Dataset Information

DAC University of Cologne

ABSTRACT: Data Access Committee EGAC00001000064

OTHER RELATED OMICS DATASETS IN: PXD006006

PROVIDER: EGAC00001000064 | EGA |

REPOSITORIES: EGA

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Publications

Comprehensive genomic profiles of small cell lung cancer.

George Julie J Lim Jing Shan JS Jang Se Jin SJ Cun Yupeng Y Ozretić Luka L Kong Gu G Leenders Frauke F Lu Xin X Fernández-Cuesta Lynnette L Bosco Graziella G Müller Christian C Dahmen Ilona I Jahchan Nadine S NS Park Kwon-Sik KS Yang Dian D Karnezis Anthony N AN Vaka Dedeepya D Torres Angela A Wang Maia Segura MS Korbel Jan O JO Menon Roopika R Chun Sung-Min SM Kim Deokhoon D Wilkerson Matt M Hayes Neil N Engelmann David D Pützer Brigitte B Bos Marc M Michels Sebastian S Vlasic Ignacija I Seidel Danila D Pinther Berit B Schaub Philipp P Becker Christian C Altmüller Janine J Yokota Jun J Kohno Takashi T Iwakawa Reika R Tsuta Koji K Noguchi Masayuki M Muley Thomas T Hoffmann Hans H Schnabel Philipp A PA Petersen Iver I Chen Yuan Y Soltermann Alex A Tischler Verena V Choi Chang-min CM Kim Yong-Hee YH Massion Pierre P PP Zou Yong Y Jovanovic Dragana D Kontic Milica M Wright Gavin M GM Russell Prudence A PA Solomon Benjamin B Koch Ina I Lindner Michael M Muscarella Lucia A LA la Torre Annamaria A Field John K JK Jakopovic Marko M Knezevic Jelena J Castaños-Vélez Esmeralda E Roz Luca L Pastorino Ugo U Brustugun Odd-Terje OT Lund-Iversen Marius M Thunnissen Erik E Köhler Jens J Schuler Martin M Botling Johan J Sandelin Martin M Sanchez-Cespedes Montserrat M Salvesen Helga B HB Achter Viktor V Lang Ulrich U Bogus Magdalena M Schneider Peter M PM Zander Thomas T Ansén Sascha S Hallek Michael M Wolf Jürgen J Vingron Martin M Yatabe Yasushi Y Travis William D WD Nürnberg Peter P Reinhardt Christian C Perner Sven S Heukamp Lukas L Büttner Reinhard R Haas Stefan A SA Brambilla Elisabeth E Peifer Martin M Sage Julien J Thomas Roman K RK

Nature 20150713 7563

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We dis ...[more]

PMID: 26168399

Publication: 1/5

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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 of Cologne

Publications

Comprehensive genomic profiles of small cell lung cancer.

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