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Department of Urology [T. H., Z. L., T. S., R. S., N. T., H. T., N. S., S. S., K. S., T. Kat.], Akita University School of Medicine, Akita 010-8543, Japan, and Department of Urology [Y. K., T. Kam., O. O.], Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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enzyme, which mediates two key steps in the
sex steroid synthesis. There is a polymorphism (a T-to-C substitution)
in the 5'-untranslated region, which may influence the transcription
level of CYP17 mRNA. There is a continuing controversy
as to whether the variant allele is associated with a subset of breast
cancer or polycystic ovary syndrome. In prostate cancer research, there
are contradictory data concerning the CYP17 risk allele.
We explored the association between CYP17
polymorphism and a risk of prostate cancer or benign prostatic
hyperplasia (BPH) in a Japanese population. This study included 252
prostate cancer patients, 202 BPH patients, and 131 male controls. A
451-bp fragment encompassing the polymorphic site was amplified by PCR,
treated with restriction enzyme MspA1, and
electrophoresed on an agarose gel. The MspA1-undigested
allele with the published sequence and the
MspA1-digested variant allele were designated as A1 and
A2, respectively. There was a significant difference
(P < 0.05) in the genotypes between
prostate cancer patients and male controls, and between BPH patients
and male controls. Men with the A1/A1 CYP17 genotype had
an increased risk of prostate cancer [odds ratio (OR), 2.57; 95%
confidence interval (CI) = 1.39–4.78] and BPH (OR,
2.44; 95% CI = 1.26–4.72) compared with those with the
A2/A2 genotype. Men with the A1/A2 genotype had an intermediate
increased risk of prostate cancer (OR, 1.45; 95% CI = 0.84–2.54) and BPH (OR, 1.60; 95% CI = 0.89–2.87)
compared with those with the A2/A2 genotype. The trend of an
increasing risk of prostate cancer and BPH with an increasing number of
the A1 allele was statistically significant (prostate cancer
versus male control, P = 0.003; OR, 1.57; 95% CI = 1.16–2.12; BPH
versus male control, P = 0.008; OR, 1.55; 95% CI = 1.12–2.13). There was no
significant association between the CYP17 genotype and
the tumor status (grade and stage) of prostate cancer. Our results
suggest that the A1 allele of the CYP17 polymorphism is
associated with an increased risk of prostate cancer and BPH,
with a gene dosage effect. However, the CYP17 genotype
does not seem to influence the disease status in prostate cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There has been accumulating evidence that endogenous levels of androgens and estrogens are associated with the development of prostate cancer (4) . The strikingly divergent incidence of prostate cancer across different populations may come in part from differences in the prevalence of common inherited genetic variations (polymorphisms) in genes coding for enzymes involved in the synthesis and metabolism of androgens and estrogens.
The CYP17 gene, which locates on chromosome 10 and consists
of eight exons, encodes the cytochrome P450c17 enzyme
(5)
. The cytochrome P450c17 mediates both steroid
17-hydroxylase and 17,20-lyase activities and functions at key steps
in the genesis of human sex steroid hormones. The 5'-untranslated
promoter region of CYP17 contains a single-bp T-to-C
polymorphism that may create a new Sp-1 site (CCACC box) at 34 bp
upstream from the initiation of translation and downstream from the
putative transcription start site, therefore providing an additional
promoter activity with an increased rate of transcription of
CYP17 mRNA (6)
. On the other hand, a more
recent in vitro study showed no binding of the transcription
factor Sp-1 to the variant sequence (7)
.
Considering the significance of the cytochrome P450c17 enzyme in sex
steroid hormone synthesis, the CYP17 polymorphism may play a
crucial role in the etiology of hormone-related cancers such as
prostate cancer and breast cancer. To date, molecular epidemiological
studies have indicated that a variant allele (the A2 allele) is
associated with an increased risk of advanced breast cancer
(8)
, breast cancer in young women (9)
, male
breast cancer (10)
, and higher serum hormone levels in
healthy individuals or in polycystic ovary syndrome (11
- 13)
. Others, however, reported a negative association between
the CYP17 polymorphism and breast cancer or steroid hormone
levels (7
, 14, 15, 16, 17)
. Three recent studies presented
contradictory results concerning the CYP17 genotype in
prostate cancer patients (18, 19, 20)
. Two studies, from the
United States and Austria, reported that the presence of the A2 allele
may increase the risk of prostate cancer (18
, 20)
, whereas
another study from Sweden claimed that the A1/A1 genotype may
significantly increase the risk (19)
.
