seminars in CANCER BIOLOGY, Vol 8, 1997: pp 37–44
The genetic analysis of prostate carcinoma
Rebecca Roylance, Nigel Spurr* and Denise Sheer
The molecular events underlying prostatic tumorigenesis
remain incompletely understood. The application of
cytogenetic, molecular genetic and molecular cytogenetic
techniques have led to the identification of consistent genetic
changes. This paper will discuss these techniques, review the
genetic aberrations discovered, and consider how these
aberrations contribute to our knowledge of the initiation,
progression, metastatic spread and resistance to hormonal
therapy of prostate cancer.
Key words: comparative genomic hybridization /
cytogenetics / fluorescence in-situ hybridization / loss of
heterozygosity / prostate cancer
©1997 Academic Press Ltd
PROSTATE CANCER REPRESENTS a significant worldwide
health problem. The increasing incidence has led to
predictions that it will be the most common cause of
male cancer death by the year 2010. Yet only recently
have research efforts focused attention upon it. Over
the past two decades there has been a rapid expansion
in the understanding of the basic molecular events
underlying tumorigenesis. A useful working model is
the hypothesis that cancer results from an accumula-
tion of genetic changes that affect the expression of
certain critical genes.1 Most genetic changes occur in
somatic cells, but some occur as germline defects that
can result in an inherited predisposition to cancer
development. Familial prostate cancer accounts for
approximately 9% of all prostate cancers. The region
of the genome thought to contain a gene responsible
for about one third of these hereditary cancers has
recently been identified on 1q24–252 (see chapter by
Bishop and Kiemeney, this issue).
Prostate cancer is a biologically variable disease.
Fifty percent of patients will present with localized
disease, but there is considerable heterogeneity in
biological aggressiveness and prognosis.3 There is
presently no accurate way to predict the course of the
From the Imperial Cancer Research Fund, 44 Lincoln’s Inn
Fields, London WC2A 3PX, and *SmithKline Beecham Pharma-
ceuticals, Third Avenue, Harlow, Essex CM19 5BR, UK
©1997 Academic Press Ltd
1044-579X/97/010037 + 08$25.00/0/se970051
37
disease in individual patients and no consensus on the
most appropriate means of treating localized disease.
Surgery, radical radiotherapy and observation of
localized disease all result in the same 10-year survival
rates. Genetic markers of prognosis that will allow
specific targeting and evaluation of therapy, are
urgently needed. Patients with potentially aggressive
localized disease could be offered more intensive
therapy with the hope of increasing survival. For
patients with metastatic disease, however, hormonal
manipulation by androgen blockade is the preferred
treatment. Although 80% of patients initially respond,
the tumour eventually becomes hormonally unre-
sponsive and the average time to death is then six
months.
Cytogenetic, molecular genetic and molecular cyto-
genetic techniques have been applied to prostate
cancer. This review is divided into two sections. In the
first, we describe these techniques in relation to the
study of prostate cancer. In the second section we will
consider in detail the consistent genetic changes that
have been identified and their potential role in
prostate cancer initiation, progression, metastasis and
response to hormonal therapy.
Techniques
Cytogenetic analysis
Cytogenetic analysis has been applied, to date, to
approximately 350 prostatic tumours.4-12 However, no
specific cytogenetic abnormalities have been identi-
fied. Most tumours (75%) have revealed a normal
male diploid karyotype (46,XY). This contrasts with
the cytogenetic analysis of haematological and mesen-
chymal malignancies, which has found abnormalities
resulting in the identification of specific genes and
pathways for malignant transformation.
