Increased Risk of Prostate Cancer and Benign - Cancer Research

Increased Risk of Prostate Cancer and Benign - Cancer Research

[CANCER RESEARCH 60, 5710 –5713, October 15, 2000] Increased Risk of Prostate Cancer and Benign Prostatic Hyperplasia Associated with a CYP17 Gene Po...

136KB Sizes 0 Downloads 10 Views

Recommend Documents

Diet, Tobacco Use, and Fatal Prostate Cancer - Cancer Research
determine the risk of cancer associated with diet, tobacco use, and other factors. During the ... Since the LBS2 cohort

Prostate Cancer 2017: The Coming Sea-Change of Prostate Cancer
Aug 17, 2017 - Prostate Cancer 2017: The Coming Sea-Change of Prostate Cancer Care | Simms/Mann-UCLA Center for Integrat

Pim kinase inhibitors sensitize prostate cancer - Cancer Research
Andrew S. Kraft, Department of Medicine, Medical University of South Carolina, 86. Jonathan Lucas Street, Charleston, SC

Meat and Cancer Risk - Cancer Society NZ
who eat smaller amounts. Scientists have found some chemicals in red and processed meat that may explain the increased c

AccelerAting Discovery - Prostate Cancer Foundation
Lawrence J. and Joyce Stupski. Tarnopol Family Foundation .... Laurence and Karen Mandelbaum. Bernard Marcus ... Henry a

Cancer Registration - Cancer Research UK
Achievements made possible by cancer registration information: • research showing that there are at least. 10 differen

Thank you - Prostate Cancer UK
The Milly Apthorp Charitable Trust. - The Open Agency. - The Rangers Charity Foundation. - The Simon Gibson Charitable T

banana bread - Prostate Cancer UK
Angela Hartnett MBE. BANANA BREAD. Makes one loaf (12 slices). Ingredients. • 100g Sultanas. • 75ml rum. • 4 Small

international cancer research conference - Windsor Cancer Research
Nov 22, 2014 - Justin Peterson*, Adam Farag, Trevor Szekeres, Eli Gibson, Aaron Ward, Joseph Chin, Stephen. Pautler, Gle

Aspirin and Colorectal Cancer - Clinical Cancer Research
Mar 1, 2014 - Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la. Chapelle .... Stark LA, Reid K, Sansom OJ

[CANCER RESEARCH 60, 5710 –5713, October 15, 2000]

Increased Risk of Prostate Cancer and Benign Prostatic Hyperplasia Associated with a CYP17 Gene Polymorphism with a Gene Dosage Effect1 Tomonori Habuchi,2 Zhang Liqing,2 Takehiro Suzuki, Ryusei Sasaki, Norihiko Tsuchiya, Hiroshi Tachiki, Naotake Shimoda, Shigeru Satoh, Kazunari Sato, Yoshiyuki Kakehi, Toshiyuki Kamoto, Osamu Ogawa, and Tetsuro Kato3 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

ABSTRACT The CYP17 gene (CYP17) codes for the cytochrome P450c17␣ enzyme, which mediates two key steps in the sex steroid synthesis. There is a polymorphism (a T-to-C substitution) in the 5ⴕ-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) ⴝ 1.39 – 4.78] and BPH (OR, 2.44; 95% CI ⴝ 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 ⴝ 0.84 –2.54) and BPH (OR, 1.60; 95% CI ⴝ 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 ⴝ 0.003; OR, 1.57; 95% CI ⴝ 1.16 –2.12; BPH versus male control, P ⴝ 0.008; OR, 1.55; 95% CI ⴝ 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 Ethnic and geographic differences in clinical prostate cancer incidence have been well documented (1–3). The incidence in AfricanAmericans and that in American Whites is at least 10 times and 5 times higher, respectively, than in the Japanese (2, 3). However, Japanese immigrants in the United States have experienced a marked increase in prostate cancer incidence, although the rate is still less than half of that of Whites (2, 3). These epidemiological data emphasize

that the incidence of prostate cancer is influenced by genetic, dietary, and environmental factors. 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 –17). Three recent studies presented contradictory results concerning the CYP17 genotype in prostate cancer patients (18 –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). MATERIALS AND METHODS

