Cancer of the Prostate: Molecular Genetics
193
Normal prostate
Prostate adenocarcinoma
AR pathway alterations
growth factors
Hormone-resistant prostate cancer
Advanced prostate cancer
Metastatic prostate cancer
Prostatic intraepithelial neoplasia
ERB
, telomerase
hypermethylation
(
HIC, P16, GSTP1
)
?RER
+
Hereditary factors:
HPC1, HPCX
AR polymorphisms
HSD3B2, SRD5A2
P53, RAS, RB, ?MY
C
FGF, TGF
RER+
CDH1, CTNNA1
CCAM,
Integrins
KAl1, CD44, PTEN
Fig. 1
Schematic illustrating the potential factors in the development of
prostatic intraepithelial neoplasia and prostate cancer and the subsequent
progression of prostate cancer. AR
=
androgen receptor;
FGF
=
┬▒broblast growth factor; TGF
=
transforming growth factor;
RER
=
replication error.
prostate cancer diagnosed under the age
of 55 years, or prostate cancer in each of
three generations in the paternal or mater-
nal lineage.
Genome-wide analysis in 66 high-risk
prostate cancer families suggested evi-
dence of linkage to a locus on the long
arm of chromosome 1 (1q24-25). This
hereditary prostate cancer locus (HPC1)
demonstrated linkage in an additional 25
North American and Swedish families
studied. The gene has not yet been cloned,
but candidate genes in the region include
SKI, ABL2, TRK
,and
LAMC2
.O
the
rre
-
ports, however, have shown no evidence of
linkage and no signiFcant loss of heterozy-
gosity (LOH) at the
HPC1
locus. Narod
and colleagues suggested a recessive or
X-linked gene in hereditary prostate can-
cer. A second prostate cancer susceptibility
gene (
HPCX
) has recently been identi-
Fed, accounting for approximately 16% of
hereditary prostate cancer cases. A total
of 360 prostate cancer families in North
America, ┬▒inland, and Sweden were ana-
lyzed, and linkage to chromosome Xq27-28
wasobserved.ThisFndingwasconFrmed
in a study of another 153 families as well as
in a study of 104 German prostate cancer
families.
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