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Epidemiology and Prevention |
Yale University School of Medicine, New Haven, Connecticut 06510 [J. M. J., R. P.], and Departments of Biostatistics and Epidemiology [J. M. J., A. H. W., S. M., T. R. R.], Urology [S. B. M., K. V. A., A. J. W.], and Pathology and Laboratory Medicine [J. T.], University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6021
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-reductase type II, is
responsible for converting testosterone to the more metabolically
active dihydrotestosterone. Therefore, SRD5A2 may be
involved in the development or growth of prostate tumors. To examine
the effects of allelic variants in the gene SRD5A2 on
the presentation of prostate tumors, we studied a sample, primarily
Caucasian, of 265 men with incident prostate cancer who were
treated by radical prostatectomy. We assessed the relationship of the
A49T and V89L polymorphisms at
SRD5A2 with clinical and pathological tumor
characteristics of these patients. We found no association of
V89L genotypes with any of the characteristics studied.
The presence of the A49T variant was associated with a
greater frequency of extracapsular disease [odds ratio (OR), 3.16;
95% confidence interval (CI), 1.03–9.68] and a higher pathological
tumor-lymph node-metastasis (pTNM) stage (OR, 3.11; 95% CI,
1.01–9.65). In addition, the A49T variant was
overrepresented in two poor prognostic groups, which have been
correlated with reduced rates of biochemical disease-free survival. One
group included men with at least two of the following poor prognostic
variables: (a) stage T3 tumor; (b) PSA
level >10; and/or (c) Gleason score, 7–10 (OR, 3.46;
95% CI, 1.04–11.49). The second group included men with positive
margins and high Gleason score (OR, 6.28; 95% CI, 1.05–37.73).
Our results suggest that the A49T mutation may influence
the pathological characteristics of prostate cancers and, thus, may
affect the prognosis of these patients. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-reductase type II. This enzyme is responsible for
converting testosterone to
DHT3
(1, 2, 3)
. DHT has greater androgen activity in the prostate
than testosterone itself (4
, 5)
and, when bound to the
androgen receptor, activates a number of genes involved in prostate
development and growth (6
, 7)
. Prior studies have provided
a strong rationale for the role of 5-reductase type II and the
SRD5A2 gene in the etiology of prostate cancer. Several
studies have assessed 5-reductase activity levels through
measurements of the enzyme metabolite AAG. These studies have reported
decreased levels in races with a lower incidence of prostate cancer
(Chinese and Japanese; Refs. 8
, 9
) and elevated levels in
races with higher prostate cancer rates (for example, African
Americans; Ref. 10
). Subsequent studies were undertaken to
determine whether genetic variants in SRD5A2 correlate with
androgen metabolism and prostate cancer risk. Makridakis et
al. (11)
reported a missense mutation that resulted
in the substitution of a leucine for a valine amino acid in position 89
in this enzyme (denoted V89L), which was associated with
lower levels of AAG. They reported that the prevalence of this mutation
in African-American, Asian, and Latino men parallels the frequency
of prostate cancer in these races. However, the V89L
mutation did not have substantial effects on the
Vmax of 5-reductase, which raised
questions about the functional significance of this polymorphism
(12)
. Reichardt et al. (13)
reported another SRD5A2 variant that changes an alanine to a
threonine residue at amino acid 49 (denoted A49T). The same
authors correlated this variant with an increase in 5-reductase
activity. This variant was reported to be more common in
African-American and Latino men with prostate cancer, as compared with
healthy African-American and Latino controls, and was found to be most
common in African-American and Latino men with advanced disease
(13)
. More recently, Makridakis et al.
(14)
provided additional support for the hypothesis that
the A49T variant was associated with prostate cancer risk in
African-American and Hispanic men and also reported that the variant
enzyme had a higher Vmax in
vitro than the normal enzyme. The effects of this mutation in
other races have not been previously reported.