Received 4/10/00; accepted 8/16/00. 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 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: 81-18-8362619; E-mail: [email protected]

Subjects. A total of 585 subjects consisting of 252 prostate cancer patients, 202 BPH4 patients, and 131 male controls treated at Akita University Medical Center and related community hospitals were enrolled in this study. Most subjects were previously enrolled in a study of vitamin D receptor gene polymorphisms and prostate cancer risk (21). All of the prostate cancer patients were diagnosed histologically with specimens obtained from transrectal needle 4 The abbreviations used are: BPH, benign prostatic hyperplasia; PSA, prostatespecific antigen; OR, odds ratio; aOR, age-adjusted odds ratio; CI, confidence interval.

5710

Downloaded from cancerres.aacrjournals.org on March 6, 2018. © 2000 American Association for Cancer Research.

PROSTATE CANCER AND CYP17 GENE POLYMORPHISM

biopsy or transurethral resection of the prostate for voiding symptoms. All of RESULTS the BPH patients had various degrees of lower urinary tract symptoms and The present study included 252 cases of histologically confirmed showed an apparent prostatic enlargement by digital rectal examination. The PSA levels were measured in all of the BPH patients, and men with elevated prostate cancer, 202 cases of BPH with lower urinary tract symptoms, PSA levels (ⱖ4.0 ng/ml; the Tandem-R assay; Hybritech Inc., San Diego, CA) and 131 male controls. The mean ages (⫾SD) of prostate cancer were proved not to have prostate cancer by transrectal biopsies. Serum PSA patients, BPH patients, and male controls were 72.2 ⫾ 8.5, was measured using the Tandem-R assay in most cases. When serum PSA was 70.5 ⫾ 9.4, and 75.3 ⫾ 7.2 years, respectively. Frequencies of the CYP17 genotype in the three groups (prostate 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 cancer, BPH, and male control) are shown in Table 1. The CYP17 (22). The male control group consisted 131 volunteers ⬎60 years old who were allelic distribution in each group was in the Hardy-Weinberg equilibselected mainly from among the patients admitted because of nonurological rium (P ⬎ 0.05; data not shown). Statistical analyses of the genotype diseases and showed no signs of prostate cancer and no prostatic enlargement prevalence showed significant differences between prostate cancer by digital rectal examination. They all were tested for serum PSA levels (the patients and the male controls (P ⫽ 0.022), and between BPH patients Tandem-R assay), and men with abnormal PSA levels were omitted from the and the male controls (P ⫽ 0.018; Table 1). Genotype analysis normal controls or received further examination, including prostate biopsy, to indicated that the presence of the A1 allele might increase the risk of rule out any prostatic disease conditions. prostate cancer and BPH, when non-adjusted and age-adjusted ORs Pathological grading of the prostate cancer was determined according to were calculated against the A2/A2 genotype (Table 1). Age-adjusted the General Rule for Clinical and Pathological Studies on Prostate Cancer logistic analysis showed that men with the A1/A1 CYP17 genotype by the Japanese Urological Association and the Japanese Society of Pahad an increased risk of prostate cancer (aOR, 2.57; 95% CI ⫽ 1.39 – thology, which is based on the WHO criteria and the Gleason pattern (23). 4.78) and BPH (aOR, 2.44; 95% CI ⫽ 1.26 – 4.72) compared with Well, moderately, and poorly differentiated carcinoma generally correthose with the A2/A2 genotype. Although not statistically significant, sponds to Gleason patterns 1–2, 3– 4, and 5, respectively (23, 24). In 26 patients, the final pathological grade was not determined because a differ- males heterozygous for the A1 allele also seemed to have an intermediate increased risk of prostate cancer (aOR, 1.45; 95% CI ⫽ 0.84 – ent or inadequate grading system was used. The clinical or pathological stage was determined by review of the medical records and classified using 2.54) and BPH (aOR, 1.60; 95% CI ⫽ 0.89 –2.87) compared with the Tumor-Node-Metastatis system (25). Prostate cancer was classified into males with the A2/A2 genotype. In addition, using an A2/A2 genothe localized group consisting of T1-4N0M0 (stage A, B, or C by the type, an A1/A2 genotype, and an A1/A1 genotype as the values 0, 1, Whitmore-Jewett system) tumors and the metastatic group consisting of and 2, respectively, we found a statistical significance