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Identification, structural and functional characterisation of disease genes in pancreatic cancer

Objectif



Pancreatic cancer is the fifth cause of cancer related deaths in industrialised countries, with a dismal prognosis, an increasing incidence and no or only ineffective means of treatment. It represents thus a health problem with a major socio-economic impact. The development of new treatment modalities, diagnostic and preventive approaches require the understanding of the molecular mechanisms of the complex multi step process of tumour genesis in the pancreas. During the past years members of the concerted action (CA) have used a variety of techniques to detect genetic alterations occurring at the levels of genomic DNA and of RNA in pancreatic cancer cells. Using a combination of automated molecular cDNA library technology and differential hybridisations hundreds of genes with pancreatic cancer specific gene expression were identified. Approximately 50% of these sequences were homologous to known genes, which allowed providing for the first time a pancreatic-cancer specific expression profile. In addition around 250 novel genes with cancer-specific expression were identified. Several members of the CA have finalized projects aimed at identifying chromosomal alterations occurring in pancreatic cancer. One group participated in the application of a strategy to identify chromosomal areas of allelic loss based on allelo typing of pancreatic cancer nude mice xenografts, which finally led to the detection of a new tumour suppressor gene denominatedDPC4 (Deleted in Pancreatic Cancer) located at chromosome 18q21.1.

Additional data concerning chromosomal aberrations in pancreatic cancer has been generated by members of the CA using techniques as AP-PCR (arbitrarily-primed PCR) and CGH (comparative genomic hybridisation). To summarize, the members of the CA have identified a large number of genes with pancreatic cancer specific expression and chromosomal areas amplified or deleted in pancreatic cancer. At present members of the CA are involved in the isolation of the genes contained in these aberrations. Differentially expressed genes and genes from chromosomal aberrations represent potential disease-associated genes or disease genes asegoncogenes or tumour suppressor genes. It will be the main task of this concerted action to device procedures allowing to use this selection of candidate disease genes to identify respectively select genes associated with processes relevant for cancer genesis in the pancreas as e.g. tumour cell proliferation, differentiation, metastasis and invasion. In addition, specific strategies and technologies will be developed and applied allowing a structural and functional characterization of these genes. Selected genes will be tested for the usefulness as therapeutic and diagnostic tools in experimental models. As no single laboratory will be able to accomplish these goals alone, we will combine the efforts of ontological and basic molecular and cytogenetic research laboratories in a European Network allowing the combined use of resources and facilities, exchange of scientific expertise and the exchange of personnel for scientific training.

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Coordinateur

UNIVERSITY OF ULM
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Adresse
8,Robert-Koch-Strasse 8
89081 Ulm
Allemagne

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