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Identification of Chromosomal Regions That Harbor Novel Genes Important for Pancreatic Cancer Pathogenesis By Genome-Wide Screening Methods
Sabrina Thieltges*1, Tanya Kalinina1, Ronald Simon2, Maximilian Bockhorn1, Emre F. Yekebas1, Jakob R. Izbicki1
1Department of General-, Visceral- and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 2Department of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
Background: Pancreatic adenocarcinoma is a genetically highly complex and heterogenous tumor type with strong genetic instability which makes it resistant to therapy. Known amplifications of oncogenes such as KRAS or MYC and deletions of tumor suppresor genes such as CDKN2A and SMAD4 have demonstrated the importance of genetic alteration in this tumor type. Methods: We report the use of an Affymetrix Genome-Wide Human single nucleotide polymorphism (SNP) Array 6.0 (906,600 SNPs) to screen for gene copy number changes and allelic imbalances in 8 microdissected primary pancreatic tumors and 7 established pancreatic cancer cell lines. The Gene Chip Human Genome U133 2.0 Array served for RNA expression profiling. Mutation analysis of KRAS and M-FISH analysis of cell lines was performed. Results: SNP arrays confirmed the presence of previously reported cytogenetic abnormalities in the cell lines and primary tumor probes, including MYC amplifikation at 8q24, gain of 17q12 (ERBB2/HER2), 7p12 (EGFR) and 12p12.1 (KRAS). KRAS mutation was found in 5 from 7 cell lines. We identified several alterations in signaling pathways such as Wnt/Notch Signaling and KRAS signaling. Approximately half of the cell line samples (7/15) showed an amplikon at 19q13.1-13.2 in which the serine/threonine kinase Mirk/Dyrk1B is localized, a downstream effector of oncogenic KRAS. There was also strong concordance between primary tumors and cell lines with respect to gains on 8q, 12p and 18q. Analysis of gene expression was used to localize potential target genes. M-FISH analysis showed chromosome rearrangements such as 9p- and 18q-, regions that are known to harbor tumor suppressor genes (CDKN2A, SMAD4 and TP53). Conclusions: Several signaling pathways mediate tumor cell survival. Analysis of gene amplification and RNA expression profile provide molecular biological characteristics and an individual gene sinature of the tumor which allow us to choose more efficient drugs to an individualized treatment. Pathways activated by KRAS such as DYRK1B may offer new therapeutic targets. Further functional characterization is needed to provide evidence for the actual role of any putative target gene.
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