Cancer of the Prostate: Molecular Genetics
gene (2
synthetase dependent), identifed by a po-
sitional cloning/candidate gene method,
maps to the HPC-predisposition locus at
1q24-q25 (HPC1) and was recently shown
to harbor truncating mutations in two
Families with linkage to HPC1. A non-
sense mutation and a mutation in an
initiation codon oF RNASEL segregate in-
dependently in two HPC1-linked Families.
Microdissected tumors with a germ-line
mutation showed loss oF heterozygosity
and loss oF RNase L protein, and that
RNASEL activity was reduced in lym-
phoblasts From heterozyogous individuals
compared with Family members who were
homozygous with respect to the wild-
type allele. Thus, germ-line mutations in
RNASEL may be oF diagnostic value, and
the 2-5A pathway might provide opportu-
nities For developing therapies For those
with prostate cancer. Thus, there is strong
evidence oF genetic Factors in the potential
For development oF prostate cancer. The
gene may play a role in up to a third
oF hereditary prostate cancer cases. ±ur-
ther work should identiFy the
gene products and their Functions,
as well as other potential prostate cancer
susceptibility genes.
Genetic Alterations in Precursor Lesions
a precursor lesion oF prostate cancer.
Changes noted in both high-grade PIN and
early invasive prostate cancer include dis-
ruption oF the basal cell layer, alterations
in markers oF secretory diFFerentiation,
nuclear and nucleolar enlargement, and
increased cell proliFeration. Identifcation
oF similar molecular changes in PIN and
prostate cancer Further strengthens this
hypothesis. Sequential magnifcation oF
the abnormalities in PIN is seen in the
progression to localized cancer, metastatic
cancer, and hormone-reFractory cancer.
Allelic loss is common in both PIN
and prostate cancer (Table 1). Qian and
colleagues used centromere-specifc flu-
in situ
hybridization (±ISH)
probes against chromosomes 7, 8, 10, and
Y, to demonstrate chromosomal anoma-
lies in 50% oF PIN and carcinoma Foci.
±oci oF metastatic cancer demonstrated in-
creased chromosomal anomalies. Other al-
terations oF chromosome 8 are common in
both PIN and prostate cancer, with gain oF
chromosome 8q being the most Frequent.
Using polymerase chain reaction (PCR)
and a novel microdissection technique, al-
lelic imbalance oF chromosome 8p12-21 in
64% oF PIN Foci and 91% oF cancer Foci has
been described; no LOH at chromosome
8p12-21 was Found in benign tissue. Addi-
tional LOH at chromosomes 8p, 10q, and
16q has been identifed in 29% oF PIN and
42% oF primary tumors. Taken together,
PIN is a precursor oF prostate cancer
and exhibits abnormalities in biomarkers,
Tab. 1
Genetic alterations in prostate cancer.
Prostalic intraepithelial
7, 8q, 10
8p, 10q, 16q, Y
Prostate adenocarcinoma
7, 8q, 10, X
2q, 5q, 6q, 7q, 8p, 9p, 10q, 13q, 15q, 16q,
16p, 17p, 17q, 18q, 20q, 22q, Y
previous page 868 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 870 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off