The limited information yielded by karyotypic
analysis reflects two factors: the inherent difficulties of
the technique, and those difficulties specifically
related to prostate cancer. Prostate tumours are a
heterogeneous mixture of epithelial cells and sur-
rounding stroma and also show focal heterogeneity.13
R. Roylance et al
Different malignant foci can show varying degrees of
differentiation, and are interspersed with both benign
tissue and premalignant areas of prostatic intra-
epithelial neoplasia (PIN). Such diversity can lead to a
selection bias when using small amounts of tissue or
pieces of tissue selected at random, and has implica-
tions not only for cytogenetic analysis, but for all
genetic analysis (see later). Cytogenetic analysis uses
metaphases from cells prepared either by direct
preparation or by short-term culture.14 Direct prepa-
rations, made shortly after removal of the tumour,
although thought to be representative of the in-vivo
situation, are of limited usefulness as they contain
only a few metaphases that tend to be poor in quality.
There is a further selection bias in that only those cells
about to divide immediately before removal of the
tumour are subject to analysis. Short-term culture
yields more metaphases that are of higher quality than
direct preparations. However it too has several limita-
tions, principally the difficulty of identifying which
cells are actually under study. Whilst it is possible to
immunostain cells in culture to determine whether
they are epithelial in origin,15 at present the differ-
entiation between benign and malignant epithelium
is not possible. The predominantly normal karyotype
seen in prostate tumours may be due to the resolution
limits of karyotyping, with any changes present being
submicroscopic.14 Alternatively there may be over-
growth of normal cells or selection in vitro against
aneuploid cells. The evidence for the latter comes
from two studies15,16 where FISH performed on direct
preparations revealed clonal aberrations and aneu-
ploidy which were subsequently lost following culture.
This selection against aneuploid cells may be a result
of the methods used in preparation of the tissue. It
has been shown that collagenase, used to disrupt the
tumour prior to culture, results in loss of the
aneuploid population that is not seen when mechan-
ical disruption alone is used.15
Despite the difficulties of cytogenetic analysis dis-
cussed above, it nevertheless has an important role to
play in the understanding of prostate cancer. It is
important to emphasize, for example, that cytogenetic
analysis is the only technique among those reviewed
here that has the ability to identify novel chromoso-
mal translocations.
Fluorescent in-situ hybridization (FISH)
FISH has revealed more clonal aberrations than
conventional cytogenetic analysis. It can be per-
formed on interphase nuclei and therefore has the
38
advantage that culturing of the tumour is unnecessary,
eliminating the problems discussed above. FISH can
be performed on archival paraffin-embedded sam-
ples. Tumour architecture is maintained, allowing
examination of intratumour heterogeneity and evalu-
ation of premalignant lesions. However, it is still
important to ensure that the tissue being studied has
a high proportion of malignant cells and that con-
taminating normal tissue is kept to a minimum. Other
tissue samples which can be examined include frozen
and touch preparations and isolated nuclei. The study
of isolated nuclei obviously means that tumour
architecture is not maintained, but there are other
advantages; principally the absence of sectioning
artefact.17 The limitations of most studies using FISH
is that only centromeric probes have been used and
not all chromosomes have been investigated. The
information gained using centromeric probes is
extrapolated to the whole chromosome, an assump-
tion which may not be accurate. The use of region-
specific probes has been limited, mainly due to
technical difficulties as centromeric probes give far
brighter and clearer signals than single copy probes.
Comparative genomic hybridization (CGH)
CGH is a relatively new technique.18 Tumour DNA is
fluorescently labelled and competitively hybridized
with fluorescently labelled normal DNA (ideally from
the same person) onto metaphase spreads. Use of
different fluorescent labels for tumour and normal
DNA results in differential labelling of the metaphase
spreads that can be used to characterize gains and
losses of genomic material. As CGH can be used to
examine the entire genome it is a rapid screening
technique. Changes identified can be confirmed
using other methods. For differences to be seen it is
important that the tumour DNA has minimal normal
contamination.19 Microdissection of the tumour is
usually necessary, especially for prostate tumours. The
sensitivity of CGH is currently limited to the detection
of deletions > 10–20 Mb and amplifications, if the
total amount of amplified DNA is > 2 Mb.19 There are
five published studies using CGH to investigate
prostate cancer,20-24 revealing more aberrations than
the other techniques reviewed here, see Figure 1.