To further evaluate whether genotypes at SRD5A2 are
associated with clinical and pathological features of prostate cancers,
we examined the effects of the V89L and A49T
variants in a sample made up predominantly of Caucasian men with newly
diagnosed prostate cancer. We hypothesize that genotypes associated
with higher levels of 5-reductase activity, and, hence, enhanced
metabolism of testosterone to DHT, are correlated with more serious
disease presentation and, thus, may provide information relevant to
prostate cancer detection, prognosis, and treatment outcome.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Data Collection.
Genomic DNA for this study was self-collected by each study subject
using sterile cheek swabs (Cyto-Pak Cytosoft Brush; Medical Packaging
Corporation, Camarillo, CA). We processed the genomic DNA by using a
protocol modified from that of Richards et al.
(15)
. Briefly, the swab brush was placed inside a 1.5-ml
microcentrifuge tube, and 600 µl of 50 mM NaOH
was added. The closed tube was vortexed for 5 min and then heated at
95°C for 10 min. Finally, 120 µl of 1 M Tris
(pH 8.0) was added, after which the brush was removed and discarded.
Preoperative clinical and pathological characteristics were obtained by medical records review. These characteristics included: (a) prostate cancer screening history; (b) preoperative PSA levels (ng/ml); (c) Gleason score of the surgical specimen (primary plus secondary grade; Ref. 16 ); (d) capsular extension status (positive or negative); (e) surgical margin status (positive or negative); (f) tumor volume (% of gland replaced by tumor); and (g) seminal vesicle involvement (positive or negative). Tumor extending into but not through the prostatic capsule was considered negative for extracapsular extension. Staging was performed using a modification of the TNM system to reflect surgical margin status (17) . Risk factor information, including demographic and family history data, was obtained from the subjects by self-report using a standard questionnaire.
Genotype Analysis.
A modification of the assay of Vilchis et al.
(18)
was used to genotype study subjects for the
V89L and A49T variants in SRD5A2. The
primer sequences used to amplify SRD5A2 were 5'-GCA GCG GCC
ACC GGC GAG G-3' and 5'-AGC AGG GCA GTG CGC TGC ACT-3'. The PCR
reaction mixture consisted of 25 µl of double-distilled
H20, 6 µl of DMSO, 10 µl of 10x PCR buffer
(The Perkin-Elmer Corp., Foster City, CA), 4 µl of 25
mM Mg+2, 2 µl of 10
mM deoxynucleotide triphosphate, 10 µl each of
the two PCR primers at 5 µM concentration, 10
µl of template DNA, 0.9 µl of Taq polymerase (Amplitaq,
Perkin-Elmer) in 22.1 µl of double distilled
H20, for a total reaction volume of 100 µl. The
temperature profile for the PCR reaction was one cycle each at 95°C
for 5 min and 82°C for 1 min, at which time the Taq polymerase was
added to the reaction mixture; this was followed by 20 cycles at 94°
for 1 min, 68°C for 1 min with a 0.5°C per cycle decrease, and
72°C for 1 min, and 15 cycles at 94° for 1 min, 58°C for 1 min,
72°C for 1 min, with a final single 10-min cycle at 72°C completing
the cycling profile.
The PCR product mixture was subjected to restriction enzyme fragment
analysis. The V89L variant was identified with
RsaI, which produced 169-, 105-, 64-, and-19-bp fragments
corresponding to the V allele, and 169-, 105-, and 83-bp
fragments corresponding to the L allele. The A49T
variant was identified with the restriction enzyme MwoI,
which produced 90-, 70-, 46/47-, and 17/20/21/22-bp fragments
corresponding to the A allele, and 107-, 70-, 46/47-, and
20/21/22-bp fragments corresponding to the T allele.
Visualization of the fragments was accomplished on a 4% Metaphor
(FMC Corp.) gel after staining with ethidium bromide (Fig. 1)
.
