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Fraser. J Transl Genet Genom 2018;2:21. I https://doi.org/10.20517/jtgg.2018.27 Page 3 of 15

Figure 1. Schematic of androgen-driven ERG expression following TMPRSS2:ERG fusion. Fusion of the 5’ regulatory region of the
TMPRSS2 gene (21q22.3) - including an upstream androgen response element (ARE) - to the coding region of the ERG oncogene (21q22.2)
results in a fusion product in which ERG expression is induced in an androgen-responsive manner. This fusion can be detected using
fluorescence in situ hybridization [28] or indirectly through ERG immunohistochemistry

aberrations, the influence of germline background is highly relevant, as evidenced by the preponderance of
genomic loci linked to the onset and aggression of localized prostate cancer [16-21] .

THE MOLECULAR LANDSCAPE OF PROSTATE CANCER
GRs
The origins of our understanding of the molecular determinants of prostate cancer tumorigenesis and ag-
gression predates the current genomic era. The effectiveness of androgen ablation in the treatment of pros-
[22]
tate cancer has been recognized for decades , and this association strongly (and correctly) suggested a link
[23]
between AR activity and prostate cancer progression . Clinical studies revealed that AR mutations are
common in advanced prostate cancer and arise during the course of ADT [24,25] .

A major breakthrough came with the discovery that the ETS-family oncogene, ERG, is over-expressed in
[26]
a large proportion of primary prostate cancers , and the subsequent finding that this is secondary to an
androgen-dependent GR on chromosome 21q22.2-22.3 that results in a fusion between the 5’ regulatory re-
[27]
gion of the TMPRSS2 gene and the coding region of ERG [Figure 1]. This fusion results from one of two
independent-but-related processes: homozygous deletion of the intervening ~2.8 Mbp between the TMPRSS2
and ERG genes (termed “edel”) or translocation of the intervening region to other chromosomal locations
(termed “esplit”) . These can be distinguished using three-colour fluorescence in situ hybridization (FISH)
[28]
analysis, and edel fusions can also be inferred from copy number loss of the intervening genomic region (see
below).

The TMPRSS2:ERG fusion (T2E) is present in ~45% of all localized prostate cancers, while another ~5%-10%
[29]
harbor a fusion involving other ETS-family proto-oncogenes (e.g., ETV1, ETV4) . Fusion of the TMPRSS2
promoter, which contains a strong ARE, to the 5’ end of ERG leads to androgen-driven ERG overexpression,
which can be detected in clinical specimens by immunohistochemistry against ERG [30,31] . The T2E fusion
is also readily detectable using FISH and qPCR [28,32] . Molecular heterogeneity and subclonality studies have
consistently demonstrated that the T2E fusion is one of the earliest molecular events in prostate tumori-
genesis . Despite this, no clear picture has emerged regarding the precise function of T2E in this regard.
[33]
Moreover, large studies have failed to establish a prognostic effect of T2E for differential clinical outcomes in