Download Clinically localised prostate cancer is microsatellite stable

Urological Oncology
LOCALISED PROSTATE CANCER IS MICROSATELLITE STABLE
AZZOUZI
et al.
Clinically localised prostate cancer is microsatellite stable
Abdel-Rahmene Azzouzi*†, James W.F. Catto‡, Ishtiaq Rehman‡, Stephane Larre†,
Morgan Roupret†, Kenneth M. Feeley§, Oliver Cussenot†¶, Mark Meuth∞ and
Freddie C. Hamdy‡
*Service d’Urologie, CHU d’Angers, †Centre de Recherche pour les Pathologies Prostatiques, Université Paris VII, Paris,
France, ‡The Academic Urology Unit, University of Sheffield, §Department of Pathology, Royal Hallamshire Hospital,
Sheffield, UK, ¶Service d’Urologie, Hôpital Tenon, GHU Est, France and °The Institute for Cancer Studies, University of
Sheffield, UK
Accepted for publication 12 October 2006
OBJECTIVES
same instability rate (4%) amongst the EMAST
markers. These four tumours were all unstable
at one locus of the 10 markers of the BCP that
classified them as MS stable.
To determine the frequency of microsatellite
instability (MSI) change with mono-, di- and
tetranucleotide markers in clinically localized
prostate cancer, and to correlate those
markers with clinical and pathological
variables.
second variety of MSI is best seen at selective
tetranucleotide repeats, i.e. elevated
microsatellite alterations at select
tetranucleotides (EMAST). Prostate specimens
were taken from 50 patients. The MS analysis
used the Bethesda consensus panel (BCP) and
four tetranucleotide loci shown to detect the
presence of EMAST.
MATERIALS AND METHODS
RESULTS
Two forms of MSI have been described in
human cancer: MSI typical of hereditary
nonpolyposis colon cancer, defined with
mono- and dinucleotide repeat MS; and a
All but four tumours were stable for the 14
loci investigated. There were two (4%) cases
with adenomatous polyposis coli (APC)
instability among the BCP markers and the
KEYWORDS
INTRODUCTION
pentanucleotide repeat sequences, found in
both exonic and intronic DNA. Whilst their
function is unknown, they are useful markers
of genetic instability and for linkage analyses.
MSI, as seen in hereditary nonpolyposis colon
cancer (HNPCC) is caused by defective DNA
mismatch repair (MMR). Loss of MMR can
occur by mutation of one of the central genes
(either hMLH1 or hMSH2 in HNPCC) or
methylation of the promoter (of hMLH1 only,
in most sporadic cancers with MSI) [3–5]. MSI,
due to deficient MMR, is usually defined with
mono- and dinucleotide markers. There are
different definitions of MSI at mono- and
dinucleotide markers. Honchel et al. [6]
classified a tumour as MSI when ≥30% of the
loci investigated were unstable, whereas
others recommended the use of a panel of 10
MS markers and instability in ≥40% of MS loci
was taken to indicate MSI [7]. In addition to
those different definitions of MSI, the
National Cancer Institute workshop on MSI
for cancer-detection recommendations seems
to be the most appropriate approach to study
the field. They characterized MSI as:
• High-frequency MSI (MSI-H), if two or more
of a panel of five markers show instability
• Low-frequency MSI (MSI-L), if only one of
the five markers shows instability
• Distinct from MS stable (MSS), none or one
of 10 markers shows instability, and MSI-L
needs a panel of 10 markers [8].
Prostate cancer is a major burden in the
industrialized Western world; it is the most
prevalent cancer in males and the second
leading cause of cancer deaths [1]. Molecular
genetic mechanisms involved in the
progression of prostate cancer are not well
understood, due to extensive tumour
heterogeneity and a lack of suitable models.
It is suggested that increased genomic
instability is associated with decreased
androgen responsive and progressive
behaviour of human prostate tumours.
