E.E.T.-Pipeline

European Embryonal Tumor Pipeline

 

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© 2007

Freund/OncoLab

 

The group

Our neuroblastoma research group in the Center for Medical Genetics in Ghent (http://medgen.ugent.be) focuses on the identification of genes and pathways that are implicated in the pathogenesis of neuroblastoma. Through a combined approach of high throughput genome, transcriptome, epigenome and microRNAome analyses, we aim to identify aberrant genes and pathways perturbed in neuroblastoma. Unravelling these pathways is crucial for understanding neuroblastoma pathogenesis and subsequent identification of molecular therapeutic targets. Equally important is the further search for signatures and markers for improved therapeutic prognostic stratification and selection of patients for future clinical trials for assessment of innovative treatment protocols.
 The past years, we have made significant contributions to the characterisation of genomic alterations in neuroblastoma. Molecular cytogenetic studies revealed 17q gain as the most frequent chromosomal alteration in neuroblastoma which was subsequently recognised as strongest independent prognostic factor. In addition, we identified a new genetic subgroup in neuroblastoma characterised by single copy MYCN status and presence of 11q deletion. Recently, this work was extended using high resolution genomic profiling (arrayCGH) leading to refined genomic classification and more accurate delineation of critical regions in neuroblastoma.   Our group also has gained internationally recognised expertise in real-time quantitative gene expression analysis, and was first to achieve the gene expression profile of the neuroblastoma progenitor cells, i.e. the foetal adrenal neuroblasts. Ongoing research is focussed on combining these unique genomic and expression data in the search for key genes implicated in neuroblastoma oncogenesis, and the search and validation of MYCN transcriptional target genes. Given the fact that altered gene expression can also result from epigenetic modifications, we initiated genome wide studies unravelling the nature and consequences of aberrant DNA methylation and chromatin modification in neuroblastoma. As mentioned above, one of our primary goals is the identification of new therapeutic targets for neuroblastoma. Recent studies provided promising in vitro data for anti-tumour activity of nutlin-3 in neuroblastoma cells. This new small molecule acts as an MDM2 inhibitor which leads to reactivation of TP53 in TP53 intact tumours, leading to massive apoptosis.

 

Our role in EET-Pipeline

Detection of genomic copy number changes of embryonal tumours selected from the Virtual EET-BioBank will be performed using high-resolution arrayCGH. For this purpose, we will provide our extensive expertise in the design and analysis of arrayCGH. Extensively validated protocols will be used and data will be analysed and visualised with an in-house developed database (http://medgen.ugent.be/arrayCGHbase).
These whole genome arrayCGH profiles will help us to define chromosomal regions with prognostic and diagnostic relevance in the different embryonal tumour entities. Based on these data, we will construct MLPA (multiplex ligation-dependent probe amplification) assays to detect the typical copy number changes in embryonal tumours. The MPLA technology is increasingly being used nowadays for the detection of copy number alterations in several genetic diseases. In addition, dedicated mini-BAC arrays will be constructed, validated and compared with the MLPA method for the detection of the typical aberrations.
In parallel, we will evaluate the feasibility of the novel absolute quantification (AQUA) method for peptide quantification in complex protein mixtures form cultured cell media and cancer patient sera. For this purpose five serum proteins relevant for diagnostic test development will be identified and included in the AQUA test.

 

Staff Member

 

Top 5 publications

1. Hoebeeck J, Michels E, Menten B, Van Roy N, Eggert A, Schramm A, De Preter K, Yigit N, De Smet E, De Paepe A, Laureys G, Vandesompele J, Speleman F.   Related Articles, Links Abstract High resolution tiling-path BAC array deletion mapping suggests commonly involved 3p21-p22 tumor suppressor genes in neuroblastoma and more frequent tumors. Int J Cancer. 2007; 120(3):533-8.

2. Van Maerken T, Speleman F, Vermeulen J, Lambertz I, De Clercq S, De Smet E, Yigit N, Coppens V, Philippe J, De Paepe A, Marine JC, Vandesompele J. Related Articles, Links Abstract Small-Molecule MDM2 Antagonists as a New Therapy Concept for Neuroblastoma. Cancer Res. 2006; 66(19):9646-55.

3. De Preter K, Vandesompele J, Heimann P, Yigit N, Beckman S, Schramm A, Eggert A, Stallings RL, Benoit Y, Renard M, De Paepe A, Laureys G, Pahlman S, Speleman F. Related Articles, Links Free in PMC Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes. Genome Biol. 2006;7(9):R84. Erratum in: Genome Biol. 2007; 8(1):401.

4. Vandesompele J, Baudis M, De Preter K, Van Roy N, Ambros P, Bown N, Brinkschmidt C, Christiansen H, Combaret V, Lastowska M, Nicholson J, O'Meara A, Plantaz D, Stallings R, Brichard B, Van den Broecke C, De Bie S, De Paepe A, Laureys G, Speleman F. Related Articles, Links Abstract Unequivocal delineation of clinicogenetic subgroups and development of a new model for improved outcome prediction in neuroblastoma. J Clin Oncol. 2005; 23(10):2280-99. 

5. Bown N, Cotterill S, Lastowska M, O'Neill S, Pearson AD, Plantaz D, Meddeb M, Danglot G, Brinkschmidt C, Christiansen H, Laureys G, Speleman F, Nicholson J, Bernheim A, Betts DR, Vandesompele J, Van Roy N. Related Articles, Links Free Full Text Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med. 1999; 340 (25):1954-61.