|Abstract||Pancreatic cancer is a highly aggressive malignancy with poor prognosis because of the late disease stage at diagnosis. A comprehensive analysis of DNA amplifications was undertaken to identify genes involved in pathogenesis of pancreatic carcinoma which can potentially serve as diagnostic markers and drug targets for this dismal disease.
Initially, 26 fresh frozen primary pancreatic carcinomas were profiled by matrix-CGH with a spatial resolution of 2 Mb across the whole genome. Thus, 50 commonly amplified regions (CARs) were identified; they were covered by 1,113 contiguous genomic DNA clones on the newly-developed 1.1k contig chip. High-resolution profiles of 42 fresh frozen primary pancreatic tumors narrowed the 50 CARs down to 55 recurrent amplifications containing 60 minimal CARs (MCARs) and allowed the identification of target genes that might confer a selective advantage on the tumor. Furthermore, transcription profiles of six pancreatic ductal adenocarcinomas were created with the Affymetrix HG-U133 Plus 2.0 platform. The superimposition of genomic and transcription profiles revealed that 280 and 48 of 1474 overexpressed genes were enriched in recurrent amplifications and MCARs, respectively, thus emphasizing the contribution of genomic instability to disease formation.
Quantitative RT-PCR verification and functional in vitro characterization led to a set of novel candidate oncogenes comprising CD14, COL1A1, COL5A1, COL6A3, CORO1A, CTSK, DOK5, ECM1, EMILIN1, FPR1, HCK, MMP9, NUSAP1, PLAUR, S100A9, SPON2, SULF2, TSPAN2, TUBA1B and TUBA1C. The results demonstrate a strong influence of tumor cells on the composition of the extracellular matrix and an enhanced reaction to those changes by overexpression of certain surface molecules and downstream associated proteins. Furthermore, also structural and regulatory components of the actin and tubulin cytoskeleton contribute significantly to the increase of migration, invasion and proliferation of tumor cells.||dc.description.abstract