Genetic instability is important in human
carcinogenesis and has traditionally been
classified into two categories, according to
genomic targets [2]. Chromosomal instability
is characterized by frequent chromosomal
losses and gains, but to date the cause is
unknown. Microsatellite instability (MSI) is
characterized by alterations at the individual
DNA nucleotide level, and is best seen in the
MS regions of DNA. These are ubiquitous
repetitive mono-, di-, tri-, tetra- and
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CONCLUSIONS
The MSI related to a mismatch repair
deficiency or to the EMAST does not seem to
be important in prostate cancer in the early
stages of the disease.
microsatellite instability, mismatch repair
system, EMAST, prostate cancer
More recently, a novel form of MSI was
described that is best seen in selective
tetranucleotide repeats; this was termed
EMAST, for ‘elevated MS instability at selected
tetranucleotide repeats’ [8] and appears to be
distinct from the MSI seen in HNPCC and
related tumours [9]. Although the underlying
mechanism causing EMAST is unclear, an
association with p53 mutations was reported
[10,11] and exposure to environmental
carcinogens can induce EMAST [12]
Our objectives were to determine the incidence
of MSI at mono- and dinucleotide and EMAST
markers in clinically localized prostate cancer,
and to correlate those markers with clinical
and pathological variables.
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PATIENTS AND METHODS
Prostate specimens were taken from 50
patients who had radical surgery (radical
prostatectomy in 43 and incidental prostate
cancer from radical cystoprostatectomy in
seven) between March 1996 and March 2002
at the Royal Hallamshire Hospital (Sheffield,
UK). The patient age, PSA level, pathological
stage (pT), pathological Gleason score, and
follow-up and recurrence data, were
recorded. Ethics committee approval was
granted, and informed consent was obtained
from all patients before starting the study.
From each prostate specimen, six slides of 10µm formalin-fixed, paraffin wax-embedded
sections were microdissected to obtain
cancerous (>80% tumour) and normal tissue,
which was distant from the malignancy. DNA
was extracted from the microdissected
specimens using the QIAamp® kit (Qiagen, UK)
according to the manufacturer’s guidelines.
MS was analysed for each prostate cancer
using paired normal and tumour DNA. The
MSs studied were composed of the
standardized Bethesda consensus panel (BCP)
consisting of BAT25, BAT26, MFD15
(D17S250), D2S123, APC (D5S346), BAT40,
D10S197, MYC1L, D18S58, D18S69 [9]; and
four tetranucleotide loci known to detect the
presence of EMAST (ACTBP2, CSF1R, D20S82,
D11S488) [9,11].
FIG. 1. MSI in clinically localized prostate cancers. Fluorescence-labelled PCR products are shown from the
four unstable tumours (U) and compared to three representative stable tumours (S). All the samples shown
were extracted from tumoral areas.
APC
U
U
D20S82 D11S488
S
U
(patient 41) (patient 42)
The PCR set up was automated using the
RoboAmp® 4200 PE (MWG Biotech, UK).
Briefly, PCR using fluorescence-labelled
primers (MWG Biotech) was performed for
each sample at each locus. The primer
sequences were published previously [7,11].
PCR was done in a 12-µL volume reaction,
composed of 1 pmol fluorescence-labelled
forward and unlabelled reverse primers, 50 ng
of DNA template and a pre-made PCR
mastermix solution of Taq DNA polymerase,
dNTPs, 1.5 mM MgCl2 and buffers (Abgene,
Surrey, UK). For each MS locus a standard
reaction was used with 40 cycles of
amplification using a ‘Priamus 96’ thermal
cycler (MWG Biotech). Each cycle consisted of
denaturation (95 °C for 30 s), annealing and
extension (72 °C for 30 s). A final extension at
72 °C was done for 5 min. Annealing
temperatures varied for each MS locus and
are listed elsewhere [13]. The PCR product was
analysed on a LICOR automated sequencer
(MWG Biotech). The presence of extra or
shifted bands in tumours when compared to
their normal counterparts was scored as MSI.