In this study, we analyzed the CYP17 genotype in a native Japanese male population who are considered to be less influenced by environmental factors for prostate cancer than those in Western countries (3) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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4.0 ng/ml; the Tandem-R assay; Hybritech Inc., San Diego,
CA) were proved not to have prostate cancer by transrectal biopsies.
Serum PSA was measured using the Tandem-R assay in most cases. When
serum PSA was measured by kits other than the Tandem-R, the measured
PSA level was adjusted to that of the Tandem-R assay using a formula
published elsewhere (22)
. The male control group consisted
131 volunteers >60 years old who were selected mainly from among the
patients admitted because of nonurological diseases and showed no signs
of prostate cancer and no prostatic enlargement by digital rectal
examination. They all were tested for serum PSA levels (the Tandem-R
assay), and men with abnormal PSA levels were omitted from the normal
controls or received further examination, including prostate biopsy, to
rule out any prostatic disease conditions. Pathological grading of the prostate cancer was determined according to the General Rule for Clinical and Pathological Studies on Prostate Cancer by the Japanese Urological Association and the Japanese Society of Pathology, which is based on the WHO criteria and the Gleason pattern (23) . Well, moderately, and poorly differentiated carcinoma generally corresponds to Gleason patterns 1–2, 3–4, and 5, respectively (23 , 24) . In 26 patients, the final pathological grade was not determined because a different or inadequate grading system was used. The clinical or pathological stage was determined by review of the medical records and classified using the Tumor-Node-Metastatis system (25) . Prostate cancer was classified into the localized group consisting of T1-4N0M0 (stage A, B, or C by the Whitmore-Jewett system) tumors and the metastatic group consisting of T1–4N+M0–1 or T1–4N0–1M1 (stage D by the Whitmore-Jewett system) tumors. In 11 patients, no definite clinical stage was determined due to inadequate information.
CYP17 Genotyping Analysis.
DNA was extracted from blood samples collected from each patient using
a QIAamp Blood Kit (QIAGEN) or by the standard method with proteinase K
digestion followed by phenol-chloroform extraction. The 421-bp fragment
encompassing the polymorphic site in the promoter region of
CYP17 was amplified by PCR using primers CYP17-F1:
5'-CCATTCGCACTCTGGAGTCAT and CYP17-R2: 5'-GACAGGAGGCTCTTGGGGTA. PCR was
carried out in a 25-µl aliquot containing 
50 ng of genomic DNA, 50
pmol of each primer, 125 µM deoxynucleotide
triphosphates, 1 unit of Taq polymerase
(Ampli-Taq Gold DNA polymerase, PE Applied Biosystems), and
1x reaction buffer supplied by the manufacturer (PE Applied
Biosystems). PCR amplification conditions were 10 min of initial
denaturation and activation of Ampli-Tag Gold DNA polymerase at 94°C,
followed by 35–40 cycles of 30 sec at 94°C, 30 s at 55°C, and
90 s at 72°C, followed by 7 min of a final extension at 72°C.
The PCR products were digested overnight with 10 units of
MspAI (MspA1I; New England Biolabs, Inc.,
Beverly, MA) and electrophoresed on 2.0% agarose gels. When the
MspA1 I site was present, the 421-bp PCR fragment was
divided into 130 and 291 bp by the endonuclease digestion. The
genotypes were designated as "A1" when the restriction site
was absent, and as "A2" when the restriction site was present, as
defined in the other studies (6)
. Genotyping was performed
and checked by laboratory personnel (T. H. and Z. L.) unaware of the
case-control status.
Statistical Methods.
All data were entered into an access database (FileMakerPro, Version
4.0, Claris Co.) and analyzed by Excel 98 and SPSS (Version 6.1, SPSS,
Inc.) software. Differences in genotype frequencies and Hardy-Weinberg
equilibrium analysis between the three groups and between the subgroups
of prostate cancer patients were evaluated by a two-sided 2 x 3 or 3 x 3 contingency table analysis.
