Abstract A31: Human prostate cancer transcriptome reveals distinct signaling pathway dysregulations associated with TMPRSS2:ERG fusion

Abstract

Abstract Introduction: The gene rearrangement leading to the fusion of the TMPRSS2 and ERG genes on chromosome 21 occurs in about 50% of prostate cancer cases. TMPRSS2:ERG fusion is believed to contribute to prostate tumorigenesis in mice and has been shown to be associated with aggressive disease in patients with prostate cancer. However, the molecular mechanisms driving the clinical aggressivity of fusion-positive prostate cancer remain unknown. Hypothesis: We postulate that dissecting the molecular events taking place in prostate tumors with or without ERG fusion might lead to the discovery of novel targets for prostate cancer therapy. Methods: RNA was purified from benign (n=8) and malignant (n=13) human prostate specimens. Malignant specimens were previously tested for the occurrence of ERG fusion and included 6 fusion(+) and 7 fusion(−) samples. We performed gene expression profiling using cDNA microarrays, and conducted in silico analysis of gene expression data, followed by detailed canonical pathway analysis and regulatory network identification. Results: Gene expression data revealed differential expression of 3039 genes in fusion positive cancer, while only 2386 genes were differentially expressed in fusion negative cancer. Among these genes, 1096 were differentially expressed regardless of the fusion status of the tumor. Pathway analysis performed on differentially expressed genes showed that fusion positive tumors showed the highest impact occurred on genes classified in the Nitric Oxide Signaling in the Cardiovascular System Pathway and the Cardiac β-Adrenergic Signaling Pathway, while the most impacted pathways in the fusion negative tumors were the Ephrin Receptor Signaling Pathway and the Fatty Acid Biosynthesis Pathway. Conclusion: TMPRSS2:ERG gene fusion highlights a distinct molecular subtype of prostate cancer. A better understanding of the molecular consequences of the fusion will lead to the identification of new molecular targets for diagnosis and therapy of prostate cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A31.