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S
(patient 44)
For each case of MSI, the PCR reaction was
independently repeated to confirm the result.
All loci were studied in each tumour. When no
product was detected after PCR, the reaction
was repeated twice to confirm that no
amplification was possible.
The chi-square test was used to examine
relationships between the clinicopathological
and MS data; P < 0.05 was considered to
indicate statistical significance.
RESULTS
From the MS analysis, all but four tumours
were MSS for the 14 loci investigated. All four
MSI-positive tumours were from patients
who had had a radical prostatectomy. There
were two (4%) cases with APC instability
among the BCP markers and the same
instability rate (4%) amongst the EMAST
markers (D11S488 and D20S82) (Fig. 1). These
U
S
(patient 50)
four tumours were all unstable at one locus of
the 10 markers of the BCP, which classified
them as MSS whatever definition was used.
The median (range) age, PSA level and Gleason
score at diagnosis were, respectively,
62.3 (36–80.8) years, 9.25 (1.5–24.1) ng/mL
and 6 (4–8). Of the 50 tumours 23 (46%) were
pT2 and 27 were pT3 (54%). The median
follow-up was 41.2 (1–84) months. The
biochemical recurrence rate was 25.6%. There
was no association between the four MSIunstable tumours and any clinical or
pathological data, including the recurrence
status (Table 1).
DISCUSSION
According to the definitions of MSI by
previous authors and the Bethesda Consensus
Workshop, most of the population in the
present study was MSS. Interestingly, the rate
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of instability at mono- and dinucleotide loci
(BCP) was equal to that seen at
tetranucleotide (EMAST) loci (4%).
Initially, we planned to use
immunohistochemistry to evaluate the
hMLH1 and hMSH2 protein expression status
on the prostate cancer slides. However, as the
results clearly showed that clinically localized
prostate cancer tumours were all MSS, the
immunohistochemistry became irrelevant.
MSI at mono- and dinucleotide markers was
identified with a frequency of 2.5–65%
in human prostate cancer [14–21]. The
discrepancy in frequencies of MSI in prostate
cancer found by different investigators could
be explained by the use of different MS loci
markers as well as different definitions of the
MSI. The choice of these particular mono- and
dinucleotide markers was based on the
international criteria for determining MSI in
colorectal cancer [8]. Also, the preparation of
the cancer tissue, which could be a possible
cause of differences in MSI incidences among
different studies, should be considered. In the
present study we retained the Bethesda
definition, although the results would be
identical with the Honchel et al. [6] or
Dietmaier et al. [7] definitions. Interestingly,
applying different definitions to the studies
cited previously [14–21] gives variable results
(Table 2).
Gao et al. [21] published the first report
investigating MSI in prostate cancer, and
found the highest MSI frequency (65%)
published to date. It appears that 44% of
these tumours showed MSI at multiple loci,
although a correlation with the BCP is
difficult. Terell et al. [14] reported a low
instability rate (2.5%) very close to the
present rate (4%). All MS changes were seen
solely in those non-dinucleotide markers that
reduce the instability rate to zero if we only
consider the instability linked to MMR
deficiency.
Crundwell et al. [15] found an instability rate
of 19% in 72 patients with prostate cancer,
using a panel of 21 markers. None of the
internationally recognized definitions showed
an instability rate of >9.5% for that study.
Egawa et al. [16] screened 66 patients with
prostate cancer for somatic instability, and
classed 19.7% of the tumours as unstable. In
eight cases, genetic instability could be
detected in at least two MS (12.1% MSI-H
rate according to the BCP definition). Uchida
et al. [17] assessed 24 DNA samples from
primary prostate cancer, and detected genetic
TABLE 1 The clinical and pathological data of patients with an unstable MS locus
Patient no.
