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[CANCER RESEARCH 55, 2418-2421,
June 1, 1W5|
Genomic Instability of Microsatellite
Relationship to Clinicopathological
Repeats in Prostate Cancer:
Variables
Shin Egawa,1 Toyoaki Uchida, Kazuho Smania. Chunxi Wang, Makoto Ohori, Satoshi Irie, Masatsugu Iwamura, and
Ken Koshiba
Department of Urology, Kitasato University School of Medicine, 1-15-1 Kilasato, Sagamihara, Kanagawa 228, Japan
surgery (3 patients). It was also isolated from 25 paraffin-embedded
ABSTRACT
Sixty-six
patients with prostatic
adenocarcinoma
were screened
for
somatic instability at 8 microsatellite marker loci on 5 chromosomes.
Differences in unrelated microsatellites for tumor and normal DNA were
detected in 13 (19.7%) patients. Only extraglandular spread (nodal in
volvement and distant metastasis) was found to show significant associa
tion with somatic instability after controlling for other Clinicopathological
variables (P < 0.05).
Microsatellite instability may possibly occur during the early stages of
neoplastic transformation in a subset of prostate cancer rather than as a
late event. This may be related to a phenotype with growth advantage. The
frequency of this imitator phenotype is much higher in the United States
than Japan, reflecting racial differences in the molecular tumorigenesis of
this malignancy.
INTRODUCTION
Prostate cancer is unique among potentially lethal human malig
nancies in terms of the striking differences in its mortality rate and
incidence according to country (1, 2). Environmental factors and
differences in the probability of genetic events requisite for tumor
progression may possibly be factors of cancer cell proliferation.
Molecular mechanisms for prostate carcinogenesis are poorly under
stood despite these considerations (1-3). Recent studies on colorectal
cancer (4-6), pancreatic cancer (7), gastric cancer (7), endometrial
carcinoma (8), bladder cancer (9), and renal cell carcinoma (2) dem
onstrate ubiquitous somatic mutations in simple repeated sequences,
including microsatellite instability at (CA)n-(GT)n repeats, indicating
a new molecular mechanism for carcinogenesis. The mutator pheno
type of nucleotide repeats has also been implicated to be frequently
involved in the development and progression of human prostate
cancer (3). The authors have conducted an independent study to assess
significance of this type of mutation as a causative factor of prostate
carcinogenesis (1). Preliminary data suggest that altered microsatellite
instability is a late molecular event, but the limited numbers of
samples preclude any definitive conclusion. Our latest findings based
on analysis of many tumor specimens are thus presented and dis
cussed in the following study.
MATERIALS
AND METHODS
DNA samples from 66 patients with prostate cancer were analyzed for
somatic instability: 66 primary tumors, 3 metastatic lymph nodes, and 2 PIN2,
grade 3. No patient had a history of hereditary nonpolyposis colorectal carci
noma. All samples were obtained from Japanese patients following surgery or
biopsy at the Kitasato University Hospital. Genomic DNA was isolated from
44 frozen, primary, and metastatic tumors from patients who had undergone
radical prostatectomy (13 patients), transurethral resection of the prostate gland
(20 patients), needle biopsy (8 patients), or lymph node dissection during
Received 3/7/95; accepted 3/31/95.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with
18 U.S.C. Section 1734 solely to indicate this fact.
1To whom requests for reprints should be addressed.
2 The abbreviations used are: PIN, prostatic intraepithelial neoplasia; RER, replication
error; LOH, loss of heterozygosity.
primary
prostate cancers following radical prostatectomy. DNA samples from the area
of PIN, grade 3, were analyzed for two cases. Analysis of DNA from corre
sponding peripheral blood samples was made at the same time. To detect
alterations with greater sensitivity, sequential frozen sections were mounted on
glass slides, stained, and microscopically examined to find areas preferentially
containing more tumor or fewer nontumor cells. Areas of tumor involvement
exceeding 80% on histológica! sections were located and used for analysis. An
average of five biopsy cores were obtained transrectally from the area of a
hypoechoic, bulky tumor using a Biopty gun under sonographic guidance. One
core was evaluated pathologically to determine whether it had been replaced
completely with a tumor. Genomic DNA was extracted by proteinase K
digestion and phenol/chloroform extraction. DNA pellets were dissolved in
1/10 TE (1 mM Tris-HCl-0.1 mM EDTA). All specimens were graded and
staged according to the Gleason grading system and TNM classification (10).
