196
Cancer of the Prostate: Molecular Genetics
chromosomes. Alterations as detected by
CGH are present in up to 70% of prostate
cancer cases, with losses Fve times more
common than
gains.
Areas
of
losses
involve chromosomes 2q, 5q, 10q, 13q,
15q, 16q, 16p, 17p, 17q, 18q, 9p, 20q, and
Y, whereas gains involve chromosomes
11p, 1q, 3q, 9q, 20, 23, and 2p. New
alterations revealed by CGH include loss
at chromosomes 6q, 9p, and 22q and
ampliFcations at chromosome 8q24. ±ISH
and
molecular
methods
of
restriction
fragment length polymorphism and PCR
have generally conFrmed these regions
of change detected by CGH. The more
frequent Fnding of DNA loss suggests that
inactivation of tumor suppressor genes
i
nt
h
e
s
ea
r
e
a
sm
a
yp
l
a
ya
nim
p
o
r
t
a
n
t
role in prostate cancer development. More
recent studies have speciFcally examined
alterations in Y chromosome number.
It was found that prostate cancer cell
lines were able to consistently induce an
increase in the number of copies of the
Y chromosome in three murine tumor
cell lines
in vivo
.±ISHdemons
tra
tedtha
t
the majority of cells had two to three
copies of the Y chromosome and that the
ampliFcation was speciFc, without other
chromosomes being involved. However,
signiFcant changes were not found in
Y chromosome number. Using touch
preparations from prostate tumors, 42
specimens
were
analyzed
by
whole
Y
chromosome
paint
±ISH.
Only
a
single case of Y chromosome gain, and
no
evidence of
loss
of
the
entire
Y
chromosome, was found.
4
Tumor Suppressor Genes
Cancer
development
relies
on
alter-
ations in normal homeostatic mechanisms
exhibiting precise control on cellular pro-
liferation. The genes involved in negative
regulation of cell growth can be disrupted,
thus allowing tumorigenesis. These tumor
suppressor genes are recessive and typi-
cally require inactivation of both alleles.
As mentioned, sites of chromosomal dele-
tion from LOH studies may suggest the
presence and location of tumor suppres-
sor genes. Loss of part, or all, of the short
arm of chromosome 8 (8p) is the most
common genetic defect in prostate cancer
and has been conFrmed by several studies.
Loss of heterozygosity studies in other can-
cers such as lung, colon, and breast also
demonstrate frequent chromosome 8p
loss, further suggesting the presence of a
potential tumor suppressor gene that may
be fundamental in tumor development.
Smaller regions of deletion, chromosomes
8p11-12 and 8p22, have been reported.
Only recently has a candidate tumor sup-
pressor gene been identiFed from the
chromosome 8p22 region. This
N
33 gene,
expressed in most tissues, is downregu-
lated in colon cancer cell lines; however,
studies in prostate cancer cell lines have
not revealed mutations in
N
33 or evidence
of downregulation. No other candidate tu-
mor suppressor gene has been reported
in these regions. Another frequent site of
loss, initially described by classic cytoge-
netic analysis, is the terminal region of
chromosome 10q (10q24-25). A potential
tumor suppressor gene,
MXI1
, has been
mapped to this chromosomal region. The
protein acts as a negative regulator of the
MYC
oncogene, and its inactivation may
potentially result in increased activity of
the MYC protein. Mutations of the
MXI1
gene have been found to be rare, and it has
been demonstrated that the allelic losses
of chromosomes 10q24-25 occur near the
chromosome 10q23-24 boundary and not
at the
MXI1
locus. 44, 45 P53 is one of the
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