41
42
44
50
P
Age at diagnosis, years
62.8
63.1
53.9
57.6
0.42
Pathological stage
3b
2c
3b
3b
0.35
Gleason score
3+3
3+3
2+3
3+3
0.45
Recurrence status
1*
0†
0
1
0.28
*1 = recurrence, †0 = no recurrence.
instability in nine of them (37.5%); five were
MSI-H (21%). Watanabe et al. [18] found 43%
MSI in 21 prostate cancers analysed by 36 MS
markers, 34 of which were dinucleotide loci. In
three tumours there was instability at more
than one locus. Thus the MSI-H rate could be
considered as high as 14.3% according to
the Bethesda definition, but is zero by the
other definitions; notably, the tri- and
tetranucleotide marker instability rate was
zero in that study.
Cunningham et al. [19] analysed 55 prostate
cancers using 135 polymorphic MS markers;
18 tumours had alterations at one or two loci
of the 135. Of the 5803 genotypes, MSI was
detected only at 22. These tumours are all
MSS by any definition. Eventually, Dahiya
et al. [20] investigated the genomic instability
associated with prostate cancer using 36 MS
markers. Their results suggest that 45% (18 of
40) of the tumours had genomic instability.
Again, the instability rate was <15% by any of
the internationally recognized definitions.
Overall, in these previous studies, the original
results of MSI fluctuated between 2.5% and
65%. However, applying strict recognized
definitions reduces most of the results to
≈10%, except for the study of Uchida et al.
[17], at 20.8%.
Recently, Sun et al. [22] evaluated the
presence of MSI in six cell lines and 22
xenografts from either high-grade primary
tumours or metastases of prostate cancer.
They found a 14% incidence of MSI in the
xenografts, which suggested a similar
frequency of MSI to that in advanced human
prostate cancer. Therefore, the frequency of
MSI should be even lower than 14% in
localized prostate cancers, because most of
such tumours are mid- to low-grade, and
genetic alterations are much less frequent in
TABLE 2 Comparison of instability rates according to different definitions of MSI. Each study has been reassessed according strict recognized definitions of MSI.
Original results
No. of
patients
40
72
66
24
21
55
40
57
Reference
Terell et al. [14]
Crundwell et al. [15]
Egawa et al. [16]
Uchida et al. [17]
Watanabe et al. [18]
Cunningham et al. [19]
Dahiya et al. [20]
Gao et al. [21]
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Instability
rates, %
2.5
19
19.7
37.5
43
Very low
45
65
Definitions
Bethesda
MSI-H, %
0
9.5
≤12.1
20.8
≤14.3
0
15
11–44
Honchel et al. [6]
Unstable, %
0
0
≤12.1
20.8
0
0
2.5
≤11
Dietmaier et al. [7]
MSI (+), %
0
0
≤12.1
20.8
0
0
0
≤11
Number of
loci studied
12
21
8
9
36
–
36
16
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A Z Z O U Z I ET AL.
mid- or low-grade tumours. The conclusion of
Sun et al. is in agreement with the present
results.
First reported in HNPCC, the MSI-H
phenotype is associated with loss of MMR
[5], probably as a result of an exogenous
mutagenic agent. In HNPCC it is the mutation
of the remaining MMR gene allele that results
in defective MMR. In sporadic MSI-H tumours,
it is the mutation or methylation of the MMR
genes that is responsible for MMR loss. Whilst
the cause of abnormal regional hyper- and
hypomethylation in cancer is unknown, its
anatomical specificity suggests that an
exogenous agent is the cause. Loss of MMR
results in the mutator phenotype, which
allows the malignant cell to accumulate
replication errors at a high frequency. These
mutations cause most disruption to the cell,
and are seen most easily in tumours with a
high mitotic activity. Prostate cancer is
typically slow growing, and therefore does
not appear to be a good candidate for MSI.
Two criteria seem to be needed for a tumour
to become MSI-H; exposure to carcinogens
and a high mitotic index of the tissue exposed.
