Clinical Cancer Research Vol. 7, 304-308, February 2001
© 2001 American Association for Cancer Research
Molecular Oncology, Markers, Clinical Correlates |
Mutations of PTEN/MMAC1 in Primary Prostate Cancers from Chinese Patients1
Jin-Tang Dong2,
Chang-Ling Li,
Tavis W. Sipe and
Henry F. Frierson, Jr.
Departments of Pathology [J. T. D., T. W. S., H. F. F.] and Biochemistry and Molecular Genetics [J. T. D.], University of Virginia Health System, Charlottesville, Virginia 22908, and Department of Urological Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing 100021, China [C. L. L.]
 |
ABSTRACT
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PTEN/MMAC1 is a putative tumor suppressor gene located on
10q23, one of the most frequently deleted chromosomal regions in human
prostate cancer. Although mutations of PTEN have often
been detected in metastases of prostate cancer, localized tumors have
shown lower rates of mutation, which have varied from 0 to 20% among
different studies. It is unknown whether the rate of
PTEN mutations is different in prostate cancer from
Asian men compared with Western men. To further clarify the role of
PTEN in prostate cancer and to examine the gene for
mutations in Asian men, we analyzed 32 cases of primary prostate
cancers from Chinese patients, each of whom was not diagnosed by
screening with serum prostate-specific antigen, for PTEN
mutations using the methods of tissue microdissection, single-strand
conformational polymorphism, and direct DNA sequencing. Seventy % of
the tumors were Gleason scores 8–10, whereas the remainder were
Gleason score 7. Six metastases of prostate cancer from American
patients were also analyzed. Five of 32 (16%) primary prostate cancers
from Chinese men and two of six metastases from American men showed
mutations in a total of 10 codons of PTEN, which
involved exons 1, 2, 5, 8, and 9. Two of the mutations were truncation
type, whereas the rest were missense mutations. The mutation frequency
in these cases from Asian patients was higher than that in our previous
study of cases in radical prostatectomy specimens from American men, in
which the 40 primary tumors were lower grade and had been detected by
serum prostate-specific antigen test. We conclude that mutation of
PTEN occurs more often in primary prostate cancers of
Chinese men, whose tumors are high grade and reflective of an
unscreened population.
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INTRODUCTION
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A candidate tumor suppressor gene designated PTEN,
MMAC1, or TEP-1 (referred to as PTEN
hereafter) was identified (1, 2, 3)
from the q23.3 region of
chromosome 10, one of the most frequently deleted regions in prostate
cancer (4)
. The PTEN gene has nine exons that
encode a 403-amino acid protein of a dual-specific phosphatase with
putative actin-binding and tyrosine phosphatase domains. Introduction
of PTEN into cancer cells that lack PTEN function
inhibits cell migration and induces cell cycle arrest and apoptosis via
negative regulation of the phosphatidylinositol 3'-kinase/protein
kinase B/Akt signaling pathway (5, 6, 7)
. Mutation and
down-regulation of the PTEN gene have been detected in
various human cancers including that of the prostate
(8, 9, 10)
. In addition, germ-line mutations in
PTEN are associated with Cowden disease (11)
,
in which patients are at increased risk for certain cancers.
Thus far, PTEN appears to be the most frequently mutated
gene in metastases of prostate cancer, occurring in at least 1
metastatic site in 12 of 19 (63%) patients who had multiple metastases
(12)
and in 9 of 15 (60%) cell lines and xenografts
primarily derived from metastases of prostate cancer (13)
.
These results indicate a role for PTEN in the progression of
prostate cancer. Mutations of PTEN in localized prostate
cancers have been found at lower frequencies including 1 of 28 (4%;
Ref. 14
), 1 of 25 (4%; Ref. 15
), 1 of 40
(2.5%; Ref. 16
), 0 of 45 (17)
, and 1 of 22
(5%; Ref. 18
). Somewhat higher rates of mutations have
been observed in other studies including 10 of 80 [12.5%; 10 of 23
(43%) in cases with loss of heterozygosity at PTEN; Ref.
19
], 5 of 37 (13.5%; Ref. 20
), 8 of 60
(13%; Ref. 21
), and 1 of 10 (10%; Ref. 9
).
In hereditary prostate cancer, the role of PTEN has not been
detected (22
, 23)
.