Gleason scores of 2 to 4 were considered well differentiated, 5 and 6, mod
erately differentiated, and 7 to 10, poorly differentiated tumors.
Primer pairs of eight microsatellites, D3SÌ228(3pl4.1-14.3),
D3S643
(3p21.3),¿PC(5q21),O5S/07(5q),mJGr(8p22),
D17S261 (17pl2-ll.l),
p53 (17p), and DCC (18q21) genes, were synthesized with an Applied Biosystems Model 392 DNA/RNA synthesizer (2, 11). Standard PCR was con
ducted as described previously (2) in a 12.5 ml solution of 50 ng DNA
template, 10 mM Tris-HCl (pH 8.8), 50 mM KC1, 1.5 mM MgCl,, 0.1% gelatin,
0.2% formamide, 0.5 mM of 5'-end labeled primers, and 0.625 units Ampli Taq
polymerase (Takara Shuzo, Kyoto, Japan). 5'-end labeling of primers was
conducted using T4 polynucleotide kinase (Takara) and [7-32P]ATP at 7000
Ci/mmol (ICN, Tokyo, Japan). Each sample was overlaid with mineral oil and
processed through 40 cycles of 30 s each at 94°C,30 s at 55°C,and 1 min at
72°C.Aliquots of amplified DNA were mixed with 8 ml formamide stop dye
solution and electrophoresed on 8% polyacrylamide standard denaturing DNA
sequencing gels. The gels were dried on filter paper, followed by autoradiography at room temperature for 30 min to 24 h with an intensifying screen.
Association between variables was assessed by the Chi-square test and
stepwise multivariate logistic regression analysis using STATA statistics soft
ware package (Computing Resource Center, Santa Monica, CA). P < 0.05 was
considered statistically significant.
RESULTS AND DISCUSSION
PCR-based microsatellite instability assay was conducted on 66
patients with prostatic adenocarcinoma for possible mutator phenotypes at 8 microsatellite marker loci on 5 chromosomes. Differences
in unrelated microsatellites for tumor and normal DNA were detected
in 13 (19.7%) patients. Somatic instability at loci on chromosomes 3p,
5q, 8p, 17p, and 18q was apparent in 10.8% (7 of 65), 13.6% (9 of 66),
10.6% (7 of 66), 13.6% (9 of 66), and 17.1% (6 of 35), respectively.
In eight cases, genetic instability in at least two microsatellites could
be detected (Fig. 1). The alterations showed considerable variation
from a 2-bp change in some tumors to a larger change in length in
others. All patterns were completely reproducible in replicate assay.
No similar genetic alterations could be found in PIN, grade 3. DNAs
obtained from metastatic lymph nodes showed the same patterns as
the primary tumor in three individuals. Two of these cases demon
strated somatic instability. No significant correlation between patient
age and frequency of microsatellite instability was found (P > 0.05;
X2). Mutator phenotypes of repeated nucleotides were apparent in 3
of 13 (23.1%) with Stage T„3 of 22 (13.6%) with stage T2, 7 of
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MICROSATELLITE
INSTABILITY
24
D3S643
ARC
N T
N
D5S107
N
T
LPL5GT
p53
N T
N T
T
IN PROSTATE
CANCER
moderately differentiated tumors, and 12 of 48 (25.0%) with poorly
differentiated prostatic adenocarcinomas (Table 2). The observed
increase in the frequency of somatic instability in poorly differentiated
tumors compared with moderately and well-differentiated counter
parts was not statistically significant (P = 0.077; x2). Of 21 tumors
with distant metastasis, 6 (28.6%) displayed somatic instability to a
greater extent than 7 of 45 (15.6%) tumors without metastasis, al
though not to a statistically significant degree (P > 0.05; )C\ Table 3).
