Cancer of the Prostate: Molecular Genetics
197
most widely studied tumor proteins, and
abnormalities of the
P53
tumor suppres-
sor gene are the most common genetic
alterations associated with human malig-
nancy. P53 plays a key role in the regulation
of the cell cycle, ensuring DNA integrity
by negatively affecting cell growth after
DNA damage (Fig. 2). Overall, the inci-
dence of LOH and mutations at the
P53
locus (chromosome 17p13.1) in prostate
cancer is less than in other malignancies,
ranging between 10 and 30%. Evidence
suggests that changes in P53 are impor-
tant in the subset of patients with advanced
disease and thus may be a late event. Stud-
ies of cell lines derived from metastatic
deposits demonstrated frequent
P53
mu-
tations, and transfection of wild-type P53
resulted in suppression of growth. Ability
to detect P53 by immunohistochemistry
often accompanies mutations in the gene
caused by increases in the protein half-life,
thus allowing study of paraf±n-embedded
specimens. Nuclear accumulation of P53
correlated with metastatic disease or an-
drogen independence. In addition, P53-
positive tumors were found to have a
greater frequency of
P53
mutations. These
mutations are primarily localized to exon
7. An association between P53 expression
and poor clinical outcome has been re-
ported. Moreover, alterations in P53 may
affect and therefore predict response to ra-
diation therapy. Several regulatory genes,
including
P53
,
BCL2
,
CMYC
,and
RAS
,
have been implicated in the apoptotic pro-
cess. It is postulated that defects in these
genes may limit the ability of cells to induce
apoptosis; thus, partial resistance to agents
that act through programmed cell death
may be imparted with P53 alterations.
Several studies demonstrate an attenu-
ated response to ionizing radiation in cells
harboring
P53
mutations. Similarly,
P53
mutations adversely predict overall sur-
vival in patients with locally advanced
disease treated with androgen deprivation
after radiotherapy. Impaired apoptosis,
after either radiotherapy or androgen ab-
lation, may be important in tumors with
P53
mutations. Variations in studies of P53
mayresu
ltfrommanyfactors
.F
irst
,com
-
mercially available antibodies recognizing
P53 differ in sensitivity and speci±city.
Second, quanti±cation of P53 staining is
subject to interobserver variability. Third,
Fig. 2
Overview of the role of
P53, RB, and related proteins in
the cell cycle and regulation of
apoptosis.
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