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[Cancer Research 60, 839-841, February 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Susceptibility to Prostate Cancer: Interaction between Genotypes at the Androgen Receptor and Prostate-specific Antigen Loci1

Wenmei Xue, Ryan A. Irvine, Mimi C. Yu, Ronald K. Ross, Gerhard A. Coetzee and Sue Ann Ingles2

Departments of Preventive Medicine [W. X., M. C. Y., R. K. R., S. A. I.], Molecular Microbiology and Immunology [R. A. I., G. A. C.], and Urology [R. K. R., G. A. C.], University of Southern California, Los Angeles, California 90089


   ABSTRACT
Top
 ABSTRACT
Introduction
 Subjects and Methods
 Results
 REFERENCES
 
The androgen receptor (AR) regulates gene transcription by binding to androgen response elements in target gene promoters. The prostate-specific antigen (PSA) gene has a polymorphic androgen response element sequence with two alleles, A and G. We hypothesize that allelic differences in AR-driven PSA expression may influence prostate cancer risk. To test this hypothesis, we assayed PSA genotype for 57 prostate cancer cases and 156 controls from our previous pilot study in which prostate cancer risk was associated with the AR "CAG-short" genotype. Odds ratios (ORs) were estimated relating prostate cancer risk to AR and PSA genotypes, singly and in combination. Subjects with the PSA GG genotype were at significantly increased risk for advanced, but not for localized, prostate cancer (OR, 2.90; 95% confidence interval, 1.24–6.78). When cross-classifying subjects by AR and PSA genotypes, subjects with either a CAG-short allele (and not PSA GG) or with the PSA GG genotype (and not CAG-short) had a modest, statistically insignificant increase in prostate cancer risk overall. However, subjects with both a short CAG allele and PSA genotype GG had a more than 5-fold increase in prostate cancer risk (OR, 5.08; 95% confidence interval, 1.59–16.25). All of the ORs were substantially greater for advanced prostate cancer. Studies with larger numbers of advanced cases will be needed to confirm these results. These results indicate that polymorphism in the PSA gene promoter influences prostate cancer risk, and that the allelic variation in promoter activity may be androgen-dependent. Furthermore, these results support a multigenic etiology for prostate cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Subjects and Methods
 Results
 REFERENCES
 
It is now well-documented that androgens play a key role in prostate carcinogenesis. We have proposed a multigenic model for prostate cancer susceptibility, featuring genes involved in the androgen metabolic pathway (1, 2) . At the center of this pathway lies the AR,3 a transcription factor that mediates the proliferative effects of androgens in the prostate.

The AR gene is highly polymorphic in human populations. Length variation in a CAG microsatellite in exon 1 results in variation in the number of glutamine residues in the NH2-terminal domain of the AR protein. Because ethnic variation in CAG allele frequencies mirrors ethnic variation in prostate cancer rates and because in vitro studies suggested that AR transactivation activity varies by CAG allele length, we proposed (3) that CAG length is inversely related to prostate cancer risk. Our subsequent findings that short AR CAG alleles confer increased risk of prostate cancer, especially advanced disease (1 , 4) , were later confirmed in two large-scale cohort studies, each involving over 300 prostate cancer cases (5, 6) .

The mechanism by which short CAG alleles increase prostate cancer risk is apparently related to their increased efficiency as transactivators of androgen-regulated target genes (7, 8) . The AR regulates gene transcription by binding DNA sequences known as AREs (androgen response elements) in target gene promoters. The specific target genes that drive cell proliferation in the prostate are not known. One candidate, which is androgen-regulated in the prostate, is the PSA gene. Furthermore, the PSA gene promoter has a polymorphic ARE sequence (9) . We hypothesize that the two allelic variants may interact differently with the AR and may, thereby, differentially influence prostate cancer risk. To test this hypothesis, we assayed PSA genotype for subjects from our previous case-control study, in which prostate cancer risk was associated with AR genotype (1) .


