Oncogenic gene fusions in epithelial carcinomas - PubMed (original) (raw)

Review

Oncogenic gene fusions in epithelial carcinomas

John R Prensner et al. Curr Opin Genet Dev. 2009 Feb.

Abstract

New discoveries regarding recurrent chromosomal aberrations in epithelial tumors have challenged the view that gene fusions play a minor role in these cancers. It is now known that recurrent fusions characterize significant subsets of prostate, breast, lung and renal-cell carcinomas, among others. This work has generated new insights into the molecular subtypes of tumors and highlighted important advances in bioinformatics, sequencing, and microarray technology as tools for gene fusion discovery. Given the ubiquity of tyrosine kinases and transcription factors in gene fusions, further interest in the potential 'druggability' of gene fusions with targeted therapeutics has also flourished. Nevertheless, the majority of chromosomal abnormalities in epithelial cancers remain uncharacterized, underscoring the limitations of our knowledge of carcinogenesis and the requirement for further research.

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Figures

Figure 1. Biochemical Pathways in Gene Fusions

Biochemical effects of gene fusions cluster around tyrosine kinase (TK) signaling pathways, which alter the activity of intracellular proteins, and transcription factor (TF) activity, which control gene expression at the DNA level. Here we outline the examples of the Ras and PI-3K pathways, which are commonly involved downstream of TK activation and are frequently implicated in the oncogenic effects of gene fusions. PI-3K works via increased activity of the master regulator Akt, which controls many cellular processes including the nuclear TF NfκB. Likewise, the Ras-Raf-Mek-Erk pathway promotes activation of TFs, including Elk-1, which is a target of Erk. These signaling pathways and gene expression signatures result in the phenotypic qualities, such as invasiveness and increased proliferation, observed in cancers.

Figure 2. Gene Fusion Discovery and Targeted Therapy

Bioinformatic, sequencing and microarray methods are powerful tools for identifying potential gene fusions in epithelial cancers. By determining the genomic and transcriptomic events in human cancers, clinical management of the disease may be impacted, and gene fusions, such as the TMPRSS2-Ets fusions in prostate cancer, may serve as prominent therapeutic targets. If targeted therapeutics are successfully developed for critical oncogenes, clinical management of cancer may one day be determined based upon genetic evaluation of patient tumors.

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Oncogenic gene fusions in epithelial carcinomas - PubMed (original) (raw)