in a logistic T1– 4N⫹M0 –1 or T1– 4N0 –1M1 (stage D by the Whitmore-Jewett system) regression model for the risk of prostate cancer and BPH in correlatumors. In 11 patients, no definite clinical stage was determined due to tion with an increasing number of the A1 allele (prostate cancer versus inadequate information. male control, P ⫽ 0.003; OR, 1.57; 95% CI ⫽ 1.16 –2.12; BPH versus CYP17 Genotyping Analysis. DNA was extracted from blood samples male control, P ⫽ 0.008; OR, 1.55; 95% CI ⫽ 1.12–2.13). The results collected from each patient using a QIAamp Blood Kit (QIAGEN) or by the indicate that the presence of the A1 allele may increase the risk of standard method with proteinase K digestion followed by phenol-chloroform prostate cancer and BPH with a gene dosage effect. extraction. The 421-bp fragment encompassing the polymorphic site in the Next, the prostate cancer group was analyzed according to tumor promoter region of CYP17 was amplified by PCR using primers CYP17-F1: grade and tumor stage (Table 2). In the tumor grade, no significant 5⬘-CCATTCGCACTCTGGAGTCAT and CYP17-R2: 5⬘-GACAGGAG- difference in genotype frequency was found. Adjusted ORs against GCTCTTGGGGTA. PCR was carried out in a 25-␮l aliquot containing ⬃50 the male control group did not show consistent results (Table 2). In the ng of genomic DNA, 50 pmol of each primer, 125 ␮M deoxynucleotide tumor stage, there was a significant difference in the genotype prevtriphosphates, 1 unit of Taq polymerase (Ampli-Taq Gold DNA polymerase, alence between metastatic prostate cancer patients and the male conPE Applied Biosystems), and 1⫻ reaction buffer supplied by the manufacturer trols (P ⫽ 0.0224). However, no significant difference was found (PE Applied Biosystems). PCR amplification conditions were 10 min of initial between the localized prostate cancer patients and the metastatic denaturation and activation of Ampli-Tag Gold DNA polymerase at 94°C, prostate cancer patients (Table 2). These data suggested that the followed by 35– 40 cycles of 30 sec at 94°C, 30 s at 55°C, and 90 s at 72°C, CYP17 polymorphism had no significant association with the disease 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, status of prostate cancer. Finally, we investigated whether the CYP17 polymorphism influInc., Beverly, MA) and electrophoresed on 2.0% agarose gels. When the ences the age of onset of prostate cancer. On the basis of median age, 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” the prostate cancer patients were divided into two groups (Table 3). when the restriction site was absent, and as “A2” when the restriction site was Although an A1/A1 genotype is more frequently observed in prostate present, as defined in the other studies (6). Genotyping was performed and cancer patients diagnosed at ⱖ73 years old, no significant difference checked by laboratory personnel (T. H. and Z. L.) unaware of the case-control in the genotype frequency was found when compared with the prosstatus. tate cancer patients diagnosed at ⬍73 (P ⫽ 0.238; Table 3). Statistical Methods. All data were entered into an access database (FileTable 1 CYP17 genotype frequencies [n (%)] for all cases and (crude) ORs and aORs MakerPro, Version 4.0, Claris Co.) and analyzed by Excel 98 and SPSS against male controls (Version 6.1, SPSS, Inc.) software. Differences in genotype frequencies and Hardy-Weinberg equilibrium analysis between the three groups and between Genotype the subgroups of prostate cancer patients were evaluated by a two-sided 2 ⫻ 3 Study group n A1/A1 A1/A2 A2/A2 or 3 ⫻ 3 contingency table analysis. Associations between CYP17 genotypes 252 95 (38) 111 (44) 46 (18) Prostate cancera and the development of prostate cancer and BPH were assessed by ORs and OR (95% CI) 2.25 (1.25–4.06) 1.40 (0.82–2.39) 1.00 95% CIs. A multivariate logistic regression analysis was performed with the aOR (95% CI) 2.57 (1.39–4.78) 1.45 (0.84–2.51) 1.00 b 202 74 (37) 95 (47) 33 (16) BPH inclusion of a factor of age. In addition, the trend across categories of A2/A2 OR (95% CI) 2.45 (1.31–4.57) 1.67 (0.94–2.96) 1.00 (A2 homozygote), A1/A2 (heterozygote), and A1/A1 (A1 homozygote) was aOR (95% CI) 2.44 (1.26–4.72) 1.60 (0.89–2.87) 1.00 tested in a logistic regression model by using a variable with the values 0, 1, Male controls (reference) 131 33 (25) 62 (47) 36 (28) a and 2, respectively. A probability ⬍0.05 was required for statistical signifiProstate cancer versus male control, P ⫽ 0.022. b BPH versus male control, P ⫽ 0.018. cance. 5711