The incidence of prostate cancer is lower in Asian men compared with
Western men, but the specific genetic or environmental factors that are
important are unknown (24
, 25)
. Obviously, more cancers
are detected in Western men because of screening with serum
PSA3
test. The frequency of PTEN mutations in prostate cancer from Asian men
has been little studied. One study of 45 primary prostate cancers from
Japanese patients did not detect any PTEN mutation
(17)
. In this study, we analyzed primary prostate cancers
from 32 Chinese patients, who were not diagnosed using the PSA test.
Rather, they were diagnosed after showing clinical symptoms. We also
analyzed six metastases from American patients who died of prostate
cancer to document additional PTEN mutations in fatal prostatic
disease.
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MATERIALS AND METHODS
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Tumor Samples.
Thirty-two formalin-fixed, paraffin-embedded prostate cancer specimens
from radical prostatectomy from previously untreated Chinese patients
were used in this study. These patients went to physicians after
showing various symptoms of prostate cancer, e.g.,
difficulty in voiding, urodynia, urgent and frequent urination, and
hematuria. None of them were involved in PSA screening. Their prostates
were examined by one or more of the following means: rectal ultrasound
detection, digital rectal examination, computed tomography, and
magnetic resonance imaging. Biopsy was performed for the patients who
were suspected to have prostate cancer, and only those whose cancers
were at stages B–C underwent radical prostatectomy. The
prostatectomies were performed by four surgeons over a period of 5
years. All specimens were from archived paraffin blocks that had been
used in routine diagnosis of cancer, and none of them were collected
specifically for this study. In addition, DNA was available from six
distant metastases from American patients who died of prostate cancer.
The clinicopathological characteristics of the tumors are listed in
Table 1
. The exact tumor stage for the Chinese patients was not available.
Tumor cells for DNA isolation were collected from 7 µm H&E-stained
sections by microdissection using a protocol described previously
(26)
, which typically ensured a minimum of 70% neoplastic
cells for each sample. Nonneoplastic cells collected were present on
the same slides as cancer cells and included stromal cells,
lymphocytes, and urothelium; in most cases, they did not include
nonneoplastic prostatic epithelium. For the cases of metastases,
nonneoplastic cells were collected from lymph nodes or seminal
vesicles. Use of the human specimens in this study was approved by the
institutional human investigation committee.
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Table 1 Clinicopathological characteristics of prostate
cancer specimens analyzed and mutation status of PTEN in
each case
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PCR-SSCP Analysis.
Each of the primary prostate cancers was first screened for mutation by
using the PCR-SSCP approach. Primers used for each PTEN exon
were the same as described previously (16)
. PCRs for the
SSCP contained 5–10 ng of genomic DNA, 1x PCR buffer [20
mM Tris-HCl (pH 8.8), 10 mM
KCl, 10 mM
(NH4)2SO4,
2 mM MgSO4, 0.1% Triton
X-100, and 0.1 mg/ml BSA], 1 µM of each
primer, 3 µM of each deoxynucleotide
triphosphate, 1 µCi of [
-32P]dCTP (3000
Ci/mmol), 0.6 unit of Taq DNA polymerase, and 0.1 unit of Pfu DNA
polymerase and was incubated at 95°C for 5 min followed by 30 cycles
of 94°C for 30 s, 55°C for 30 s, and 72°C for 1 min.
The 32P-labeled PCR products were electrophoresed
at 5 W overnight at room temperature in a 6% nondenaturing
polyacrylamide gel in 1x TPE buffer [30 mM Tris,
20 mM PIPES (1,4-piperazinediethanesulfonic acid), and 1
mM Na2EDTA (pH 6.8)] as described previously
(27)
. PCR products were also analyzed in a 0.25x MDE gel
(FMC BioProducts, Rockland, ME) containing 10% glycerol, which was
also run at 5 W overnight at room temperature. After electrophoresis,
the gels were dried and exposed to X-ray film for 1–2 days. Samples
showing a bandshift for a specific exon were reamplified for both tumor
DNA and matched nonneoplastic cells to confirm the shift, using the
same conditions.
DNA Sequencing.
