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Fraser. J Transl Genet Genom 2018;2:21. I https://doi.org/10.20517/jtgg.2018.27 Page 9 of 15

Prostate cancer also shows evidence of substantial clonal divergence during tumourigenesis. Indeed,
[9]
Espiritu et al. recently demonstrated that only ~25% of localized, non-indolent prostate cancers are com-
posed of a single clonal population (“monoclonal”) within the index lesion. Conversely, 75% of cancers
showed strong evidence of two or more clonal populations (“polyclonal”), which diverged into unique clonal
“branches” early in the process of tumourigenesis and share very few driver aberrations (shared “trunk” mu-
tations). Interestingly, patients who harbor monoclonal tumours almost never experienced disease relapse.
Moreover, polyclonal tumours were more aggressive, and this aggression was synergistic with established
molecular predictors of adverse outcome, such as the Fraser 6-feature signature (see above) and percentage
genome alteration. These data strongly support the hypothesis that clonal evolution is a key determinant of
clinical aggression.

[79]
Wedge et al. similarly identified extensive subclonal heterogeneity and evolutionary divergence in both
localized and metastatic prostate cancer. In particular, this group found that ETS-fusion status was a signifi-
cant predictor of somatic CNAs at several loci, including amplification of 8q and deletion of the PTEN locus
on chromosome 10. Conversely, tumours lacking a truncal ETS fusion were enriched for CHD1 deletion -
consistent with the previous finding that T2E and CHD1 deletion are mutually exclusive - as well as CNAs at
several driver loci, including BRCA2, RB1, and FOXO1. Intriguingly, subclonal analyses revealed that meta-
static tumours are significantly less molecularly heterogeneous than primary tumours, consistent with selec-
tion of a small number of aggressive subclones during metastatic spread.

These findings of subclonal divergence have important potential consequences for the clinical use of molecu-
lar biomarkers. While no study has comprehensively evaluated the rates of metastatic seeding from the index
lesion vs. independent foci, there is evidence that the highest-grade focus does not always seed the “lethal
[76]
clone” . As such, clinical biomarkers based on single disease foci - such as would be obtained from an in-
dex lesion-derived biopsy - may not accurately reflect the aggressive potential of the entire prostate. Despite
this, biomarkers based on single tumour foci have shown excellent prognostic accuracy (AUCs of 0.85 or
higher). While this may reflect a deficiency in the biomarker itself, it is also possible that biomarker accuracy
is capped at ~85% due to inadequate profiling of multiple tumour foci. This is a major outstanding question
in translational cancer genomics, and a robust understanding of the effects of heterogeneity will be required
to optimize any tissue-based biomarker that ultimately achieves clinical implementation. One potential solu-
tion is the use of liquid-based biomarkers to complement tissue biomarkers, since these may better reflect the
global mutational profile across tumour foci.

Toward clinical implementation of somatic tumour genomics in prostate cancer localized prostate cancer
is associated with a very low level of recurrent non-synonymous mutation. Prostate cancer lacks the type
of near-ubiquitous driver aberrations - frequently seen in other cancers such as chronic myeloid leukemia
(BCR-ABL fusion), pancreatic cancer (KRAS mutation), or serous ovarian cancer (TP53 mutation) - which
would suggest potential novel therapeutic targets. TMPRSS2:ERG fusion is present in ~40% of all localized
[80]
prostate cancers, and peptidomimetic inhibitors of ERG have been developed , although none have yet
moved beyond the pre-clinical stage and the potential for deleterious effect of ERG inhibition on non-pros-
tate tissues may limit their therapeutic potential.

Moreover, traditional hypotheses regarding the utility of cancer genomics to identify potential drug targets
may not be as relevant to localized prostate cancer as in other cancer types or, indeed, in metastatic prostate
cancer. As noted, in PSA-screened populations, virtually all new cases of prostate cancer are diagnosed as
localized disease, with no evidence of extra-prostatic spread by bone scintigraphy and are thus potentially
curable. While 10-year prostate cancer-specific survival for localized disease approaches 99% irrespective of
[81]
treatment modality , biochemical and metastatic relapse-free rates are more variable. These endpoints are
established surrogates of PCSM [5,73] , and the heterogeneity of outcome based on these endpoints has been