Downloaded from cancerres.aacrjournals.org on March 6, 2018. © 2000 American Association for Cancer Research.

PROSTATE CANCER AND CYP17 GENE POLYMORPHISM

Table 2 CYP17 genotype frequencies [n (%)] in prostate cancer subgroups and aORs against male controls A1/A1 Study group Prostate cancer Tumor gradea Well Moderately Poorly Tumor stageb Localized Metastatic Male controls (reference)

A1/A2

A2/A2

n

n (%)

aOR (95% CI)

n (%)

aOR (95% CI)

n (%)

42 92 92

19 (45) 30 (33) 37 (40)

5.51 (1.16–18.30) 1.67 (0.78–3.61) 2.85 (1.29–6.28)

19 (45) 42 (46) 41 (45)

2.64 (0.83–8.42) 1.22 (0.65–2.29) 1.60 (0.77–3.32)

4 (10) 20 (22) 14 (15)

136 105 131

46 (34) 43 (41) 33 (25)

2.10 (1.05–4.22) 2.78 (1.29–5.97)

64 (47) 44 (42) 62 (47)

1.41 (0.76–2.63) 1.41 (0.70–2.85)

26 (19) 18 (17) 36 (28)

a The tumor grade 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 (23). Well-, moderately, and poorly differentiated carcinoma generally corresponds to Gleason patterns 1–2, 3– 4, and 5, respectively. P ⫽ 0.379 by ␹2 test. b Localized and metastatic tumor corresponds to stage A–C and stage D (the Whitmore-Jewet system), respectively. P ⫽ 0.524 by ␹2 test.

Table 3 CYP17 genotype frequencies [n (%)] and aOR stratified by age at diagnosisa Genotype Study group ⱖ73 years old Prostate cancer Male control aOR (95% CI) ⬍73 years old Prostate cancer Male control aOR (95% CI)

n

A1/A1

A1/A2

A2/A2

125 80

53 (42) 21 (26) 2.95 (1.32–6.63)

53 (42) 37 (46) 1.66 (0.79–3.49)

19 (15) 22 (28) 1.00

127 51

42 (33) 12 (23) 2.28 (0.84–6.16)

58 (46) 25 (49) 1.22 (0.52–2.84)

27 (21) 14 (27) 1.00

a Prostate cancer ⱖ73 years old versus prostate cancer ⬍73 years old; P ⫽ 0.238 by ␹2 test.