   Subjects and Methods
Top
 ABSTRACT
 Introduction
 Subjects and Methods
Results
 REFERENCES
 
Subjects.
Subjects were non-Hispanic white men from a previous study and have been described elsewhere (1) . Briefly, prostate cancer cases diagnosed in 1991 through 1992 were identified by the Cancer Surveillance Program, the population-based Surveillance, Epidemiology, and End Results cancer registry of Los Angeles Country. In early 1994, 559 of 1062 eligible cases responded to a one-time-only mailed questionnaire that requested detailed information on family history of cancer. The first 57 non-Hispanic white cases were included in that study. The age at diagnosis ranged from 51 to 68 years, with a mean age of 57.8 years and a median age of 58 years. The previous study included 169 non-Hispanic white male controls selected from the control group of an ongoing population-based case-control study of bladder cancer in Los Angles County. The 169 controls were chosen to be comparable with the prostate cancer patients in age and socioeconomic status. Of these previous 169 control subjects, 13 were excluded from this study, either because the DNA sample was depleted or because of PCR amplification failure, leaving 156 controls. Written informed consent was obtained from all of the subjects, and the investigations were approved by the University of Southern California School of Medicine’s review board.

To determine PSA allele frequencies in nonwhite populations, we also genotyped African-American and Asian controls from a previous study (4) . Thirty of the 45 African-American and 35 of the 39 Asian controls in that study had sufficient DNA remaining and are included in the present study.

Genotyping of Polymorphisms.
Two polymorphisms were genotyped: a CAG microsatellite in the AR gene and a G/A substitution polymorphism in the PSA gene. The AR CAG microsatellite is a length polymorphism, with individual alleles defined by the number of repeated units (CAG repeats) that they contain. The AR CAG allele sizes were determined on these samples as a part of our previous studies (1 , 4) .

The alleles of the G/A polymorphism at position -158 in the promoter region of the PSA gene can be distinguished by cutting with the NheI restriction enzyme. The polymorphic site was amplified by use of forward primer (5'-TTG TAT GAA GAA TCG GGG ATC GT-3') and reverse primer (5'-TCC CCC AGG AGC CCT ATA AAA-3'). PCR was performed with approximately 40 ng of genomic DNA and 20 pmol of each primer in a 50-µl reaction volume containing 2 mM MgCl2. The cycling conditions were 94°C for 10 min, followed by 35 cycles at 94°C for 1 min, 59°C for 1 min, and 72°C for 40 s with a final cycle at 72°C for 10 min. A 7-µl aliquot was digested with 1.5 units of NheI restriction enzyme (New England Biolabs, Inc) in 1.5 µl of 10x NEB2 buffer (New England Biolabs, Inc., Beverly, MA), 0.15 µl of 100x BSA and 6 µl of water at 37°C for 4 h and then separated on a 2.5% agarose gel. The three possible genotypes were defined by three distinct banding patterns: AA (300 bp), AG (150, 300 bp), and GG (150 bp).

Statistical Methods.
AR CAG allele sizes were categorized as "long (>=20 CAG repeats) or "short" (<20 repeats), as in our previous study (1) . Unconditional logistic regression was used to estimate ORs. A test of interaction was performed by adding an interaction term to the logistic model and computing the likelihood ratio statistic (10) .


   Results
Top
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
REFERENCES
 
For the PSA gene polymorphism, allele frequencies among controls were 50% A and 50% G (Table 1)Citation . Genotype frequencies among controls were nearly identical to the expected Hardy-Weinberg equilibrium frequencies of 25% AA, 50% AG, and 25% GG. There was no difference in prostate cancer risk between subjects with genotypes AA and AG. Subjects with genotype GG, however, had an approximately 60% increase in risk relative to the other two groups, which was not statistically significant.


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  		Table 1 Distribution of PSA and AR genotypes among cases and controls

 
The AR gene polymorphism was analyzed as in our previous study (1) . That study found subjects with a short AR CAG allele to have a 2-fold increase in prostate cancer risk (OR, 2.00; 95% CI, 1.07–3.75). The result in Table 1Citation differs from this previous report only in the number of controls, with no appreciable change in risk.

Thirty-one (54%) cases had disease localized to the prostate, and 26 (46%) had advanced disease [defined as a tumor invading and extending beyond the prostate capsule and/or extending into adjacent tissue or involving regional lymph nodes or distant metastatic sites (SEER 1995 clinical and pathological extent of disease codes 41–85)]. Subjects with the GG genotype were at significantly increased risk for advanced, but not for localized, prostate cancer. The GG genotype conferred a nearly 3-fold increase in risk of advanced disease (Table 2)Citation .


