198
Cancer of the Prostate: Molecular Genetics
ability to detect
P53
mutations is de-
pendent on the technique used, such as
temperature or denaturing gradient gel
electrophoresis or single-stranded con-
formation polymorphisms. In addition,
heterogeneity in the distribution of
P53
alterations can result in variations, de-
pending on which regions of the tumors
are examined. The retinoblastoma tumor
suppressor gene (
RB1
) is associated with
the development of retinoblastoma in the
immature retina as well as tumors of the
breast and lung. Because of the frequent
LOH of chromosome 13q (30 to 35%) and
the location of
RB1
at chromosome 13q14,
RB1
has been postulated to be a tumor
suppressor gene involved in prostate tu-
morigenesis. The phosphoprotein likely
interacts with transcription factors, such
as the E2F family, and negatively regu-
lates cell growth. Although decreased or
absent RB protein expression was found
in a third of tumors with LOH, few muta-
tions of the
RB1
gene have been identi┬▒ed.
The DU145 cell line possesses a mu-
tated
RB1
gene, and reintroduction of
wild-type
RB1
is able to reduce tumori-
genicity. Using single-stranded conforma-
tion polymorphism analysis of ribonucleic
acid (RNA), Kubota and colleagues re-
vealed that 4 of 25 primary cancers (16%)
had
RB
alterations. Interestingly, LOH at
RB
has been found not only in cancer
specimens but also in benign prostatic
hyperplasia (BPH) samples. More recent
data do not demonstrate prognostic signif-
icance of altered RB protein expression.
Th
et
ru
eim
p
o
r
t
an
c
eo
f
RB1
and exact
nature of LOH at 13q remain to be de-
termined. Another region at chromosome
13, 13q21, has also been found frequently
deleted in various human cancers includ-
ing prostate cancer. Frequent genomic
deletion and loss of expression as well
as cell growth suppression indicate that
KLF5 is a reasonable candidate for the tu-
mor suppressor gene at 13q21 in prostate
cancer.
In prostate cancer, chromosome 18q
locus LOH has been reported in up to
45% of primary tumors. The deleted locus
in colorectal carcinoma (
DCC
)geneisa
candidate tumor suppressor gene located
in this region and possesses homology
with neural cell-adhesion molecules. Al-
though mutations of the gene have not
been reported, decreased expression of the
DCC
gene, as well as allelic loss, suggest
a role in prostate cancers. It has been
suggested that alternative tumor suppres-
sor genes may be located at chromosome
18q21.
Pentaerythritol tetranitrate (PTEN) (the
phosphatase and tensin homolog deleted
on chromosome-10), a dual speci┬▒ty phos-
phatase,
is
a
tumor
suppressor
gene
whose inactivation has been associated
with many different types of cancer in-
cluding prostate cancer. Combined loss
of PTEN and p27 expression is associ-
ated with tumor cell proliferation by Ki-67
and increased risk of recurrent disease in
localized prostate cancer.
5
Oncogenes
The second major class of genes im-
plicated in tumor development is the
so-called oncogenes. Initially recognized
in cells transformed by retroviruses, onco-
genes are derived from normal cellular
genes, or proto-oncogenes, that contribute
to tumorigenesis once activated by muta-
tion or increased expression. The typical
functions of these proto-oncogenes in
normal cells include control of differen-
tiation and proliferation. The critical role
of oncogenes has been well documented
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