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5% versus
>5%). TNM stage was also dichotomized by combining all of the stages
that reflected capsular invasion, margins positive, and/or seminal
vesicle invasion (pT2+, pT3-, pT3+, or
pT3c, respectively), and by comparing this
combined-stage category to the more favorable
pT2-. We also considered a series of prognostic indices. The prognostic significance of each of these indices has been suggested in previous studies through measurements of bRFS. First, PSA level and Gleason score were combined to form the prognostic categories identified by Kupelian et al. (19) . The low-risk group included patients with PSA levels of 0.0–10.0 and Gleason sum 2–6 (81% bRFS at 5 years), whereas high-risk patients had PSA levels of >10.0 and/or Gleason sum 7–10 (40% bRFS at 5 years). A measure adapted from a study of radiation-treated patients (20) was used to study the combined effect of PSA level, Gleason sum, and TNM stage. The favorable prognostic group included men with PSA levels 0.0–10.0, Gleason sum 2–6, stage T1-T2 (85% bRFS at 5 years) or with any one of these factors increased (65% bRFS at 5 years). An increase in two or three of these factors placed patients in the unfavorable prognostic group (35% bRFS at 5 years). Finally, we combined margins status and Gleason sum according to the prognostic categories of Walsh (21) . The low-risk category included patients with negative margins and Gleason sum 2–6 (100% bRFS at a median of 4 years). Patients in the intermediate prognostic category had either negative margins and Gleason sum 7–10, or they had positive margins and Gleason sum 2–6 (50% bRFS at a median of 4 years). The remaining patients with positive margins and Gleason sum 7–10 formed the high-risk group (30% bRFS at a median of 4 years).
On the basis of previous data concerning the functional significance of the V89L and A49T polymorphisms and their allele frequencies (10 , 11 , 13) , all of the analyses were undertaken comparing the following genotypes: (a) homozygotes for the V allele (VV) versus the combined heterozygotes (VL) and homozygotes (LL) for the L allele of V89L; and (b) homozygotes for the A allele (AA) versus the combined heterozygotes (AT) and homozygotes (TT) for the T allele of A49T.
Descriptive analyses for discrete traits were carried out using
contingency table methods and the Fisher’s exact tests or
2 statistics. Means or medians were used to
summarize continuously distributed traits, and nonparametric
Kruskal-Wallis statistics were used to compare these values across
groups. Genotype-disease associations were undertaken using
unconditional logistic regression. Analyses considered the effect of a
genotype adjusted for potential confounders that included one or more
of the following: (a) age (at time of diagnosis);
(b) race (coded as a discrete variable with three levels:
Caucasian, African American, or other); and (c) preoperative
PSA level (ng/ml), Gleason score, and treatment by leuprolide (Lupron)
prior to surgery (yes or no). All of the Ps were based on
two-sided hypothesis tests.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, we observed an allele frequency of 0.300 overall for the
V89L variant. There was no significant difference in
the allelic distribution of V89L between Caucasians and
African Americans (2 = 2.05,
df, 2; P = 0.360; Fisher’s exact
test, P = 0.329). The frequency of the
A49T variant was 0.035, and variants were observed only in
Caucasians. Although all of the individuals were included in the
analysis, the inferences relating to A49T variants in the
subsequent sections are, therefore, limited to Caucasians. The number
of subjects in other ethnic groups was too small to derive meaningful
estimates of allele frequency.
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presents the relationship of genotype to PSA, surgical Gleason score,
and tumor volume. Overall, the mean preoperative PSA level in our study
subjects was 7.83 ng/ml (range: 0.2–43.6 ng/ml). Mean PSA was not
different in the VV (8.14 ng/ml) and
VL+LL (7.54 ng/ml) genotypes for the
V89L variant (Kruskal-Wallis,
2 = 0.52, df, 1;
P = 0.472), nor in the AA (7.87
ng/ml) and AT+TT (7.75 ng/ml) genotypes of the
A49T variant (Kruskal-Wallis,
2 = 0.01, df, 1;
P = 0.936). There was also no difference by
genotype when PSA was considered as a three-level discrete variable
(Table 2)
. Similarly, there were no significant differences in the
surgical Gleason score categories or trichotomized tumor volume for
either the A49T or V89L genotypes. Finally, when
all of these variables were collapsed into dichotomous categories to
account for small numbers in some groups, significant effects were
still not observed.
