Karima K Delattre Jean-Yves JY Huillard Emmanuelle E Mark Lathrop G G Sanson Marc M Houlston Richard S RS

Nature communications 20150612

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, w ...[more]

PMID: 26068201

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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

Molecular and Population Genetics (MPG) research at ICR DAC and POLA DAC

Publications

TCF12 is mutated in anaplastic oligodendroglioma.

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