For the samples which repeatedly showed a bandshift in the SSCP
analysis, shifted bands were cut and immersed in 20 µl of
H2O, following the protocol described by Kukita
et al. (27)
. Two µl of the released DNA were
amplified by PCR using the same primers, as in SSCP analysis, in a
50-µl of reaction. The PCR conditions were the same except that 200
µM of each deoxynucleotide triphosphate and no
[32P]dCTP were used. These PCR products were
purified by using the QIAquick PCR purification kit (Qiagen, Valencia,
CA), and were sequenced by using the ThermoSequenase Cycle Sequencing
kit (USB) following the manufacturer’s instructions. Sequencing data
were collected and analyzed by using the ScanDNASIS and MacDNASIS
software (Hitachi Software, San Bruno, CA).
For the six metastases of prostate cancer, which tended to be more
homogeneous in neoplastic cells, their DNAs were amplified by PCR for
each of the PTEN exons, and the resultant PCR products were
purified and directly sequenced by the same procedure as described
above. For an exon showing a mutation, the PCR sequencing procedure was
repeated to confirm the mutations. Once confirmed, matched normal DNA
for a specific exon was also amplified by PCR and sequenced to
determine whether a mutation was somatic or germ line.
Statistical Analysis.
The difference in the frequency of PTEN mutations between
primary tumors in the current study and that of our previous study
(16)
was analyzed statistically by the use of Fisher’s
exact test (two-tailed; Ref. 28
).
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RESULTS
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Seventy % of the 32 primary prostate cancers from Chinese men
were Gleason scores 8–10, whereas 30% were Gleason score 7. PCR-SSCP
and direct DNA sequencing analyses of these samples revealed
PTEN sequence alterations in 7 cases. Examples of bandshifts
for tumors in SSCP assay, which indicated the existence of sequence
alterations in the PTEN gene, are shown in Fig. 1
, and examples of DNA sequencing ladders that identify PTEN
mutations are shown in Fig. 2
. Tumor cases and their PTEN mutation status are listed in
Table 1
. Although 2 of the 7 cases had alterations that did not change
the PTEN polypeptide, five cases (16%) had mutations that could
potentially change PTEN function (Table 1)
. Case 113 had a nonsense
mutation at codon 20 that would truncate the majority of the PTEN
protein. Case 92 had two missense mutations in its exon 5, which
changed codons 101 and 135 from isoleucine to alanine and valine,
respectively. Cases 91, 109, and 114 showed missense mutations that
changed codons 55, 150, and 272 from arginine, glutamine, and histidine
to glycine, glycine, and tyrosine, respectively.
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Fig. 1. Examples of SSCP analysis of
PTEN in prostate cancer specimens. N and
T, nonneoplastic and tumor cells, respectively. For each
example, the case number is indicated at the top, and
exon number is at the bottom. Each case has shifted
bands in their tumor cells compared with nonneoplastic cells.
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Fig. 2. Examples of sequencing analysis of shifted
bands from SSCP experiments. Arrow, mutated nucleotide;
bottom, case number and exon number.
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We also analyzed six metastases of prostate cancer from American men,
using the methods of PCR amplification and direct DNA sequencing. Two
cases showed PTEN mutations. Case 49 had a nonsense mutation
at codon 110 in exon 5 that would truncate the PTEN protein, and case
47 had three missense mutations in exon 9 of PTEN, changing
codon 344 from lysine to arginine, codon 348 from threonine to
isoleucine, and codon 382 from threonine to serine.
Each of the above mutations was somatic, as the matched nonneoplastic
cells showed no mutations. The difference in the frequency of 16% for
PTEN mutation in the cancers from Chinese patients compared
with the frequency of 2.5% in our prior analysis of 40 resected
primary tumors detected in American men after PSA test and biopsy
(16)
showed a trend in significance (P =
0.08).
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DISCUSSION
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The PTEN gene was isolated from the q23 region of
chromosome 10, one of the most frequently deleted regions in prostate
cancer (4
, 29
, 30)
. Mutations of the gene have been
detected in various human cancers including that of the prostate
(9
, 12
, 13 , 19, 20, 21)
, implicating PTEN in the
development and/or progression of prostate cancer. It is thus far the
most frequently mutated gene in prostate cancer. Our finding of
PTEN mutations in 5 of 32 primary, high-grade prostate
cancer specimens confirms that PTEN is a major gene, if not
the target gene, for the 10q23 region of deletion in a subset of
prostate cancers.