Associations between CYP17 genotypes and the development of
prostate cancer and BPH were assessed by ORs and 95% CIs. A
multivariate logistic regression analysis was performed with the
inclusion of a factor of age. In addition, the trend across categories
of A2/A2 (A2 homozygote), A1/A2 (heterozygote), and A1/A1 (A1
homozygote) was tested in a logistic regression model by using a
variable with the values 0, 1, and 2, respectively. A probability
<0.05 was required for statistical significance.
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RESULTS |
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Frequencies of the CYP17 genotype in the three groups
(prostate cancer, BPH, and male control) are shown in Table 1
. The
CYP17 allelic distribution in each group was in the
Hardy-Weinberg equilibrium (P > 0.05;
data not shown). Statistical analyses of the genotype prevalence showed
significant differences between prostate cancer patients and the male
controls (P = 0.022), and between BPH
patients and the male controls (P = 0.018;
Table 1
). Genotype analysis indicated that the presence of the A1 allele might
increase the risk of prostate cancer and BPH, when non-adjusted and
age-adjusted ORs were calculated against the A2/A2 genotype (Table 1)
.
Age-adjusted logistic analysis showed that men with the A1/A1
CYP17 genotype had an increased risk of prostate cancer
(aOR, 2.57; 95% CI = 1.39–4.78) and BPH (aOR, 2.44;
95% CI = 1.26–4.72) compared with those with the A2/A2
genotype. Although not statistically significant, males heterozygous
for the A1 allele also seemed to have an intermediate increased risk of
prostate cancer (aOR, 1.45; 95% CI = 0.84–2.54) and
BPH (aOR, 1.60; 95% CI = 0.89–2.87) compared with
males with the A2/A2 genotype. In addition, using an A2/A2 genotype, an
A1/A2 genotype, and an A1/A1 genotype as the values 0, 1, and 2,
respectively, we found a statistical significance in a logistic
regression model for the risk of prostate cancer and BPH in correlation
with an increasing number of the A1 allele (prostate cancer
versus male control, P = 0.003;
OR, 1.57; 95% CI = 1.16–2.12; BPH versus
male control, P = 0.008; OR, 1.55; 95%
CI = 1.12–2.13). The results indicate that the presence
of the A1 allele may increase the risk of prostate cancer and BPH with
a gene dosage effect.
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. In the tumor grade, no significant difference in genotype frequency
was found. Adjusted ORs against the male control group did not show
consistent results (Table 2)
. In the tumor stage, there was a
significant difference in the genotype prevalence between metastatic
prostate cancer patients and the male controls (P = 0.0224). However, no significant difference was found between
the localized prostate cancer patients and the metastatic prostate
cancer patients (Table 2)
. These data suggested that the
CYP17 polymorphism had no significant association with the
disease status of prostate cancer.
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. Although an A1/A1 genotype is more frequently observed in
prostate cancer patients diagnosed at 73 years old, no significant
difference in the genotype frequency was found when compared with the
prostate cancer patients diagnosed at <73
(P = 0.238; Table 3
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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encoded by CYP17 has both 17 -hydroxylase and
17,20-lyase activities, CYP17 is involved in the production
of both androgens and estrogens (4
, 5)
. It has been well
accepted that most prostate cancers are androgen-dependent and that an
androgen defect prevents normal prostate growth, whereas most
breast cancers are estrogen-dependent and estrogens have promoting
effects on breast carcinogenesis (4
, 26)
. Consequently,
the present results, together with those of the previous
documents, could simply suggest that the A1 allele has a more
androgenic effect on men and the A2 allele conversely has an estrogenic
effect on women. In support of this view, a recent study by Makridakis
et al. (27)
showed that the CYP17 A1
is significantly associated with higher levels of serum androgen
metabolite (androstanediol glucronide) with a gene dosage effect. On the other hand, three previous studies reported conflicting results on the CYP17 genotype in prostate cancer patients (18, 19, 20) . One from the United States indicated an increased risk of prostate cancer in the presence of the A2 allele (OR, 1.7; 95% CI = 1.0–3.00; Ref. 18 ), whereas another from Sweden claimed that men with the A1/A1 genotype had an increased risk (OR, 1.61; 95% CI = 1.02–2.53; Ref. 19 ). More recently, Gsur et al. (20) reported an increased risk in men with the A2/A2 genotype in a small cohort of prostate cancer patients in Austria. The conclusion in the United States study seems to remain unchanged even when the analysis is restricted to a Caucasian population (18) . Although the exact reason for these contradictory results remains unclear, the identical CYP genotype may play either a protective or a promoting role in prostate carcinogenesis given different environmental and/or genetic backgrounds. In support of this view, studies showed that women with an A2/A2 genotype had higher levels of estradiol and estrone (12) and that the A2 allele was associated with significantly higher levels of estradiol (11) , whereas the A2 allele was associated with phenotypic modification of a familial form of polycystic ovaries whose sex steroid hormone balance has been shown to be more androgen-dominant than normal (6 , 13 , 28) . These documents suggest that even women with the identical CYP17 genotype have much different phenotypes as far as hormone-dependent diseases are concerned. Because of the multiple enzymatic processes required for steroid hormone syntheses, the one enzymatically hyperactive step may lead to either a hyperestrogenic or a hyperandrogenic hormonal balance according to the difference in activities of the other enzymatic processes which follow.
