Cancer of the Prostate: Molecular Genetics
Androgen Receptor
The AR mediates the actions of androgens
in both the normal and abnormal prostate
cell. This, combined with the necessity of
androgens in prostate carcinogenesis and
the inevitable development of androgen
insensitivity with continued androgen de-
privation, has focused much effort into
examining the role of AR in early and
late prostate cancer. Inherited susceptibil-
ity to prostate cancer may be transmitted
by AR polymorphisms. Two microsatel-
lite repeats, CAG and GGN, are located
within exon 1 of the
gene. Whereas
expansion of the CAG repeats from 40 to
62 is associated with spinal and bulbar
muscular atrophy (Kennedy’s syndrome),
less than 19 CAG repeats are associated
with a 1.52 relative risk for prostate cancer
04). In addition, men with shorter
CAG microsatellites were at higher risk
for metastatic disease. A 3% decrease in
prostate cancer risk with each additional
CAG repeat has been noted, and vari-
ous studies have found similar results.
However, variations in the lengths have
not been consistently associated with al-
tered AR function. Although patients with
Kennedy’s syndrome have been reported
to possess reduced androgen binding ca-
pacity, other investigators have found nor-
mal hormone binding, transactivation, and
transrepression potential in these men.
The frequency of CAG repeat lengths dif-
fers among the ethnic groups. Shorter
repeats are more common in black men,
who have a higher incidence of prostate
cancer. Conversely, more CAG repeats are
found in populations at lower risk such
as Asians and Whites. This polymorphism
could, in part, explain the ethnic differ-
ences in prostate cancer incidence. Length
of the GGN repeat has been inconsistently
associated with potential for prostate can-
cer development. Some have found any
deviation from a repeat length of 16 to
impart a higher risk (odds ratio 1.18),
whereas others report lengths less than
16 to be a risk factor. No signiFcant dif-
ferences were found between cancer cases
and controls with respect to GGN repeat
length. The observed gain of chromosome
Xq in hormone-refractory prostate cancer
suggested involvement of the AR, located
at chromosome Xq12. AmpliFcation of AR
was detected in 30% of recurrent can-
cers, but none of the primary tumors,
in patients receiving hormonal therapy.
gene ampliFcation leads to increased
mRNA levels, and high AR expression is
seen in androgen-independent tumors. Al-
most all primary and metastatic lesions
express AR, however, prior to endocrine
treatment. Thus, mechanisms other than
loss of AR are involved in progression
to a metastatic or androgen-independent
state. Indeed, prior androgen ablation may
select for
gene ampliFcation. Signif-
icantly longer median survival has been
found in patients with
than those without it.
mutations are rel-
atively infrequent, ranging from 0 to 41%.
This further suggests that the development
of prostate cancer occurs in the pres-
ence of normal AR expression. Moreover,
the AR pathway likely remains impor-
tant in advanced and hormone-refractory
cancers. Often, mutations are found in
metastatic but not primary tumors.
mutations have been found in half of the
hormone-independent, metastatic lesions,
all of which were clustered in the steroid-
binding domain (exons 4 to 8). Changes
in this area may lead to loss of repression
of AR transactivation in the absence of
androgen or increased afFnity to steroids
such as estrogen and progesterone. Over
mutations have been identiFed and
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