Mutation frequencies of PTEN in prostate cancer differ among
studies, largely because of differences in tumor grade and stage in the
study populations. Mutations up to 60% have been detected in studies
of prostate cancer cell lines and xenografts from metastases
(13)
, whereas in some studies of localized disease, few or
no mutations have been detected (16
, 17)
. In this study,
we detected PTEN mutations in 5 of 32 (16%) primary
prostate cancers from Chinese patients who were diagnosed with clinical
symptoms but without the aid of the serum PSA screening test. This
frequency was higher than that (1 of 40 or 2.5%) detected in primary
prostate cancers from American patients who were diagnosed by PSA test
in our previous study (16)
. The majority of tumors from
the Chinese patients were high grade (Gleason scores 8–10), whereas
the majority of tumors in the American patients were lower grade
(Gleason scores 5–7), indicating that PTEN mutations occur more often
in tumors with high Gleason scores, even in those that are primary
lesions. This conclusion is consistent with published studies of
primary prostate cancers (15
, 17
, 20)
. In one study of 37
primary tumors with 20 (54%) high-grade and 17 (46%) lower grade
lesions, five cases, four of which were high-grade tumors, had PTEN
mutations (20)
. In another study of 45 primary tumors that
were mainly low-grade cancers [30 (67%) lower grade cases and 15
(33%) high-grade cases], no PTEN mutations were found
(17)
. Summarizing five studies in which both tumor grade
and PTEN mutations were available (15, 16, 17
, 20)
, we found
that 9 of 67 (13.4%) high-grade tumors showed PTEN mutations, whereas
only 3 of 117 (2.6%) lower grade cases showed mutations. The former
rate is significantly higher than the latter (P = 0.01)
using the 
2 analysis-of-contingency table
(28)
. Consistent with mutation studies, loss of PTEN
expression has also been shown to correlate with high grade of primary
prostate cancer (9
, 10)
.
It has been reported that prostate cancer incidence is lower in Asian
men than in Western men (24
, 25)
. Although one study of
Japanese patients did not detect any PTEN mutations in 45
primary tumors that were mainly low-grade cancers (17)
, we
found more frequent PTEN mutations in a group of Chinese
patients that had mainly high-grade tumors in this study; the latter is
consistent with studies in Western men (20)
. These results
suggest that PTEN is likely not a genetic factor
contributing to the racial difference in prostate cancer incidence.
This conclusion is further supported by the fact that all of the
PTEN mutations were detected in prostate cancer cells only
and not in their matched nonneoplastic cells. Also, no PTEN
mutation has been detected in familial prostate cancers (22
, 23)
. The differences in PTEN mutation rates in our study
compared with that of Orikasa et al. (17)
may
be attributable to differences in the distribution of tumor grades
between the study samples.
We detected multiple mutations for PTEN in two tumors,
i.e., case 92 had two missense mutations in exon 5 and case
47 had three missense mutations in exon 9 (Table 1)
. The heterogeneous
nature of prostate cancer is well known (31)
; therefore,
it is likely that multiple mutations of PTEN in one tumor
may come from different subclones of tumor cells. In an analysis of
metastases involving multiple organ sites in patients who died of
prostate cancer, Suzuki et al. (12)
found that
different metastases within the same patient had different PTEN
mutation status, indicating a complex genetic relationship between
various subclonal lineages of prostate cancer cells. Mutation of exon 5
appears to be more frequent than that of other exons in both Cowden
disease and various somatic cancers (8)
.
In summary, PTEN mutations were seen more often in primary
prostate cancers from Chinese men compared with localized tumors from
American patients. This difference is likely attributable to the
presence of an excess of high-grade cancers in the Chinese patients.
Whether primary prostate tumors with PTEN mutations have a
greater proclivity to metastasize than those of similar grade and stage
without mutations remains to be determined.
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FOOTNOTES
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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.
1 This study was supported in part by Grant DAMD
17-98-1-8636 from the United States Army Prostate Cancer Research
Program and by Grants CA85560 and CA87921 from the National Cancer
Institute, NIH. 
2 To whom requests for reprints should be
addressed, at Department of Pathology, University of Virginia Health
System, P. O. Box 800214, Charlottesville, VA 22908-0214. Phone:
(804) 924-9011; Fax: (804) 924-9206; E-mail: jd4q{at}virginia.edu
3 The abbreviations used are: PSA,
prostate-specific antigen; SSCP, single-strand conformational
polymorphism.
Received 8/23/00;
revised 11/27/00;
accepted 11/28/00.
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ABSTRACT
INTRODUCTION