Somatic instability was apparent in 4 of 35 (11.4%) primary tumors
without and 3 of 10 (30.0%) with nodal metastasis in patients showing
no distant metastasis (P > 0.05; x2). Of 50 tumors without previous
hormone manipulation, 9 (18.0%) had somatic instability, as did also
4 of 16 (25.0%) hormone-resistant tumors (P > 0.05; x2). No tumor
from 8 patients without or 13 of 58 (22.4%) with a history of smoking
showed alterated nucleotide repeats, indicating somatic instability
(P > 0.05; x2)- These findings were also evaluated by backward
B
D5S107
N
LPL5GT
T
N
DCC
T
N
T
Fig. 1. Auloradiographs of microsatellite instability assay in prostate cancer. The
corresponding loci are indicated at the lop of each electrophoretic pattern. Alterations in
each microsatellite locus could be seen in cases 24 (A) and 216 (fl) advanced tumors (7")
in contrast to normal controls (A7).
31 (22.6%) with stage T,, and none of stage T4 diseases (Table 1).
Somatic instability was more frequent in advanced (T,-T4; 22.6%)
than localized disease (T,-T2, 17.1%). However, there was no statis
tically significant association between local tumor stage and somatic
instability (P > 0.05; x2). Somatic instability was evident in 1 of 4
(25.0%) with well-differentiated
tumors, none of 14 (0.0%) with
stepwise logistic regression analysis. Nodal (N,) and distant metasta
sis (M,) appeared to be significantly associated with somatic insta
bility after controlling for other variables (P = 0.045). Tumors that had
spread far beyond the confines of the prostate showed microsatellite
instability 5.3 times more frequently than those in less advanced
disease. No other covariates including patient age, tumor grade, local
tumor stages, status of hormone resistance, or history of smoking
showed statistical significance by multivariate analysis.
The incidence of microsatellite instability in prostate cancer was
shown here to be essentially the same as that in sporadic colorectal
carcinoma (11.6-28.0%) as reported in the literature (4-6). Two
other investigators have studied the association of microsatellite mu
tation with prostate carcinogenesis. Microsatellite mutations in androgen receptor gene at the CAG trinucleotide repeat could be found in
only 1 of 40 (2.5%) patients with prostate cancer (12). Interestingly,
this individual later manifested paradoxical agonistic response to
hormonal therapy with antiandrogen. In the other study, 37 of 57
(64.9%) patients with prostatic adenocarcinoma possessed a mutator
phenotype in at least 1 of 18 microsatellite marker loci on 12 chro
mosomes (3). Forty-four % of the patients showed microsatellite
instability at two or more loci. Somatic instability was more frequent
in advanced (T,; 69.7%) than localized disease (T2, 58.3%; P > 0.05).
Low grade tumors showed significantly lower frequency of mutator
phenotypes than high grade tumors (57.1 versus 86.7%; P < 0.05).
The authors thus considered that the mutator phenotype may be
importantly involved in the progression of prostate cancer and more
Table 1 Frequencv of niicrostitellite instability in relation to clinical stages in prostate cancer"
T.-T,
T,-T,
M„
Chromosome
%3p
Non-Re
%50.0
%18.2
%0.0
%0.0(0/2)0.0(0/2)0.0(0/2)0.0(0/2)0.0(0/1)0.0(0/2)Non-Re
%10.8
6.7
(2/30)5q
(0/1)0.0(0/1)0.0(0/1)0.0(0/1)0.0(0/1)0.0(0/1)Non-Re
(1/2)50.0
(1/2)100.0
(2/11)25.0
(0/6)0.0(0/6)16.7 (1/11)9.1
(7/65)13.6
6.7
(2/30)8p
(1/11)18.2
(9/66)10.6
(1/2)50.0
(2/2)0.0
(3/12)16.7
(1/2)50.0
(0/2)50.0
(2/12)25.0
(3/30)18q
(1/2)50.0
(1/2)0.0(0/1)100.0 (3/12)60.0
(1/11)0.0(0/6)18.2 (9/66)17.1
15.4
(2/13)10.0(3/30)TotalsRe%0.0
(1/2)50.0
(3/5)33.3
(6/35)19.7
3.3
(1/30)17p
(1/6)0.0(0/6)0.0(0/6)16.7
(2/11)9.1
(7/66)13.6
10.0
(1/2)17.1
(2/2)Non-Re
(4/12)Re
(6/35)Re%50.0
' M,,, no distant metastasis; M,, distant metastasis; Non-Re, no androgcn ablation; Re, hormone resistant.
