361with PrCa risk, described by rs117576373. Additional genotyping, conditional
regression and haplotype analyses indicated that the newly identifi ed common vari-
ants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E,
rs138213197), which has been identifi ed as a moderate penetrance PrCa suscepti-
bility allele. The potential for genome-wide associations detected through common
SNPs to be driven by rare causal variants with higher relative risks has long been
proposed; however, this is the fi rst experimental evidence for this phenomenon of
synthetic association contributing to cancer susceptibility. Synthetic associations at
genome-wide signals could therefore account for a proportion of the missing herita-
bility of complex diseases such as cancer. Such fi ndings are useful for understand-
ing some of the biological underpinnings of prostate cancer risk, but there is
possibility of fi nding other situations involving synthetic associations between com-
mon and rare variants infl uencing specifi c traits or conditions.
Diagnostics for Guiding Therapy of Prostate Cancer
Testing tissues from men with prostate cancer has demonstrated how loss of PTEN,
a gene that inhibits tumor growth, results in the uncontrolled activation of a tumor
promoting protein, AKT. AKT then activates the enzyme mTOR, which subse-
quently activates S6. This is the basis of a tumor promoting cascade, similar to a
domino effect. These biomarkers can be used to predict response to an experimental
therapy known as CCI-779, an inhibitor of mTOR. A drug that inhibits mTOR
should impact the tumor cells but have no effect on the normal cells. When mTOR
is inhibited, the cascade comes to a standstill and tumors stop growing. Prior to
identifying this method, there was no molecular method to predict which men with
prostate cancers would be sensitive to CCI-779. Now oncologists can customize
“targeted” cancer treatments for each patient based on the molecular make-up of
their tumors. These “smart drugs” selectively stop the growth of tumor cells with
the molecular abnormality. Of those, about 25–30 % were predicted to have tumors
that are missing PTEN. Therefore, the experimental drug could potentially help
about 60,000 prostate cancer patients a year, if the laboratory results are confi rmed
in clinical trials, which are ongoing.
Prostate Px (Aureon Laboratories), integrates histology, molecular biology and
clinical information and applies bioinformatics to stratify patients as high or low
risk for disease recurrence post-prostatectomy. Results are provided as the Prostate
Px score (0–100), which reports the likelihood of recurrence of the prostate cancer.
In a prospective study, integration of clinicopathological variables with imaging and
biomarker data (systems pathology) resulted in a highly accurate tool for predicting
clinical failure within 5 years after prostatectomy (Donovan et al. 2008 ). The data
support a role for androgen receptor signaling in clinical progression and duration
of response to androgen deprivation therapy.
The anticancer agent docetaxel and thalidomide shows signifi cant inter-
individual variation in their pharmacokinetic and toxicity profi les as well as wide
pharmacological variations. In one study, patients with prostate cancer enrolled in a
Personalized Management of Cancers of Various Organs