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  		Table 2 PSA genotype frequency among cases with localized and advanced disease compared with controls

 
Subjects were cross-classified by PSA and AR genotypes in Table 3Citation , with those having both of the "low-risk" genotypes, AR CAG-long and PSA AA or AG (not GG), chosen as the referent group. Subjects with a single "high-risk" genotype, either CAG-short (and not GG) or PSA GG (and not CAG-short), had modest, statistically insignificant increases in prostate cancer risk overall, relative to the referent group. In combination, however, a short CAG allele and PSA genotype GG conferred a more than 5-fold increase in prostate cancer risk (Table 3)Citation . The statistical test for interaction was not statistically significant (P = 0.28); however, power for testing interaction in this data set was small. For individuals presenting with advanced disease, all ORs were substantially greater. A statistically significant increase in risk was conferred by either CAG-short or PSA GG, either alone or in combination; however, ORs were imprecisely estimated because of the small number of advanced cases.


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  		Table 3 Prostate cancer cases and controls, cross-classified by PSA and AR genotypes

 
Discussion
This is the first report to show that polymorphism in two genes in the androgen pathway, when considered in combination, confers higher risk for prostate cancer than does polymorphism in one of the genes alone. We found that men carrying two copies of the PSA G allele had a nearly 3-fold increase in risk of advanced prostate cancer. Moreover, the risk was most elevated among men who also carried a short AR CAG allele.

The PSA gene is a target of the AR. For PSA gene transcription to occur, the AR must interact with AREs in the PSA gene promoter. Lying 170 bp upstream of the transcription start site, the most proximal of the three AREs in the PSA promoter—ARE1—has two allelic variants: AGAACAnnnAGTACT and AGAACAnnnAGTGCT (9) .

It is possible that the AR binds these two alleles with differing affinities, producing quantitative differences in PSA mRNA expression. No experimental studies have yet addressed this point; however, breast tumor tissues and cancer cell lines that harbored the A allele were reported to lack PSA expression (11) . Alternatively, the polymorphism in the ARE1 may be in linkage disequilibrium with upstream or downstream regulatory elements that affect transcription efficiency, or with coding polymorphisms that affect PSA activity. In any case, we hypothesize that short AR CAG alleles, which are especially efficient transactivators of androgen-regulated target genes (7, 8) , may amplify any functional differences between the two PSA alleles.

PSA serum concentration has long been used as a tumor marker for monitoring prostate cancer progression. However, it is increasingly apparent that PSA also plays a role in normal prostate growth and possibly in prostate carcinogenesis (12) . For example, PSA has been identified as the protease for the major IGF-binding protein, IGFBP-3 (13) . Cleavage of IGFBP-3 by PSA increases IGF-I and IGF-II bioavailability. Recent epidemiological studies have demonstrated that decreased serum IGFBP-3 and, in particular, elevated serum IGF-I are associated with increased prostate cancer risk (14 , 15) . Another target of PSA in the prostate is PTHrP (16) . The cleavage and inactivation of PTHrP by PSA may play a critical role in producing osteoblastic bone metastasis, which is common in prostate cancer (17) .

The two PSA alleles have been reported to occur with nearly equal frequencies (50% A, 50% G) in both white and African-American populations (9) . We have verified these frequencies by examining 139 white (Table 1)Citation and 30 African-American control subjects. The G allele frequency among African-Americans was 55% (95%CI, 42–68). We also examined 35 Asian subjects, and found the G allele frequency to be 81% (95%CI, 72–90). We do not expect PSA allele frequencies alone to predict disease risk in different ethnic populations because, among all cases and controls, only subjects with both PSA genotype GG and a short AR CAG allele were at high risk. This combination of genotypes is most common among African-Americans. Although the PSA G allele is most common among low-risk Asians, AR CAG-short alleles are uncommon in that population (4) .

Previously, we put forward a multigenic model of prostate cancer etiology. In this model, no single gene is sufficient to produce a Mendelian pattern of disease segregation; rather, disease risk is influenced by several genes and possibly by gene-gene and gene-environment interactions. Here we show evidence for gene-gene interaction in the etiology of prostate cancer and have extended the multigenic model to include genes downstream of the androgen-signaling pathway. More importantly, our results suggest that the androgen-mediated etiological pathway may act in conjunction with the IGF-signaling pathway and/or with PTHrP. This interaction seems more strongly associated with advanced, rather than with localized disease, which suggests that, in the constrained androgen environment of advanced disease, the influence of other growth factors may become critical.