(1/6)22.6
(7/31)Re%9.1
(2/11)Totals
(13/66)
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MICROSATELLITE INSTABILITY IN PROSTATE CANCER
Table 2 Frequency of microsatellite
instabili^
in relation to tumor grade in prostate cancer0
WellMO
MOChromosome3p5q8p17p18qTotals
M!
r'Ã-20.0(2/10)30.0(3/10)20.0(2/10)20.0(2/10
%25.0(1/4)25.0(1/4)25.0(1/4)25.0(1/4)50.0(1/2)25.0(1/4)25.0(1/4)Non-Re
%
Re
%0.0(0/9)0.0(0/9)0.0(0/9)0.0(0/9)0.0(0/1)0.0(0/9)Re%0.0(0/1)0.0(0/1)0.0(0/1)(1.0(0/1)0.0(0/1)0.0(0/1)Mod.MNon-Re
%0.0(0/1)0.0(0/1)0.0(0/1)0.0(0/1)0.0(0/1)0.0(0/1)(U)(0/14)lRe
%10.7(3/28)13.8(4/29)6.9(2/29)17.2(5/29)26.7(4/15)20.7(6/29)MRe
%0.0(0/2)0.0(0/2)0.0(0/2)0.0(0/2)0.0(0/1)0.0(0/2)25.0(12/48)14.3(1/7)14.3(
%
Non-Re
%0.0(0/3)0.0(0/3)0.0(0/3)0.0(0/3)0.0(0/2)0.0(0/3)PoorMONon-Re
%10.8(7/65)13.6(9/66)10.6(7/6
%Non-Re
" M0. no distant metastasis; M,, distant metastasis; Non-Re, no androgen ablation: Re, hormone resistant; Well, well-differentiated
tumors; Mod., moderately differentiated tumors;
Poor, poorly differentiated tumors.
likely to occur in poorly differentiated tumors. Mutation was less
frequent in this study. Poorly differentiated histology was not a
significant covariate. Microsatellites constitute one of the most abun
dant classes of repetitive DNA families in humans. Approximately
50,000 to 100,000 (CA)n repeats are scattered throughout human
genomes (5). Somatic mutations in human cancers are not restricted to
dinucleotides but are found as well in mono-, tri-, tetra-, and pentanucleotide simple repeats (3, 6, 13). Only alterations in dinucleotide
repeats were studied here. Fewer marker loci, different locations, and
repeat elements of microsatellite probes may also be an explanation.
It is thus quite likely that mutation detection will become much more
frequent through use of a number of markers. Nevertheless, if gener
alized genomic instability is a major indication of neoplastic trans
formation, distinct differences in the frequency of microsatellite in
stability in multiple loci (19.7 versus 64.9%) may be a demonstration
of racial differences in molecular tumorigenesis of prostate cancer
rather than those in assay sensitivity (3, 12). Oriental males may be
genetically less sensitive or have less chance of exposure to certain
carcinogens that cause alterations in microsatellites in prostate cancer
than other races. Smoking was shown not associated with genomic
instability. But more complete confirmation of this point is needed
because of the limited numbers of patients analyzed in this study.
Extraprostatic spread, especially nodal involvement and distant
Table 3 Frequency of microsatellite
metastasis, is a well-established serious prognostic factor in prostate
cancer. The association of somatic instability with such a factor is not
found in colorectal cancer. Alterations in RER-positive colorectal
cancers have been shown to be correlated significantly with increased
patient survival compared to RER-negative tumors (5). Somatic in
stability has been shown significantly associated with the poorly
differentiated histology of gastric cancer (7). Molecular mechanisms
involved in tumor progression may thus be organ or site specific. The
putative tumor suppressor gene, DCC, may possibly function as a
metastatic suppressor, based on observations of human colon cancer
and Dunning prostate carcinoma cell lines (14). The reduced expres
sion of this gene was inversely correlated with metastatic and invasive
potential in these tumors. Loss of DCC expression and heterozygosity
at the DCC locus was frequently seen in prostate cancer. Alterations
of microsatellites at the DCC locus may also be related to downregulation of this gene and may confer selective growth advantage to
tumor cells, with or without subsequent mutations in various microsatellite-related genes in prostate cancer.