DISCUSSION Although conflicting results have been documented (7, 14 –17), the presence of the CYP17 A2 allele has been described to be an independent risk factor for a subset of breast cancer (8 –10). However, the present results indicated that the presence of the A1 allele significantly increases the risk of prostate cancer and BPH with a gene dosage effect. Because cytochrome P450c17␣ 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 –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 hormonedependent 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 (1–3), 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 –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 (AfricanAmerican), 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

Table 4 Reported CYP17 genotype frequencies [n (%)] in normal control subjects from different ethinic groups Genotype Study group

n

A1/A1

A1/A2

A2/A2

Ref.

Blacks in United States Whites in United States Scandinavians Taiwanese Japanese Japanese, present study Japanese, combined

407 395 478 236 1097 131 1228

171 (42) 145 (37) 173 (36) 54 (23) 291 (27) 33 (25) 324 (26)

175 (43) 191 (48) 244 (51) 117 (50) 519 (47) 62 (47) 581 (47)

61 (15) 59 (15) 61 (13) 65 (28) 287 (26) 36 (28) 323 (26)

(14, 18, 29) (14, 18, 29) (7, 9, 19) (18, 30) (29, 31)

5712

Downloaded from cancerres.aacrjournals.org on March 6, 2018. © 2000 American Association for Cancer Research.

PROSTATE CANCER AND CYP17 GENE POLYMORPHISM

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. We did not find any significant association between the CYP17 genotype and disease status in prostate cancer patients. However, the frequency of the A1/A1 genotype seemed to be higher in the patients with metastatic cancer, and the lack of significant association might be due to the relatively small number in each subgroup. As for age at diagnosis, the A1/A1 genotype seemed to be over-represented in the patients diagnosed at the age of ⱖ73 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.

ACKNOWLEDGMENTS We are indebted to many physicians and urologists of the Akita University Medical Center, the Kyoto University Hospital, and other community hospitals for providing samples and clinical information.

REFERENCES 1. Parkin, D. M., Pisani, P., and Ferlay, J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int. J. Cancer, 80: 827– 841, 1999. 2. Taylor, J. D., Holmes, T. M., and Swanson, G. M. Descriptive epidemiology of prostate cancer in metropolitan Detroit. Cancer (Phila.), 73: 1704 –1707, 1994. 3. Oishi, K., Yoshida, O., and Schroeder, F. H. The geography of prostate cancer and its treatment in Japan. Cancer Surv., 23: 267–280, 1995. 4. Partin, A. W., and Coffey, D. S. The molecular biology, endocrinology, and physiology of the prostate and seminal vesicles. In: P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr., and A. J. Wein (eds.), Canbell’s Urology (Ed. 7), pp. 1381–1428. Philadelphia: W. B. Saunders Co., 1998. 5. Picado-Leonard, J., and Miller, W. L. Cloning and sequence of the human gene for P450c17 (steroid 17 ␣-hydroxylase/17,20 lyase): similarity with the gene for P450c21. DNA, 6: 439 – 448, 1987. 6. Carey, A. H., Waterworth, D., Patel, K., White, D., Little, J., Novelli, P., Franks, S., and Williamson, R. Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum. Mol. Genet., 3: 1873–1876, 1994. 7. Kristensen, V. N., Haraldsen, E. K., Anderson, K. B., Lonning, P. E., Erikstein, B., Karesen, R., Gabrielsen, O. S., and Borresen-Dale, A. L. CYP17 and breast cancer risk: the polymorphism in the 5⬘ flanking area of the gene does not influence binding to Sp-1. Cancer Res., 59: 2825–2828, 1999.