Intestinal, respiratory and urinary tracts and
skin match these two criteria, and therefore
the MSI-H phenotype is common for tumours
arising from these organs. Conversely, tissues
poorly or unexposed to carcinogens with low
(prostate) or absent (brain) mitotic index
rarely have a MSI-H phenotype [14,18,23].
Even gliomas, which are associated with
HNPCC in Turcot’s syndrome, have a very low
instability rate (<4%) [24]. The liver is even
more interesting, as it is highly exposed to
carcinogens but has a very low mitotic index.
Some studies suggest that MSI is a rare event
during hepatocarcinogenesis [25]. Another
interesting comparison is with breast cancer,
often mentioned as the ‘female prostate
cancer’. In agreement with the present results,
reports show a low frequency of MSI-H in
breast cancer [26]. For prostate cancer, as for
breast cancer, a low level of MSI-H is
expected, as the natural history suggests the
cause is likely to be hormone-related, rather
than related to exogenous exposure to
carcinogens.
In a recent report by Burger et al. [27],
HNPCC-type MSI, detected by the National
Cancer Institute consensus panel, appeared to
be rare in prostate cancer (7.6%). Also, for the
first time those authors investigated the role
of EMAST in prostate carcinoma and found
that only 5% of all cases showed EMAST. This
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is the lowest frequency of EMAST detected in
several cancer types published, and indicates
a minor role of this specific form of MSI in
prostate carcinogenesis. Both HNPCC type
MSI and EMAST results of Burger et al. [27]
are in agreement with the present findings. In
two previous studies, the prevalence of
tetranucleotide instability was, respectively,
zero and 2.5% [14,17], similar to the present
results. Conversely, Perinchery et al. [28]
found that 25% (10 of 40) of tumours had
tetranucleotide instability, although only one
marker of five was unstable in each tumour.
Whether or not these tumours could be
classified as EMAST(+) is unclear.
In the present study we assessed only
clinically localized prostate cancer. The
frequency of p53 mutations is reported to be
≈5% in organ-confined prostate cancer [29].
These results are in accordance with the 4%
of EMAST(+) found in the present study.
Indeed, Ahrendt et al. [30] suggested that a
non-MMR pathway might be involved in the
mechanism underlying MS alterations in
EMAST, which is probably related to
abrogation of a p-53-dependent repair
pathway.
In conclusion, consistent published reports,
including the present study, suggest that MSIH is rare in clinically localized prostate cancer.
This is supported as follows: (i) most studies
of MSI in prostate cancer show <10% of MSIH tumours when re-assessed using strictly
recognized definitions; (ii) unlike cancers with
frequent MSI-H phenotype, the prostate is
neither exposed to carcinogens nor has a high
mitotic index tumour; (iii) in breast cancer,
which in many aspects is similar to prostate
cancer, MSI-H is uncommon; (iv) p53
mutations, which might be associated
with EMAST, are rare in clinically localized
prostate cancer; (v) a higher incidence of
prostate cancer is not seen in HNPCC
kindred. In addition, as confirmed by
many studies, there is no correlation between
the MSI rate and stage, histopathological
characteristics or recurrence rate of prostate
cancer, and therefore identifying MSI
seems to have no clinical significance as a
biomarker for prostate cancer, at least at an
early stage.
CONFLICT OF INTEREST
None declared.
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Correspondence: Abdel-Rahmene Azzouzi,
Service d’Urologie, CHU d’Angers, 4, rue
Larrey, 49933 Angers, France.
e-mail: [email protected]
Abbreviations: MS(S)(I); microsatellite,
(stable) (instability); EMAST, elevated
microsatellite alterations at select
tetranucleotides; HNPCC, hereditary
nonpolyposis colon cancer; MMR, DNA
mismatch repair; BCP, Bethesda Consensus
Panel; MSI-H, high-frequency MSI; MSI-L,
low-frequency MSI.
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