Page 69 - Read Online

Page 6 of 15 Fraser. J Transl Genet Genom 2018;2:21. I https://doi.org/10.20517/jtgg.2018.27

identified very few genes mutated at rates exceeding 5%. The most frequently mutated gene in localized
prostate cancer in SPOP, which encodes a transcriptional regulator implicated in the DNA damage response,
maintenance of genome integrity, and inactivation of signaling pathways involved in cell proliferation and
survival [10,38,61,62] . SPOP mutation frequently co-occurs with CHD1 deletion and both events are mutually
exclusive from TMPRSS2:ERG fusion. While the understanding of the molecular mechanism for these as-
sociations is incomplete, recent data suggest that impairment of androgen signaling in cells lacking CHD1 or
[63]
SPOP is likely a major contributor. CHD1 is required for androgen-dependent TMPRSS2:ERG fusion and
SPOP inhibits androgen signaling via ubiquitylation of the AR steroid receptor coactivator-3 and of AR it-
[64]
self . Recent evidence suggests that SPOP mutation is subject to negative selection during the development
of mCRPC, perhaps reflecting the reduced dependence on androgen signaling in this disease state. From a
therapeutic standpoint, SPOP mutation (and CHD1 deletion) are predictive of improved response to the anti-
[37]
androgen abiraterone .
Mutations in TP53 are also relatively common in localized prostate cancer (3%-5% recurrence), and these
[10]
tend to cluster in the central DNA binding domain of p53 , suggesting an important functional contribu-
tion of this canonical tumour suppressor pathway. Similarly, mutations in the ATM gene, while somewhat
rarer than those in TP53 (~2% recurrence), are strongly associated with rapid biochemical relapse in localized
[10]
disease . The mechanisms underlying this clinical aggression are unclear, since the majority of these muta-
tions do not map to established hotspots or functional domains within the ATM protein. Nevertheless, the
finding that ATM is frequently mutated in the germline in patients with mCRPC [65,66] underlies the impor-
tance of this pathway as a determinant of prostate tumourigenesis and progression. Moreover, ATM mutant
[67]
cancers may be uniquely sensitive to PARP inhibitors , suggesting a potential role as a predictive biomarker
for these mutations.

[38]
Other genes affected by recurrent SNVs include MED12 , which is implicated in the clinical aggression of
[15]
hereditary prostate cancer in men who carry a germline BRCA2 mutation , and FOXA1, which encodes a
[68]
Forkhead family transcription factor and is associated with poor outcomes in ER+ breast cancer .
One intriguing category of SNVs are those that occur in non-coding regions of the genome (ncSNVs). Sev-
[10]
eral ncSNVs are recurrent at rates that approach those of non-synonymous SNVs (i.e., 2%-4%) . These likely
represent true hotspot mutations because they occur recurrently at the same nucleotide. While the precise
role of these ncSNVs remains unclear, it is possible that they interfere with transcriptional regulation, either
through cis-mediated effects on nearby genes or via alterations in three-dimensional genome structure.
CRISPR-based knock-in models will greatly enhance our understanding of the biology of these recurrent
aberrations.

THE WHOLE-GENOME LANDSCAPE OF PROSTATE CANCER
The first deep analysis of the prostate cancer genome [Table 2] emerged in 2011. Garraway and colleagues
sequenced the whole genomes of seven localized prostate cancers (and patient-matched normal specimens)
[69]
to a mean depth of ~30x, sufficient to detect most clonal mutations . This group demonstrated that local-
ized prostate cancer harbours an intermediate SNV burden, relative to other solid tumour types. While this
study lacked sufficient statistical power to detect all but the most recurrent mutations, several genes, includ-
ing SPTA1 and SPOP, were altered above the expected background rate. This report also identified a unique
pattern of GR in prostate cancers in which closed loops of rearrangements occur in a copy-neutral manner
to generate complex fusion products that dysregulate numerous genes, including cancer-associated genes
such as TP53, ABL1, and TBK1. These rearrangements were enriched in ChIP-seq peaks associated with open
chromatin, active transcription and both AR and ERG binding. GRs were also identified in other prostate
[70]
cancer-associated genes, such as PTEN .