8. Feigelson, H. S., Coetzee, G. A., Kolonel, L. N., Ross, R. K., and Henderson, B. E. A polymorphism in the CYP17 gene increases the risk of breast cancer. Cancer Res., 57: 1063–1065, 1997. 9. Bergman-Jungestrom, M., Gentile, M., Lundin, A. C., and Wingren, S. Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int. J. Cancer, 84: 350 –353, 1999. 10. Young, I. E., Kurian, K. M., Annink, C., Kunkler, I. H., Anderson, V. A., Cohen, B. B., Hooper, M. L., Wyllie, A. H., and Steel, C. M. A polymorphism in the CYP17 gene is associated with male breast cancer. Br. J. Cancer, 81: 141–143, 1999. 11. Feigelson, H. S., Shames, L. S., Pike, M. C., Coetzee, G. A., Stanczyk, F. Z., and Henderson, B. E. Cytochrome P450c17␣ gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res., 58: 585–587, 1998. 12. Haiman, C. A., Hankinson, S. E., Spiegelman, D., Colditz, G. A., Willett, W. C., Speizer, F. E., Kelsey, K. T., and Hunter, D. J. The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer. Cancer Res., 59: 1015–1020, 1999. 13. Diamanti-Kandarakis, E., Bartzis, M. I., Zapanti, E. D., Spina, G. G., Filandra, F. A., Tsianateli, T. C., Bergiele, A. T., and Kouli, C. R. Polymorphism T–⬎C (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome. Fertil. Steril., 71: 431– 435, 1999. 14. Weston, A., Pan, C. F., Bleiweiss, I. J., Ksieski, H. B., Roy, N., Maloney, N., and Wolff, M. S. CYP17 genotype and breast cancer risk. Cancer Epidemiol. Biomark. Prev., 7: 941–944, 1998. 15. Helzlsouer, K. J., Huang, H. Y., Strickland, P. T., Hoffman, S., Alberg, A. J., Comstock, G. W., and Bell, D. A. Association between CYP17 polymorphisms and the development of breast cancer. Cancer Epidemiol. Biomark. Prev., 7: 945–949, 1998. 16. Techatraisak, K., Conway, G. S., and Rumsby, G. Frequency of a polymorphism in the regulatory region of the 17 ␣-hydroxylase-17,20-lyase (CYP17) gene in hyperandrogenic states. Clin. Endocrinol., 46: 131–134, 1997. 17. Dunning, A. M., Healey, C. S., Pharoah, P. D., Foster, N. A., Lipscombe, J. M., Redman, K. L., Easton, D. F., Day, N. E., and Ponder, B. A. No association between a polymorphism in the steroid metabolism gene CYP17 and risk of breast cancer. Br. J. Cancer, 77: 2045–2047, 1998. 18. Lunn, R. M., Bell, D. A., Mohler, J. L., and Taylor, J. A. Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2). Carcinogenesis (Lond.), 20: 1727–1731, 1999. 19. Wadelius, M., Andersson, A. O., Johansson, J. E., Wadelius, C., and Rane, E. Prostate cancer associated with CYP17 genotype. Pharmacogenetics, 9: 635– 639, 1999. 20. Gsur, A., Bernhofer, G., Hinteregger, S., Haidinger, G., Schatzl, G., Madersbacher, S., Marberger, M., Vutuc, C., and Micksche, M. A polymorphism in the CYP17 gene is associated with prostate cancer risk. Int. J. Cancer, 87: 434 – 437, 2000. 21. Habuchi, T., Suzuki, T., Sasaki, R., Wang, L., Sato, K., Satoh, S., Akao, T., Tsuchiya, N., Shimoda, N., Wada, Y., Koizumi, A., Chihara, J., Ogawa, O., and Kato, T. Association of vitamin D receptor gene polymorphism with prostate cancer and benign prostatic hyperplasia in a Japanese population. Cancer Res., 60: 305–308, 2000. 22. Kuriyama, M., Akimoto, S., Akaza, H., Arai, Y., Usami, M., Imai, K., Tanaka, Y., Yamazaki, H., Kawada, Y., Koiso, K., Yoshida, O., Kotake, T., Ymanaka, H., Machida, T., Aso, Y., and Shimazaki, J. Comparison of various assay systems for prostate-specific antigen standardization. Jpn. J. Clin. Oncol., 22: 393–399, 1992. 