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. However, there were significant associations of these traits and
A49T genotypes. Invasion beyond the prostatic capsule, found
in 59 (22.4%) study subjects, occurred significantly more often in men
with the A49T variant than men without this variant
(2 = 5.11, df, 1;
P = 0.024). AT+TT
genotypes were also overrepresented in patients with higher stage
disease (capsular extension and/or positive margins, Table 3
). Whereas
the majority (73.3%) of the men with the AA genotype had
pT2- disease (organ-confined and margins
negative), only 46.7% of men with the A49T mutation were
diagnosed with this favorable stage (2 = 4.92, df, 1; P = 0.026).
None of the 15 men with seminal vesicle invasion carried the
A49T variant, and it was, therefore, impossible to evaluate
the effect of genotype on this aspect of pathological staging. Although
not statistically significant, positive margins were observed in 33.3%
of men with the A49T variant and in 18.6% of men with the
wild-type allele (2 = 1.95,
df, 1; P = 0.163), which suggests
that a larger study sample may be required to observe a statistically
significant effect.
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, the A49T variant was overrepresented in multiple high-risk
prognostic groups defined by PSA level, margin status, Gleason
sum, and/or TNM stage. Specifically, the A49T variant had a
statistically significant effect in the prognostic categories of
Zelefsky et al. (20)
, which combined PSA,
Gleason score, and TNM stage, as well as in the prognostic categories
of Walsh (21)
, which combined margin status and Gleason
score. The other prognostic grouping, a combination of PSA and Gleason
score (19)
, was associated with the
A49Tgenotype with an OR estimate greater than 2. However,
this association did not reach statistical significance, presumably
because of insufficient statistical power. Therefore, the
A49T variant was associated with not only individual stage
variables but also multiple indices of prognosis.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We also report that the V89L variant of the
SRD5A2 gene had no significant impact on the pathological or
clinical manifestations of tumors in a predominantly Caucasian sample
of prostate cancer patients who underwent radical prostatectomy.
However, some very small and statistically nonsignificant magnitude
effects were observed that might be associated with the V89L
variant in a larger study with greater statistical power. A recent
study by Makridakis et al. (12)
reported
that this genotype did not exhibit a substantial decrease in the
Vmax of 5-reductase activity, in
contrast to a previous study that suggested decreased formation of the
metabolite AAG in men with this mutation (11)
. Our study,
along with the study of Makridakis et al., provides evidence
that the V89L variant may not be associated with prostate
carcinogenesis, despite its greater prevalence in races with a lower
incidence of this disease (e.g., Chinese and Japanese men).
The hypothesis that SRD5A2 may be involved in
modifying the presentation of prostate cancer is based on knowledge of
testosterone metabolism. The enzyme product of SRD5A2,
5-reductase type II, is responsible for the conversion of
testosterone to DHT, the principal androgenic hormone that promotes
cell proliferation in the prostate. Cell proliferation appears to be a
necessary precursor to the genetic changes leading to prostate
tumorigenesis, such as activation of proto-oncogenes or inactivation of
tumor suppressor genes (22
, 23)
. Therefore, it is
biologically plausible that genetic variants that are associated with
increased 5-reductase activity may promote androgen-mediated
prostate tumor growth and, thus, increase the severity of prostate
tumors.
Previous studies support the role of 5-reductase type II in
the development and progression of prostate cancer. Higher levels of
DHT have been found in prostate cancer tissue compared with
noncancerous tissue (24)
. Inhibitors of 5-reductase
type II have been shown to reduce the growth of certain types of
androgen-dependent prostate tumors in both rodents and humans, with an
associated decrease in tissue DHT levels (25
, 26)
.
