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Page 2 of 12 Lorenzin et al. J Transl Genet Genom 2019;3:5. I https://doi.org/10.20517/jtgg.2019.01

and genetically heterogeneous disease. Although the 5-year relative survival rate of patients diagnosed with
localized disease is higher than 99%, a minority of patients progress to an aggressive form with metastasis
[1]
spreading and high mortality .
At disease initiation, PCa relies on the androgen receptor (AR) signaling pathway for growth. Hence, the
mainstay of therapy for PCa is represented by androgen deprivation therapy (ADT) as initially described
[2,3]
by landmark work of Charles Huggins and colleagues in 1941 . At recurrence upon prostatectomy
or radiotherapy, ADT usually involves ablation of androgen synthesis through chemical castration by
administration of gonadotropin-releasing hormone agonists and antagonists and the use of competitive
androgen receptor antagonists to further impede AR signaling. Despite this first-line therapy, most PCas
adapt to androgen deprivation and restore AR signaling in the setting of low androgen production, a
state referred to as castration-resistant prostate cancer (CRPC). The development of next-generation AR
[4-7]
pathway inhibitors, such as abiraterone and enzalutamide , allowed for survival benefits to patients with
CRPC thanks to their ability to inhibit de novo androgen synthesis or to bind to and inactivate AR itself,
respectively. However, drug resistance ultimately emerges.

GENOMICS OF ADVANCED AND LOCALIZED DISEASE
The genomics of PCa has been more challenging to study with respect to other solid tumor types due
to multiple reasons, including intra-patient tumor heterogeneity and prevalence of structural genomic
[8]
changes . In the past ten years, technological advances in next generation sequencing finally facilitated the
deep genomic and epigenomic characterization of hormone naïve and castration resistant disease. This led
to a more refined definition of molecular subclasses that could ultimately be used by clinicians to adjust the
therapeutic strategies when resistance emerges. Over the last decade, a plethora of studies based on tumor
tissue analyses (from prostatectomies, tissue biopsies or rapid autopsy program samples) has been published.
More recently, the development of genomic and molecular profiling of prospectively collected liquid biopsy
samples from individual patients has improved the critical evaluation of ongoing therapies thanks to the
timely detection of mutations that arise in the resistant tumors.

Primary prostate cancers are usually characterized by a diploid genome, low mutational burden, genomic
rearrangements mainly involving the ETS genes and copy number aberrations, including deletions and
amplifications. The overall genomic burden is associated with tumor grade [9-12] and with biochemical
recurrence [13,14] . Large and complex chromosomal rearrangements - such as chromoplexy and chromothripsis
- are also prominent features of the prostate cancer genome [15-17] . CRPCs are highly aneuploidic, with
approximately 40% of tumors being triploid and with a higher mutational load [18-21] . The comparison of the
genomic status of primary prostate tumors and CRPCs identified lesions in TP53, AR, RB1, APC and BRCA2,
among others, as enriched in the latter. These studies have shed light on the genomics driving prostate
cancer resistance, which includes genomic rearrangements, point mutations and epigenetic changes [18,22-24] .
This review will focus on the main mechanisms driving resistance to ADT therapy in advanced tumors that
is mainly achieved either by restoration of the AR signaling or by enhanced lineage plasticity and activation
[25]
of alternative pathways, thereby sustaining tumor growth independently from AR . The review will
emphasize relevant aspects related to genomic features and functional studies reported for each mechanism
of resistance [Figure 1].

GENOMIC FEATURES OF AR-DEPENDENT RESISTANCE
AR is a nuclear hormone receptor that upon activation by androgens [testosterone and 5-alpha-
dihydrotestosterone (DHT)] translocates into the nucleus and binds to specific regulatory regions [AR
responsive elements (ARE); in promoters and enhancers], regulating specific target genes and promoting
prostate cell proliferation and survival.