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Page 2 of 15 Fraser. J Transl Genet Genom 2018;2:21. I https://doi.org/10.20517/jtgg.2018.27
[1]
populations . Localized prostate cancer is triaged into groups that largely define treatment options, risk of
disease progression and prostate cancer-specific mortality (PCSM). These risk groups (i.e., low, intermediate,
high) are based primarily on three clinical prognostic factors: serum PSA concentration, Gleason/Inter-
[2]
national Society for Urological Pathology grade of the tumour biopsy, and clinical TNM stage . Low risk
disease can usually be effectively managed through active surveillance. Intermediate risk prostate cancer is
generally treated with curative-intent radical prostatectomy or image-guided radiotherapy (IGRT; external-
beam and/or high dose-rate brachytherapy), while high risk disease is managed with IGRT and (neo)adju-
[3]
vant androgen-deprivation therapy (ADT) or radical prostatectomy, with or without adjuvant IGRT .

Despite these prognostic factors, clinical outcomes are highly heterogeneous across the risk spectrum. For
example, 20%-25% of men on active surveillance for low risk prostate cancer will experience clinical or
[4]
pathological progression, necessitating definitive therapy . Similarly, 10%-15% and 30%-40% of men with
intermediate or high-risk prostate cancer, respectively, will experience disease recurrence within 3 years fol-
[5]
lowing curative-intent therapy, portending a lethal clinical course . As such, current prognostic factors do
not accurately define the risk of disease progression for an individual man with prostate cancer. There is,
therefore, an urgent need to define novel prognostic and predictive biomarkers to inform precision medicine
protocols for localized prostate cancer. Such biomarkers would allow for more appropriate pre-treatment tri-
age, thus reducing over-treatment of indolent prostate cancer and intensifying treatment for men at high risk
for progression to potentially-lethal metastatic disease.

THE PROSTATE GLAND
The prostate is an androgen-dependent tissue, involved in normal reproductive function. Chemical or physi-
cal castration of mice results in complete regression of the prostate, which is rescued by exogenous andro-
[6]
gen . Testosterone is primarily synthesized from cholesterol in the Leydig cells of the testis (a small amount
is synthesized in the adrenal gland), and is converted to 5-alpha-dihydrotestosterone (DHT) in androgen-
responsive tissues such as the prostate. DHT has a 2-5-fold higher affinity for the androgen receptor (AR)
and a 10-fold higher effect on AR-induced gene expression than testosterone. AR is a prototypical steroid
hormone receptor, which, when bound by androgen, translocates into the nucleus and interacts with andro-
gen-responsive elements (ARE) in the promoter and enhancer regions of target genes such as TMPRSS2 and
[7]
KLK3, which promote proliferation and survival of prostate epithelial cells .

GENOMIC DRIVERS OF PROSTATE CANCER TUMORIGENESIS AND PROGRESSION
An understanding of the molecular features of prostate cancer requires dissection of the differential biol-
ogy of primary, treatment-naïve, potentially-curable localized disease vs. incurable metastatic, castration-
resistant prostate cancer (mCRPC) that has evolved in the context of multiple rounds of ADT. Primary pros-
[8]
tate cancer is a C-class tumor , characterized by a paucity of driver single-nucleotide variants (SNVs) with
recurrent driver structural variants, including DNA copy number aberrations (CNAs) and genomic rear-
rangements (GRs) [9-11] . Conversely, mCRPC is associated with increased genomic instability and mutational
burden, and with enrichment of gene mutations which drive androgen-independent growth and metastatic
dissemination [12-14] . This review will focus upon genomic aberrations associated with localized, potentially-
curable disease, with a particular emphasis on molecular aberrations that define novel disease subtypes and
clinically-relevant biomarkers of aggressive localized disease. While epigenomic aberrations are highly rel-
evant driver events in localized prostate cancer and may have substantial value within prognostic signatures,
a detailed discussion of prostate cancer epigenomics is beyond the scope of this review, which will focus pre-
dominantly on genomic aberrations that result in changes in DNA sequence or structure. Similarly, cancer
evolves in the context of unique germline genotypes, which can fundamentally alter tumour somatic pheno-
types and aggression; a classic example is the unique somatic molecular profile of aggressive prostate cancer
[15]
in men harbouring a germline mutation in the BRCA2 gene . While this review will focus on somatic