ETS Fusion Genes in Prostate Cancer

Abstract

In 2005, we reported the discovery of recurrent chromosomal rearrangements resulting in the fusion of the 5′ untranslated region of an androgen regulated gene, TMPRSS2, with members of the ETS transcription factor family (ERG or ETV1). After nearly a decade, enormous progress has been made in understanding the diversity of ETS gene fusions, their genesis, and oncogenic roles in vitro and in vivo. Similarly, ETS gene fusions provide a rational basis for the comprehensive molecular subtyping of prostate cancer, especially in light of recently described co-­occurring or mutually exclusive genetic events, which may have utility in risk prediction as well as therapeutic targeting. Given their remarkable cancer specificity, ETS gene fusions have enormous potential as biomarkers, and clinical translation is ongoing. We discuss the utility of ETS gene fusions for both tissue based diagnosis, risk stratification of precursor lesions, and early detection. Similarly, given the attention on distinguishing “aggressive” from indolent prostate cancer, we have reviewed the potential of ETS gene fusions in this context and focus on the important caveats required to interpret such studies, including the ETS gene fusion detection method, the clinical cohort characteristics, and how aggressiveness and outcome are determined. Importantly, these factors are important not just for evaluating ETS fusions, but all prostate cancer biomarkers. Lastly, as the most prostate cancer-­specific biomarker yet reported, we review the potential of ETS gene fusions as both indirect and direct therapeutic targets.