Finally, prostate cancer has not been reported in men with a
constitutional 5-reductase deficiency (27)
.
The small number of participants with the A49T mutation is
the major analytical limitation of our study. This variant had an
allele frequency of approximately 4%, and, hence, we may have had
insufficient statistical power to detect significant effects for some
of the variables of interest. This may likely explain the effects that
were suggestive, as evidenced by ORs greater than 2, but had confidence
intervals that overlapped with a value of 1. Margin positivity,
as well as one of the prognostic indices presented in Table 3
, is an
example of this phenomenon. Future studies of the A49T
variant and these traits will, therefore, require larger samples sizes.
More prominent effects for margin status might also be seen if
the degree of margin positivity (i.e., focal
versus extensive) were assessed, because these distinctions
represent significant differences in disease severity (28
, 29)
. These data were not available in our data set. An
additional limitation of the present study is that it was restricted to
men who had undergone radical prostatectomy. As a result, the range of
patient characteristics and clinical phenotypes was limited to those
men who were eligible to undergo this surgery. Studies of men with a
wider range of clinical diagnoses or pathological types may be quite
different from those reported here. Finally, our case-case study design
does not allow us to directly address the role of the SRD5A2
allele in the etiology of prostate cancer. Case-control studies are
currently being undertaken to address this issue.
Our findings have potential implications for prostate cancer detection,
prognosis, and treatment. First, our capsular and pTNM stage findings
imply that the A49T variant at SRD5A2 is
associated with extraprostatic extension and/or positive margins. These
are pathological features that are associated with a poorer prognosis.
Once cancer extends beyond the prostate, it is associated with a 40%
10-year actuarial failure rate in the absence of adjunctive
postoperative treatment (reviewed in Ref.30
). Furthermore,
extraprostatic extension is correlated with the presence of advanced
pathological features such as seminal vesicle invasion and lymph node
metastasis, which were variables not analyzed in our study (31
, 32)
. Conversely, tumor that is pathologically confined to the
prostate has an excellent prognosis, with most studies reporting 5–10
year progression rates of <10% in these patients (28
, 33
, 34)
. The potential prognostic significance of our findings is
further supported by the overrepresentation of the A49T
genotype in two of the high-risk prognostic categories (combined
PSA-Gleason-TNM stage and combined margins-Gleason), that have been
associated with reduced biochemical relapse-free survival (20
, 21)
. In addition to potential prognostic value, knowledge of
SRD5A2 genotypes may also have applications in prostate
cancer screening. Patients at risk for pathologically significant
tumors could potentially benefit from increased screening and early
detection of disease. Finally, the 5-reductase inhibitor finasteride
Proscar has recently been tested as a treatment in men with metastatic
prostate cancer (35)
, as well as in men with low-level
postprostatectomy PSA elevation (36)
, with promising
results. Its value as a chemopreventive agent is also being assessed
(37)
. The efficacy of such interventions may be in part
determined by SRD5A2 genotype.
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FOOTNOTES |
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1 Supported by grants from the USPHS [ES08031 and
CA85074 (to T. R. R.)] and the University of Pennsylvania Cancer
Center, and by the NIH Cancer Education Grant, Medical Student Training
Fellowship. 
2 To whom requests for reprints should be
addressed, at Department of Biostatistics and Epidemiology, University
of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian
Drive, Philadelphia, PA 19104-6021. Phone: (215) 898-1793; Fax: (215)
573-2265; E-mail: trebbeck{at}cceb.med.upenn.edu
3 The abbreviations used are: DHT,
dihydrotestosterone; TNM, tumor-(lymph)node-metastasis
(classification); pTNM, pathological TNM (classification); AAG,
androstanediol glucuronide; HUP, Hospital of the University of
Pennsylvania; PSA, prostate-specific antigen; bRFS, biochemical
relapse-free survival; OR, odds ratio; CI, confidence interval.
Received 11/11/99. Accepted 1/18/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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