Because of the small sample size of this study, our results clearly need to be confirmed in studies with larger numbers of advanced cases. If confirmed, our findings lend support to a multigenic etiology for prostate cancer. Our findings also support the idea that certain multigenic profiles may strongly predict risk of advanced disease and, therefore, might be useful for decision-making in prostate cancer treatment or for targeting preventive interventions.


   FOOTNOTES
 
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 in part by United States Public Health Service Grants CA17054 and CA65726 from the National Cancer Institute, NIH, Department of Health and Human Services; by the Elsa U. Pardee Foundation; and by The Stop Cancer Foundation. Back

2 To whom requests for reprints should be addressed, at University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue MS#44, Room 6419, Los Angeles, CA 90089. Phone: (323) 865-0498; Fax: (323) 865-0473; E-mail: ingles{at}hsc.usc.edu Back

3 The abbreviations used are: AR, androgen receptor; PSA, prostate-specific antigen; ARE, androgen response element; IGF, insulin-like growth factor; IGFBP-3, IGF binding protein 3; PTHrP, parathyroid hormone-related protein; OR, odds ratio; CI, confidence interval. Back

Received 9/15/99. Accepted 12/23/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Subjects and Methods
 Results
 REFERENCES
 

  1. Ingles S. A., Ross R. K., Yu M. C., Irvine R. A., La Pera G., Haile R. W., Coetzee G. A. Association of prostate cancer risk with genetic polymorphism in vitamin D receptor and androgen receptor. J. Natl. Cancer. Inst., 89: 166-170, 1997.[Abstract/Free Full Text]
  2. Ross R. K., Pike M. C., Gerhard A. C., Reichardt J. V., Yu M. C., Feigelson H., Stanczyk F. Z., Knolonel L. N., Henderson B. E. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res., 58: 4497-4504, 1998.[Abstract/Free Full Text]
  3. Coetzee G. A., Ross R. K. Prostate cancer and the androgen receptor. J. Natl. Cancer Inst., 86: 872-873, 1994.[Free Full Text]
  4. Irvine R. A., Yu M. C., Ross R. K., Coetzee G. A. The CAG and GGC microsatellites of androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res., 55: 1937-1940, 1995.[Abstract/Free Full Text]
  5. Stanford J. L., Just J. J., Gibbs M., Wichlund K. G., Neal C. L., Blumenstein B. A., Ostrander E. A. Polymorphic repeats in the androgen receptor gene: molecular markers for prostate cancer risk. Cancer Res., 57: 1194-1198, 1997.[Abstract/Free Full Text]
  6. Giovannucci E., Stampfer M. J., Krithivas K., Brown M., Brufsky A., Talcott J., Hennekens C. H., Kantoff P. W. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc. Natl. Acad. Sci. USA, 94: 3320-3323, 1997.[Abstract/Free Full Text]
  7. Chamberlain N. C., Driver E. D., Miesfeld R. L. The length and location of CAG trinucleotide repeat in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res., 22: 3181-3186, 1994.[Abstract/Free Full Text]
  8. Kazemi-Esfarjani P., Trifiro M. A., Pinsky L. Evidence for a repressive function of the. long polyglutamine tract in the human androgen receptor: possible pathogenic relevance for the (CAG)n-expanded neuropathies. Hum. Mol. Genet., 4: 523-527, 1995.[Abstract/Free Full Text]
  9. Rao A., Cramer S. D. Identification of a polymorphism in the ARE 1 region of the PSA promoter. Proc. Am. Assoc. Cancer Res., 40: 65 1999.
  10. Breslow, N. E., and Day, N. E. Statistical methods in cancer research Vol. 1. Lyon, France: IARC, 1980.
  11. Majumdar S., Diamandis E. P. The promoter and the enhancer region of the KLK3 (prostate specific antigen) gene is frequently mutated in breast tumors and in breast carcinoma cell lines. Br. J. Cancer, 79: 1594-1602, 1999.[Medline]
  12. Peehl D. M. Prostate specific antigen role and function. Cancer (Phila.), 75(Suppl.): 2021-2026, 1995.
  13. Cohen P., Peehl D. M., Rosenfeld R. G. Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease. J. Endocrinol., 142: 407-415, 1994.[Abstract]
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  15. Cohen P. Serum insulin-like growth factor-I levels and prostate cancer risk-interpreting the evidence. J. Natl. Cancer Inst., 90: 876-879, 1998.[Free Full Text]
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