They have shown that losses of genetic material are
much more common than gains of genetic material.23
This suggests that in prostate cancer the most
important changes are loss of tumour suppressor
genes rather than oncogene amplification.

Loss of heterozygosity (LOH) studies
Only a limited number of LOH studies have been
conducted using prostate tumours. The studies have
revealed a number of abnormalities but they, like
FISH, are limited to analysing specific regions of the
genome, for example, detecting loss of part of a
chromosome arm in a set of tumours. They are also
limited, as discussed above, by the need to have
malignant tissue with minimal normal contaminating
tissue and normal tissue from the same patient to
serve as a control.
Genetic aberrations
Chromosome 8
Loss of 8p
The most intensively investigated region in prostate
cancer to date has been 8p. Several regions on 8p are
of interest as possible sites for tumour suppressor
genes, with both 8p12 and 8p21–23 found to be
deleted in a range of carcinomas.25 Although no
candidate gene has yet been identified for 8p12,
recently cell adhesion kinase β (CAKβ), a protein-
tyrosine kinase of the focal adhesion kinase subfamily,
Figure 1. Partial ideogram showing a summary of the genetic changes found using cytogenetic,
molecular and molecular cytogenetic techniques. Gains are shown on the right and losses are on
the left. X represents chromosomal breakpoints. Note how CGH has revealed more abnormalities
than all the other techniques.
39
Genetic analysis of prostate carcinoma
has been mapped to 8p21.1.26 Loss of 8p has been
confirmed by classical cytogenetics,7,11 FISH,27-30
LOH31,32 and CGH.21,23 Whilst LOH studies have
defined a region of minimal loss at 8p12–21,32 FISH
studies have found deletion of 8p12,27 8p2227-30 and
8p23.30 It is thought that 8p loss may be an early event
in prostate tumour formation,27 and this is supported
by the finding of loss in PIN lesions.27,33 It has been
suggested that as well as being lost early, loss of genes
at band 8p23 may contribute to evolution from a well
to a moderately differentiated tumour.30
Gain of 8q
Gain of 8q has been found in other malignancies
including ALL, malignant melanoma, squamous cell
carcinoma, and gastric carcinoma.34 Evidence for
amplification of the band 8q24.1–8q24.2 has been
found in two cultured prostate cancer samples35 and
gain of the whole arm has also been seen.11 Amplifica-
tion of the whole of 8q has been found to be one of
the most common aberrations in CGH studies20-23
and would appear to be a late finding. In one study, it
was seen in 89% of recurrent tumours compared to
6% of primary tumours.23 Both CGH and FISH
studies have shown that 8q gain is frequently asso-
ciated with loss of 8p.20,23,29 This has lead to the
theory that 8p is lost as an early event with the
R. Roylance et al
formation of isochromosome i(8q) occurring later. A
candidate gene on 8q is c-MYC located at 8q24 and a
recent FISH study using a probe for c-MYC has shown
amplification.36
Trisomy 8
Trisomy 8, rarely seen in culture,37 has been a
frequent finding in FISH studies.28,38-42 This has been
associated with an increased gleason score40,41 and
metastatic potential.38,43 Since these findings are from
FISH studies using centromeric probes, it has been
assumed that gain of the centromere represents gain
of the whole chromosome. However, as mentioned
above, this may not be correct. An alternate explana-
tion for these findings would be loss of 8p with i(8q)
formation, followed by a nondisjunction event.20
Chromosome 7
The most common clonal aberration seen with
conventional cytogenetics has been gain of chromo-
some 7.4,37,12 This aberration has also been seen using
FISH38-47 and CGH which has found both gains of the
whole chromosome,23 and also gains of only the long
arm.21,22 The biological significance of this change