23. The Japanese Urological Association and the Japanese Society of Pathology. General Rules for Clinical and Pathological Studies on Prostate Cancer, Ed. 2. Tokyo, Japan: Kanahara-Shuppan Co., 1992. 24. Gleason, D. F., and the VACURG. Histological grading and clinical staging of prostatic carcinoma. In: M. Tannenbaum (ed.), Urologic Pathology, pp. 171–197. Philadelphia: Lea & Febiger, 1977. 25. International Union Against Cancer. Urological tumours: prostate. In: P. Hermanek and L. H. Sobin (eds.), TNM Classification of Malignant Tumors, Ed. 4, pp. 141–144. Berlin: Springer-Verlag, 1992. 26. Bernstein, L., and Ross, R. K. Endogenous hormones and breast cancer. Epidemiol. Rev., 15: 48 – 65, 1993. 27. Makridakis, N., Reichardt, J., Pike, M., Stanczyk, F., Yu, M., Kolonel, L., Ross, R., Coetzee, G., and Henderson, B. Genetic control of human androgen metabolism by the CYP17 and SRD5A2 genes. Am. J. Hum. Genet. (Suppl.), 61: A257, 1997. 28. Qin, K. N., and Rosenfield, R. L. Role of cytochrome P450c17 in polycystic ovary syndrome. Mol. Cell. Endocrinol., 145: 111–121, 1998. 29. Feigelson, H. S., McKean-Cowdin, R., Pike, M. C., Coetzee, G. A., Kolonel, L. N., Nomura, A. M., Le Marchand, L., and Henderson, B. E. Cytochrome P450c17␣ gene (CYP17) polymorphism predicts use of hormone replacement therapy. Cancer Res., 59: 3908 –3910, 1999. 30. Huang, C. S., Chern, H. D., Chang, K. J., Cheng, C. W., Hsu, S. M., and Shen, C. Y. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res., 59: 4870 – 4875, 1999. 31. Huang, J., Ushiyama, T., Inoue, K., Mori, K., and Hukuda, S. Possible association of CYP17 gene polymorphisms with the onset of rheumatoid arthritis. Clin. Exp. Rheumatol., 17: 721–724, 1999. 32. Sanda, M. A., Beaty, T. H., Stutzman, R. E., Childs, B., and Walsh, P. C. Genetic susceptibility of benign prostatic hyperplasia. J. Urol., 152: 115–119, 1994. 33. Partin, A. W., Oesterling, J. E., Epstein, J. I., Horton, R., and Walsh, P. C. Influence of age and endocrine factors on the volume of benign prostatic hyperplasia. J. Urol., 145: 405– 409, 1991. 34. Greenwald, P., Kirmiss, V., Polan, A. K., and Dicks, V. S. Cancer of the prostate among men with benign prostatic hyperplasia. J. Natl. Cancer Inst., 53: 335–340, 1974.

5713

Downloaded from cancerres.aacrjournals.org on March 6, 2018. © 2000 American Association for Cancer Research.

Increased Risk of Prostate Cancer and Benign Prostatic Hyperplasia Associated with a CYP17 Gene Polymorphism with a Gene Dosage Effect Tomonori Habuchi, Zhang Liqing, Takehiro Suzuki, et al. Cancer Res 2000;60:5710-5713.

Updated version

Cited articles Citing articles

E-mail alerts Reprints and Subscriptions Permissions

Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/60/20/5710

This article cites 28 articles, 9 of which you can access for free at: http://cancerres.aacrjournals.org/content/60/20/5710.full#ref-list-1 This article has been cited by 14 HighWire-hosted articles. Access the articles at: http://cancerres.aacrjournals.org/content/60/20/5710.full#related-urls

Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected] To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/60/20/5710. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.

Downloaded from cancerres.aacrjournals.org on March 6, 2018. © 2000 American Association for Cancer Research.