Recurrent gene fusions in prostate cancer

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Abstract
Approximately 50% of prostate cancers from serum prostate-specific antigen (PSA)-screened cohorts harbour recurrent gene fusions. The gene fusions in prostate cancer are characterized by 5′ genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors. TMPRSS2–ERG is the most common gene fusion, present in about half of all localized prostate cancers analysed. TMPRSS2 also fuses to other Ets family genes such as ETV1, ETV4 and ETV5 in a small percentage of prostate cancers. ETV1, ETV4 and ETV5 have additional 5′ fusion partners that differ in their prostate specificity and response to androgen. Many Ets gene fusion transcript variants have been identified with different 5′ and 3′ partner sequences, probably with prognostic and/or diagnostic implications. Prostate cancers harbouring TMPRSS2–ERG gene fusion display characteristic morphological features of prostate cancers, such as macronucleoli and intraductal tumour spread as well as rare blue-tinged mucin, cribriform growth pattern and signet-ring cell. ERG overexpression imparts invasiveness to prostate cells in vitro and induces plasminogen activation and matrix metalloproteinase pathways. Ets gene fusion-positive and Ets gene fusion-negative prostate cancers have distinct chromosomal aberrations, expression signatures, morphological features and clinical outcomes, suggesting that they are fundamentally different classes of prostate cancer. Sensitive and specific diagnostic tests and targeted therapeutics will affect the detection and management of Ets-positive prostate cancer.