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.
The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours. Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of haematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5′ genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors, leading to the overexpression of oncogenic transcription factors. Ets gene fusions probably define a distinct class of prostate cancer, and this might have a bearing on diagnosis, prognosis and rational therapeutic targeting.
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We apologize to all the authors whose work could not be included in this manuscript owing to space constraints. We thank J. Granger for her scientific editorial assistance. We thank R. Mehra, N. Palanisamy, and S. M. Dhanasekaran for useful discussions. We thank R. Kunkel for help with the artwork for figures. This work was supported in part by Department of Defense, the National Institutes of Health, the Early Detection Research Network, and the Prostate Cancer Foundation grants to A.M.C. A.M.C. is supported by a Clinical Translational Research Award from the Burroughs Wellcome Foundation. S.A.T. is a Fellow of the Medical Scientist Training Program and is supported by the GPC Biotech Young Investigator Award from the Prostate Cancer Foundation.
The University of Michigan has filed for a patent on the recurrent gene fusions in prostate cancer and S.A.T. and A.M.C. are named as co-inventors. The technology has been licensed to Gen-Probe Inc. to developed a molecular diagnostic. A.M.C. is a consultant to Gen-Probe.
National Cancer Institute
National Cancer Institute Drug Dictionary
- Androgen ablation
A core prostate cancer treatment modality that involves severing androgen signalling in prostate cancer either by physical means (castration) or biochemically (by injecting oestrogens, anti-androgens, or androgen receptor agonists or antagonists). Charles Huggins was awarded the Nobel Prize in Physiology or Medicine in 1966 for this development in 1941.
The E26 transformation-specific family of genes encode nuclear transcription factors, characterized by DNA-binding Ets domains and various protein interaction domains. Ets family proteins are involved in cell growth, signal transduction, cell cycle regulation, apoptosis, haematopoietic, neuronal and myogenic differentiation, and in several human malignancies, such as Ewing tumours, leukaemias and prostate cancer.
- Gene fusion
A physical linking of two genes (typically accompanied by deletion of portions of the two partner genes) such that they come to share a common regulatory element and/or open reading frames, the latter encoding chimeric proteins, for example BCR–ABL1 or TMPRSS2–ERG.
- Prostatic intraepithelial neoplasia
(PIN). This defines foci of rapidly dividing prostate epithelial cells, believed to be the precursor of prostate cancer. PINs are typically classified as high-grade, medium-grade and low-grade, depending on their level of differentiation. Approximately one-third of men with high-grade PIN develop prostate cancer.
- Interstitial deletion
Loss of material from within a chromosome, not involving the ends (telomeres).
- Molecular Concepts Map
(MCM). Gene expression signatures of sets of biologically connected genes, such as 'lipid biosynthesis genes' or 'androgen-activated genes'. have been defined as 'molecular concepts'. Over 40,000 such concepts have been compiled in Oncomine. The MCM involves interrogating a set of user-defined genes (such as an expression signature or genes identified in a functional screen) against all concepts in the MCM to identify molecular networks enriched in the query set.
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Kumar-Sinha, C., Tomlins, S. & Chinnaiyan, A. Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8, 497–511 (2008). https://doi.org/10.1038/nrc2402
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