Cancer of the Prostate: Molecular Genetics
with progression and metastatic disease
rather than with tumor initiation and has
limited value in diagnosis and staging.
mutations, detected by molecular
techniques, are rare in Western popula-
tions (
5%) and almost absent in localized
prostate cancer. In Japan, however, muta-
tions in the
gene have been found
in up to 25% of cases. These data sug-
gest that different mechanisms of prostate
cancer initiation and progression may ex-
ist within different ethnic or geographic
groups. Recent studies showed that stable
expression of Ras effector-loop mutants
that activate the Ras/MAP kinase path-
way is sufFcient to reduce the androgen
requirement of LNCaP prostate cancer
cells for growth, prostate-speciFc antigen
(PSA) expression, and tumorigenicity; and
attenuation of Ras signaling restores an-
drogen sensitivity to hormone-refractory
C4-2 prostate cancer cells.
DNA Repair Genes
The classic paradigm of tumor devel-
opment involves oncogenes and tumor
suppressor genes. More recent research
describes a third class of genes that lead
to tumorigenesis, those involved in DNA
repair. Maintenance of genomic integrity
is essential to prevent the acquisition of
mutations; thus, genetic instability allows
accumulation of changes, which may lead
to tumor formation. It has been estimated
that mutation in up to 100 genes can re-
sult in genomic instability. Efforts have
focused primarily on microsatellite insta-
bility, originally described in hereditary
nonpolyposis colorectal cancer (HNPCC).
Mutations, either inherited or acquired, in
DNA mismatch repair genes lead to the
replication error phenotype (RER). Sev-
eral of these genes have been identiFed
in humans (
and are homologous to the same genes in
yeast. Defects are manifested by variations
in the lengths of noncoding mono-, di-, tri-,
and tetranucleotide repeats, the so-called
microsatellites. Whereas microsatellite in-
stability is found in HNPCC as well as
sporadic colorectal, endometrial, stomach,
and pancreatic cancers, the frequency in
prostate cancer ranges from 5 to 70%.
Two studies reported high frequency of
alterations at speciFc microsatellite loci,
although microsatellite instability at multi-
ple loci is rare in prostate cancer. We found
frequent microsatellite instability (45%) in
prostate cancer using normal and tumor
cells of 40 microdissected prostate cancer
specimens. It is essential to use pure ep-
ithelial cells isolated by microdissection
from 5-
sections of prostate tissue. Vari-
ations in results may be the product of
differences in PCR primer and tissue selec-
tion as well as deFnitions of RER. Recent
reports have not found the RER phenotype
in prostate cancer, with the more com-
mon Fnding being focal instability and the
lack of widespread microsatellite instabil-
ity. Evidence of microsatellite instability in
19% of cancers has been found, with no
difference between clinically apparent tu-
mors and incidentally discovered cancers
at transurethral prostatectomy. In an anal-
ysis of 10 loci in 60 prostate cancers, 113
RER was found in both areas of cancer
and PIN but rarely in areas of glandular
hyperplasia. Racial differences have been
noted in the frequency of microsatellite
instability. Another report suggested that
the frequency of RER is much higher in
the United States when compared with
Japan. The DU145 cell line demonstrates
microsatellite instability and mutations in
. Overall, RER is not
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