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Fraser. J Transl Genet Genom 2018;2:21. I https://doi.org/10.20517/jtgg.2018.27 Page 5 of 15

sor [9,10,29] . This CNA is present in roughly 20% of all localized cancers and is distributed equally between
[9]
tumour phylogenetic trunks and branches . PTEN-/- mouse embryonic fibroblasts are sensitive to poly-ADP
ribose polymerase (PARP) inhibitors [42-45] , possibly through decreased homologous recombination-mediated
DNA repair via transcriptional down-regulation of RAD51 [45,46] . However, correlative studies have failed to
[47]
establish any link between PTEN status and RAD51 expression in prostate cancer , and it is likely that
this effect is tissue-specific [43-45] , since follow-up clustered regularly interspaced short palindromic repeats
(CRISPR)-based screens for PARP inhibitor sensitivity have failed to recapitulate the importance of PTEN
[48]
in this regard . Other recurrent somatic deletions include NKX3-1 (8p21.2), CHD1 (5q15-q21.1; see below),
CDH1 (16q22.1), RB1 (13q14.2), CDKN1B (12p13.1), BRCA2 (13q13.1) and TP53 (17p13.1) [9,10,29] , and several of
[49]
these may have significant prognostic value for adverse outcomes in localized disease .
The most frequently amplified region of the somatic prostate cancer genome is chromosome 8q. Several
significant amplification peaks exist on this chromosomal arm, the most prominent of which (8q24.21) har-
bours the MYC oncogene. This region is amplified in 8%-10% of localized cancers [9,10,29] , and is prognostic of
adverse clinical outcomes following definitive therapy [10,50-52] . Interestingly, the rate of MYC amplification is
substantially increased in localized prostate cancers in men who harbour a deleterious germline mutation
in the BRCA2 gene [15,53] . Consistent with a role for MYC amplification as a determinant of poor clinical out-
come, these familial cancers have an extremely aggressive clinical course, with 5-year overall survival rates
[54]
approaching 50% .
[29]
Recurrent amplifications of chromosome 8q - outside of those affecting the MYC gene - are also com-
[29]
monly observed and may have important biological and clinical relevance . For example, amplification of
the NBN gene (8q22.1), which encodes the DNA damage sensor protein NBS1, is predictive of poor response
[55]
to external beam radiotherapy in low/intermediate risk prostate cancer . Similarly, the PCAT1 long non-
coding RNA gene, which is implicated in aggressive localized and metastatic prostate cancer, is located on
[56]
a frequently-amplified region of chromosome 8q immediately upstream of the MYC locus . Intriguingly,
[57]
PCAT1 lies within a common fragile site (FRA8C) , which may help to explain the recurrent instability at
this locus.

Beyond chromosome 8q, recurrent amplifications have been identified on chromosome 3q26, 11q13, and
the entirety of chromosome 7 [10,29] . Because these amplifications involve megabase stretches of the genome,
identification of the putative driver genes in each region has proven difficult. However, it is clear that at least
some of these large-scale amplifications have prognostic value in localized prostate cancer; indeed, amplifi-
cation of chromosome 7 defines a unique CNA-based cluster of prostate cancer, and is associated with de-
[58]
creased time to biochemical relapse in men treated with IGRT for intermediate risk prostate cancer .
The prognostic importance of somatic CNAs is now well-established. CNA burden - the proportion of the
genome affected by a CNA - is associated with reduced time to biochemical relapse in men with localized
prostate cancer [58,59] . Moreover, unbiased, machine learning-based approaches have identified CNA-based
gene signatures that accurately classify patients for risk of biochemical and metastatic relapse following de-
finitive, curative-intent therapy for localized prostate cancer [10,58,60] . These signatures significantly outperform
[58]
RNA-based classifiers as well as established clinical prognostic factors such as Gleason grade and pre-
treatment PSA. Moreover, CNA-based classifiers can be derived from pre-treatment biopsy specimens and
are readily adapted for clinical implementation via clinical laboratory improvement amendments-compatible
[60]
platforms such as NanoString .
Single nucleotide variants
In contrast to other solid tumour types such as serous ovarian and pancreatic cancers, localized prostate
cancer harbours a paucity of recurrent driver somatic SNVs. Indeed, several well-powered studies have