Considering the striking differences in the age-adjusted incidence of
prostate cancer between different racial groups (1, 2, 3)
, we
reviewed the frequency of the CYP17 genotype in normal
control subjects in the eight previous studies with various clear
ethnic backgrounds (Table 4
; Refs. 7
, 9
, 14
, 18
, 19
, 29, 30, 31
). The CYP17
genotype frequency in the male control group in the present study is
comparable to those of Japanese controls in two other studies
(A1/A1 = 27%, A1/A2 = 47%,
A2/A2 = 26%; P = 0.157. Table 4
; Refs. 29
, 31
). Asians, including Japanese, who have the
lowest incidence of clinical prostate cancer, seem to have a higher
frequency of the A2/A2 genotype and a lower frequency of the A1/A1
genotype than American Blacks (African-American), American Whites, and
Scandinavians. For example, the difference in these genotype
frequencies are statistically significant between Japanese and American
Blacks (P < 0.0001), and between Japanese
and American whites (P < 0.0001). No
significant difference was observed between American Blacks and
American whites (P = 0.260). On the other
hand, the higher frequency of the A1 allele in American Blacks or
American Whites than in Asians does not reflect the ethnic difference
in breast cancer incidence (1)
. Presumably, the distinct
biological condition caused by the CYP17 genotype will be
among various genetic, dietary, and environmental factors regulating
hormonal and nonhormonal conditions in the development of prostate
cancer and breast cancer.
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73 years. It would be interesting to know whether the
CYP17 genotype influences the tissue or serum androgen
levels more significantly in an older population than in a younger one. Our results indicated that the CYP17 genotype is associated with the development of BPH as well as that of prostate cancer to almost the same degree. This connection is in line with the observation that a subset of BPH has a genetic transmission (32) . It has been reported that the volume of BPH is positively correlated with serum testosterone, estradiol, and estriol levels (33) , therefore indicating a rather complicated departure or imbalance of the androgen and estrogen environment in the development of BPH. A distinct sex-steroid hormone environment caused by the CYP17 genotype will presumably contribute to the development of BPH as well as prostate cancer. On the other hand, BPH and most prostatic cancer arise from a different part of the prostate gland, and BPH itself presumably does not substantially increase the risk of clinically significant prostate cancer (34) . These and our findings suggest that the CYP genotype is involved in distinct pathways of cellular growth of the prostate gland.
In conclusion, the present study indicated that CYP17 gene polymorphism may be significantly associated with a risk of prostate cancer, and BPH may be significantly associated with a gene dosage effect. However, the genotype has no significant influence on the disease status in prostate cancer patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants-in-aid from the Ministry of
Education, Science, Sports and Culture of Japan (B12470327, B10470331,
B10470330, and B10470336), grants-in-aid from the Ministry of Health
and Welfare of Japan (11-10), and by the Seventh Annual Grant-in-Aid
from the Japanese Urological Association. 
2 These authors contributed equally to this work.
3 To whom requests for reprints should be
addressed, at Department of Urology, Akita University School of
Medicine, 1-1-1 Hondo, Akita 010-8543, Japan. Fax: 81-18-836-2619;
E-mail: tkato{at}med.akita-u.ac.jp
4 The abbreviations used are: BPH, benign
prostatic hyperplasia; PSA, prostate-specific antigen; OR, odds ratio;
aOR, age-adjusted odds ratio; CI, confidence interval.
Received 4/10/00. Accepted 8/16/00.
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