remains controversial. Not only is trisomy 7 found in
other malignancies such as gliomas and bladder
carcinomas but also in benign tissues, for example
atherosclerotic plaques and rheumatoid synovitis.48
This has led some authors to suggest that it is a neutral
genomic mutation.48 This is disputed by Alcarez et
al 44 and other workers38,41,42 who have found it to be
of prognostic significance and involved in the progres-
sion of prostate cancer. Bandyk et al45 in an interesting
comparison of primary carcinoma with paired metas-
tases (but from only two samples), found that trisomy
7 in cells increased from 4–7% in the primary tumour
to 42–45% in the bone marrow. Candidate genes on
chromosome 7 include ERBB-1, PAI and RAF. Con-
versely, LOH studies have identified the region 7q31
to be the possible site for a tumour suppressor
gene.49
Loss of 13q
Loss of 13q has been a frequent finding of LOH50 and
CGH studies.20,21,23 The retinoblastoma (RB1) gene
located at 13q14 is a tumour suppressor gene that may
be involved. However, when tumours which showed
loss in this region were examined there was no
correlation between LOH at RB1 and absence of the
gene product.50 This lack of correlation suggests that
40
there is another tumour suppressor gene in this
region, and potentially another sited more distally on
13q, as from CGH studies the area of maximal loss is
at 13q21.1–31.23
Loss of 16q
Cytogenetic,12,51 molecular52 and CGH20-23 studies
have all identified deletions of 16q, but the role that
these changes play in the development of prostate
cancer is uncertain. Using cosmid contigs, Cher et al51
found that 50% of localized prostate carcinoma
samples had loss of 16q24, with the area of deletion
distal to 16q23.1–16q23.2. Conversely, Suzuki et al52
found loss of 16q in seven of 11 metastases but in
none of the paired primary tumours. In support of the
hypothesis that loss of 16q is important in progres-
sion, Visakorpi et al23 found that loss of 16q was seen
in 19% of primary tumours compared to 56% of
recurrent tumours. Interestingly the gene for
e-cadherin, the decreased expression of which is
known to have prognostic significance,53 maps to
16q22.1. However, although loss of this region has
been seen21,52 analysis of the gene has not shown any
mutations.52
Chromosome 17
Loss of 17p
Loss of 17p has been found predominantly by
CGH.20,21 It has been found in 50% of metastases but
in 65% of metastases which had become androgen-
resistant,21 suggesting that it may be important in
advanced disease. A candidate gene is p53 (17p13.1);
although rarely mutated in early prostate cancer,
frequent mutations are found in advanced disease.54
Loss of 17q
Williams et al 55 has used probes on 17q, including the
BRCA1 gene. Mutations in this gene are responsible
for an inherited predisposition to breast cancer, but
have also been implicated in prostate cancer.56 Sev-
enty percent of the samples showed loss of at least one
of the probes. However, a significant proportion of
samples had loss distal to BRCA1, suggesting the
possible presence of other tumour suppressor genes.
Whilst CGH has confirmed these losses20,23 it has also
found gains of genetic material on 17q.21,22
Loss of 5q
Loss of 5q has been found using CGH, predominantly

in recurrent tumours.21,23 The region 5q contains the
adenomatous polyposis coli (APC) gene at 5q21, which
has been found to be lost in 20% of advanced prostate
tumours using LOH.57 Perhaps more significantly the
α-catenin gene localizes to 5q22 and α-catenin is part
of the e-cadherin-mediated cell adhesion complex.
Loss of α-catenin function can result in loss of
e-cadherin function, which as discussed above plays a
role in the progression of prostate cancer. This would
explain the loss of e-cadherin protein despite preser-
vation of gene function as discussed above.
