Dataset Information

Down syndrome Data Access Committee (DS-DAC)

ABSTRACT: Data Access Committee EGAC01000000023

PROVIDER: EGAC01000000023 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.

Sailani M Reza MR Makrythanasis Periklis P Valsesia Armand A Santoni Federico A FA Deutsch Samuel S Popadin Konstantin K Borel Christelle C Migliavacca Eugenia E Sharp Andrew J AJ Duriaux Sail Genevieve G Falconnet Emilie E Rabionet Kelly K Serra-Juhé Clara C Vicari Stefano S Laux Daniela D Grattau Yann Y Dembour Guy G Megarbane Andre A Touraine Renaud R Stora Samantha S Kitsiou Sofia S Fryssira Helena H Chatzisevastou-Loukidou Chariklia C Kanavakis Emmanouel E Merla Giuseppe G Bonnet Damien D Pérez-Jurado Luis A LA Estivill Xavier X Delabar Jean M JM Antonarakis Stylianos E SE

Genome research 20130619 9

Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS with ...[more]

PMID: 23783273

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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

Down syndrome Data Access Committee (DS-DAC)

Publications

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome.

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