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pave the way for future studies to define the precise molecular mechanisms through which these cancers de-
velop and evolve.

Clinico-genomics in localized prostate cancer
Well-powered, clinically-focused studies of the localized prostate cancer genome have proven difficult, rela-
tive to other solid tumour types, because of both the paucity of high tumour content tissue, particularly in
low burden disease. Moreover, the development of clinically-meaningful endpoints (i.e., distant metastasis-
free survival, overall survival, etc.) in localized prostate cancer can take upward of 10-15 years. However, re-
cent advances in computational algorithms and decreases in sequencing costs have allowed for far more in-
depth analyses than have previously been possible. Moreover, recent work has established reliable surrogate
endpoints of aggressive disease.

[10]
Fraser et al. performed a deep meta-analysis of prostate cancer whole-genome (n = 200) and whole-exome (n
= 477) sequences published to date, with long-term clinical follow-up available for 130 patients with homo-
geneously staged disease. Using parallel array-based indices, the team identified a 6-feature clinico-genomic
[10]
signature of adverse clinical outcome . This signature is composed of a GR (a translocation on chromo-
some 7), two DNA methylation aberrations (TCERG1L hypomethylation, ACTL6B hypermethylation), SNVs
in ATM, copy number amplification of MYC, as well as clinical T stage. This signature accurately predicts
overall biochemical relapse and, importantly, also predicts relapse within the first 3 years following curative-
intent treatment, which is a surrogate for lethal disease [5,73] . Despite these promising insights, much larger
numbers of patients - with well-annotated long-term clinical follow-up data - will be required to both vali-
date these findings and to establish the clinical implications of aberrations occurring below the 1%-5% recur-
rence threshold.

Spatio-temporal heterogeneity, tumour evolution, and clinical outcomes approximately 75%-80% of prostate
cancers are multi-focal, as assessed at prostatectomy [74,75] . While multiple foci do not necessarily portend a
[74]
more aggressive clinical course , the index lesion does not always correspond to the malignant clone that
[76]
gives rise to distant metastases . As such, an understanding of if and how inter-focal heterogeneity af-
[49]
fects prostate cancer progression is of paramount importance. To that end, Boutros et al. sequenced the
genomes of eighteen spatially-distinct disease foci from five patients with intermediate-risk prostate cancer,
with an additional sixty-nine cases evaluated using array-based assessment of genome-wide CNAs. Inter-
focal heterogeneity was extremely high for all mutational classes. For example, in one patient, the total
number of CNAs varied by nearly 2 orders of magnitude across five tumour foci, while the percentage of
the genome affected by CNAs (percentage of genome altered; a metric of genomic instability and an inde-
pendent prognostic factor [58,59] ) varied by over 10-fold. Importantly, the index lesion was not universally
associated with the highest burden of structural variants or SNVs, consistent with reports showing that me-
[76]
tastases do not always arise from the index tumour . Moreover, several aberrations with established links
to progression and adverse outcomes (e.g., TP53 and PTEN deletion) were heterogeneous across tumour foci
from the same patient, and one patient showed strong evidence of multiple independent tumours. Likewise,
[77]
Cooper et al. sequenced the whole genomes of twelve cancer foci from three patients, along with tumour-
adjacent normal prostate epithelium from all three. The team showed compelling evidence of intermixing of
cancer clones within a single cancer focus and identified a significant burden of tumour-associated mutation
in morphologically normal prostate epithelium, consistent with a global “field defect” within the gland as a
whole. These findings of extensive heterogeneity have subsequently been recapitulated in larger, independent
[78]
cohorts. Løvf et al. recently sequenced the exomes of 153 foci from 41 patients, including both malignant
and putatively-normal prostate epithelium, and demonstrated that there is significant inter-focal heterogene-
ity, including genes with established prognostic importance or enrichment in metastatic or aggressive local-
ized prostate cancers (e.g., NKX3-1, MED12, TP53).