Chromosome 10
Cytogenetic studies have shown that the most com-
mon structural aberrations have involved 10q24.4,5,7
CGH has shown 10q loss21 and LOH studies have
shown regions of loss on both the short and long arm
of chromosome 10. 10p loss may be an early change
occurring in localized disease,58 whereas loss of 10q is
thought to be a late change, seen more commonly in
metastatic58 and advanced stage tumours.59 The
region of minimal loss on 10q has been narrowed
down to 10q23–25.60 A candidate tumour suppressor
gene which maps to 10q24–25 is MXI1, which
expresses a gene product that is a negative regulator
of the MYC oncogene, and has been found to be
mutated in a few prostate cancer cases.61 However,
Gray et al 60 showed that MXI1 maps outside the
minimal region of deletion on 10q, and in addition,
found no mutations in the gene. More significantly
another candidate tumour suppressor gene, PTEN
located at 10q23 has just been identified.62 It is
predicted that the PTEN product has a protein
tyrosine phosphatase domain and extensive homology
to tensin, a protein which interacts with actin fila-
ments at focal adhesions. The authors suggest that
PTEN may act to suppress tumour cell growth by
antagonizing protein tyrosine kinases and regulate
tumour cell invasion and metastasis through an effect
on focal adhesion.
Loss of Y
Loss of Y is the other most common cytogenetic
abnormality found.4,6,7,11,12,37 Like trisomy 7 this
change arouses controversy because its biological
significance is uncertain. It has been found in a variety
of other malignant tissues, including bladder tumours
where it is thought to have prognostic significance,63
and also in the bone marrow of elderly men.64
Takahashi et al 43 found that aneusomy Y correlated
41
Genetic analysis of prostate carcinoma
highly with metastatic potential of prostate cancer,
unlike isolated gain of Y. However, gains of Y and
aneusomy Y were associated with an increased mortal-
ity rate.
Amplification of the androgen receptor (AR) gene
Amplification of the AR gene has been found in
patients who initially responded to hormonal therapy
and then have become hormonally resistant.24 Ini-
tially CGH demonstrated amplification of the region
Xq11–q13. This region includes the AR gene at Xq12.
Southern blot, slot blot and FISH analysis confirmed
that the AR gene was amplified. The significance of
this finding is that it provides a hypothetical model by
which tumours may develop hormonal resistance.
Amplification of AR is selected for during androgen
deprivation, thus enabling prostate cells to survive
and grow in a low androgen environment. A further
recent study using FISH65 on hormonally-resistant
prostate cancer samples, which were paired with the
original tumour in almost half the cases, has repro-
duced these results. No amplification was found in
any primary tumours. Amplification was correlated
clinically with an initial good response to treatment
and a response which lasted more than one year. In
those tumours which had no gene amplification there
was no initial response to treatment and progression
occurred earlier.
Model for the malignant progression of
prostate cancer
It is apparent that although far from complete, a
model for the malignant progression of prostate
cancer is beginning to emerge. This model is schemat-
ically represented in Figure 2. Changes important in
the initiation and early stages of prostate cancer
appear to be deletion of 8p, whilst loss of 10q, 16q, 5q,
17p, and gains of 8q and chromosome 7 may be
important in progression and metastasis. Amplifica-
tion of the androgen receptor gene is important in
the development of hormone refractory disease.
Conclusion
Future studies should concentrate on modifying and
extending the use of the techniques described above.
Cytogenetic analysis with improved culture tech-
niques, capable of simulating the normal prostatic
R. Roylance et al
Figure 2. Diagrammatic representation of the possible
genetic changes involved in the malignant progression of
prostate cancer. Gains of genetic material are shown on the
right and losses are shown on the left. Genes where known
are shown, candidate genes involved are placed in
brackets.
environment, may help to prevent selective growth
pressures. FISH and LOH studies need to investigate
more regions of the genome. CGH has only been used
to date on a limited number of samples, yet has given
us more information than all the other studies. As
techniques are improving and examination of archival
material is now possible it should be easier to
correlate clinical data with tumour studies. This will
yield information important for the early diagnosis
and prognosis of patients. Finally, knowledge of the
mechanisms for hormonal resistance may offer hope
for the development of new therapies for this group of
patients.
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