Approximately 60% of advanced prostate cancer possess LOH
for chromosomes 3p, 7q, 8p, 9q, 10p, lOq, lip, 13q, 16p, 16q, 17p,
or 18q (15, 16). In this study by PCR-based microsatellite insta
bility assay, LOH was seen in eight tumors (12.1%), including
three at 3p, seven at 5q, two at 8p, three at 17p, and none at 18q.
instability in relation to tumor extension, androgen dependency, and exposure to smoking"
Status of tumor
MO
Chromosome
%3p
N0
%22.2
%14.3
%10.8
5.7
(2/9)30.0(3/10)10.0 (3/21)19.0(4/21)19.0(4/21)14.3(3/21)6.7
(2/35)5q
(2/16)18.8
(0/8)0.0(0/8)0.0(0/8)0.0(0/8)0.0(0/2)0.0(0/8)%12.3(7/57)15.5(9/58)12.1
(7/65)13.6(9/66)10.6(7/66)13.6(9/
5.7
(2/35)8p
(6/50)10.0(5/50)14.0(7/50)23.1(6/26)18.0(9/50)Re%12.5
(3/16)12.5
5.7
(2/35)17p
(1/10)20.0
(2/16)12.5
(7/58)15.5
(2/10)50.0
(2/16)0.0(0/9)25.0
(9/58)18.2
11.4
(4/35)18q
14.3
(2/14)11.4
Totals
(4/35)%N,
(3/6)30.0
(3/10)
15.6(7/45)M,
(1/15)28.6
(6/21)%10.2(5/49)12.0
(4/16)%0.0
(6/33)22.4
(6/35)19.7
(13/58)Totals
(13/66)
' M,,, no distant metastasis; Mj, distant metastasis; Non-Re, no androgen ablation; Re, hormone resistant.
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MICROSATELLITE
INSTABILITY
The difference in frequency could be due to the method used to
detect LOH. Three tumors showed alterations in band patterns due
to instability as well as LOH in the microsatellite of D5S107. Five
of eight tumors with alteration at multiple loci and two of five with
alteration at a single locus showed LOH. One tumor showed LOH
without somatic instability. No significant association between somatic
instability and LOH, inversely correlated in colorectal cancer (5), could
be detected here.
The precise mechanism by which this phenotype with RER con
tributes to tumorigenesis is unclear. Alterations have recently been
shown associated with defects in the early stage of mismatch repair
(17). The cloning of the mismatch repair gene homologue, hMSH2,
and hMLHI genes has been carried out and indicated them to be
situated on the HNPCC locus in chromosome 2p22-21 an 3p21-23,
respectively. Mutations of these genes have been detected in heredi
tary nonpolyposis colorectal carcinoma kindred and sporadic colorec
tal cancers with microsatellite instability (18-20). Loss of molecular
functions essential for controlling DNA replication/repair may in
crease the frequency of spontaneous mutations, with consequent chro
mosome loss and rearrangement. Although defects in the replication/
repair machinery of prostate cancer have yet to be identified,
mutations of HMSH2 and hMLHI genes or other subtle defects in
repair pathways may cause alterations in microsatellites in prostate
cancer.
Microsatellite instability may possibly occur initially during the
early stages of neoplastic transformation in a subset of prostate cancer
rather than as a late event. Distinct subtypes of prostate cancer may
follow different genetic pathways during tumorigenesis. Somatic in
stability may be independently related to a phenotype capable of
invading outside the confines of the prostate gland. PCR-based mic
rosatellite instability assay may serve as a useful molecular prognostic
marker in prostate cancer patients. The frequency of this mutator
phenotype is much higher in the United States than Japan, possibly
indicating underlying racial differences in the molecular tumorigen
esis of this malignancy. Microsatellite instability and the DNA repli
cation/repair mechanism in the pathogenesis of prostate cancer should
be suitable objectives for molecular epidemiológica! studies and
should be investigated in greater detail to confirm the present
observations.
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Downloaded from cancerres.aacrjournals.org on June 11, 2017. © 1995 American Association for Cancer Research.
Genomic Instability of Microsatellite Repeats in Prostate
Cancer: Relationship to Clinicopathological Variables
Shin Egawa, Toyoaki Uchida, Kazuho Suyama, et al.
Cancer Res 1995;55:2418-2421.
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Downloaded from cancerres.aacrjournals.org on June 11, 2017. © 1995 American Association for Cancer Research.