Abstract
Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.
Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.
Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).
Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.
Androgens are fundamental for the development and maintenance of the prostate gland and play a key role in prostate cancer biology. Early prostate cancer depends on androgens, and for the past 60 yr, the major therapeutic modality for metastatic prostate cancer has relied on decreasing androgen levels through surgical or pharmacological means (1). Based on the importance of androgens in prostate cancer biology, a long-standing hypothesis has been that circulating hormone levels affect prostate cancer risk, although a pooled analysis of worldwide data from 18 prospective studies (consisting of 3886 prostate cancer cases and 6438 controls) found no association between serum sex hormone concentrations and risk (2).
Androgenic action in the prostate is mediated by the androgen receptor (AR), which binds the two key androgens testosterone and dihydrotestosterone and activates expression of other androgen-responsive genes. AR mutations often lead to androgen insensitivity syndromes, and a highly polymorphic microsatellite (CAG)n located in exon 1 of the AR has been associated with AR transactivation where shorter repeats increase AR activity (3,4,5). Although some studies have found a positive correlation between CAG repeat length and serum testosterone levels (6,7), several others have not been able to replicate this (8,9,10). A recent study in 2878 men found a significant correlation between longer CAG repeats and high circulating levels of testosterone and estradiol (11).
Association studies between germline genetic variation in AR and prostate cancer risk have been inconclusive. Most published studies have focused on the CAG repeat where shorter repeats have been suggested to increase risk, but this has not been consistent (12,13). Only a few other studies have assessed other AR polymorphisms, and the two largest studies to date both found modest associations with aggressive prostate cancer (12,14).
Recognizing the need for well-powered studies in genetic epidemiology, the National Cancer Institute (NCI) initiated the Breast and Prostate Cancer Cohort Consortium (BPC3) in 2003 (http://epi.grants.cancer.gov/BPC3/). The BPC3 consists of seven large cohorts from the United States and Europe and includes to date over 8800 patients with prostate cancer and 9000 matched controls. In this study, we evaluate the impact of inherited variation in AR on circulating sex steroid levels and prostate cancer risk. The CAG repeat and six single nucleotide polymorphisms (SNPs) were genotyped in 6058 prostate cancer cases and 6725 controls, for whom DNA was available at the time of this study.
Subjects and Methods
Study Population
The BPC3 and member cohorts have been described in detail elsewhere (15). In brief, the Consortium combines resources from seven well-established cohort studies: the American Cancer Society Cancer Prevention Study II (CPS-II) (16), the α-Tocopherol, β-Carotene Cancer Prevention (ATBC) Study (17), the European Prospective Investigation into Cancer and Nutrition Cohort (EPIC; comprised of cohorts from Denmark, Great Britain, Germany, Greece, Italy, The Netherlands, Spain, and Sweden) (18), the Health Professionals Follow-up Study (HPFS) (19), the Multi-Ethnic Cohort (MEC) (20), the Physicians’ Health Study (PHS) (21), and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (22). These cohorts collectively include over 248,000 men who provided a blood sample.
Prostate cancer cases were identified through population-based cancer registries or self-reports confirmed by medical records, including pathology reports. The BPC3 data for prostate cancer consists of a series of matched nested case-control studies within each cohort; controls were matched to cases on a number of potential confounding factors, such as age, ethnicity, and region of recruitment, depending on the cohort. For the current analysis, prostate cancer cases were matched to available controls by age in 5-yr intervals, cohort, and country of residence for EPIC. Informed consent was obtained from all subjects, and each study was approved by the Institutional Review Boards at their respective institutions.
The current study was restricted to individuals who self-reported as Caucasian. Cases from other ethnic groups were contributed mostly from the MEC study, which has been published elsewhere (12). We had genotype data for a total of 6058 prostate cancer cases and 6725 controls. Data on the stage and grade of disease at diagnosis were collected from each cohort, where possible. A total of 1098 cases were classified as advanced (stage C or D at diagnosis or death due to prostate cancer), and 657 were classified as high-grade (Gleason scores 8–10 or equivalent, i.e. coded as poorly differentiated or undifferentiated).
SNP selection and genotyping
Polymorphisms were originally selected based on data from Freedman et al. (12). Freedman and colleagues genotyped 32 SNPs, but the majority of the loci were monomorphic in populations of European ancestry. Therefore, we selected six SNPs that were polymorphic and adequately captured the haplotype variation in the region of interest. The mean pairwise r2 for the 32 original SNPs with a minor allele frequency of at least 0.01 at the AR locus (in the phase II HapMap data release) captured by these six SNPs is 0.90 in the CEU HapMap population. Genotyping was done in four core laboratories (Harvard School of Public Health, Boston, MA; Strangeways Research Laboratory, Cambridge, UK; National Cancer Institute, Rockville, MD; and University of Hawaii, Honolulu, HI) using the fluorogenic 5′-endonuclease assay (TaqMan) with the ABI Prism 7900 (Applied Biosystems, Foster City, CA). TaqMan assays were designed and optimized for each SNP. Quality control was done by the manufacturer (Applied Biosystems) and by the laboratories of the Cohort Consortium for another 500 test reactions. Detailed assay information for each SNP is available on http://www.uscnorris.com/mecgenetics/CohortGCKView.aspx. For each SNP, sequence validation was done, and a 100% concordance was observed (http://snp500cancer.nci.nih.gov). The interlaboratory variation was assessed in each laboratory by running assays on 94 samples from the CEPH families, and the completion and concordance rates were above 99%. At each core laboratory, the internal genotyping quality control was done by genotyping 5 to 10% of blinded samples in duplicate or triplicate. Because AR is located on chromosome X where men are haploid, Hardy-Weinberg Equilibrium testing is not applicable.
CAG microsatellite genotyping was performed in three different core laboratories (Harvard School of Public Health, Boston, MA; National Cancer Institute, Rockville, MD; and University of Southern California, Los Angeles, CA). In brief, oligonucleotide primers flanking the CAG repeat were constructed, and genomic DNA was PCR amplified using fluorescently labeled primers. Products were analyzed by fragment analysis using an ABI 3730 capillary machine (University of Southern California, Los Angeles, CA), an ABI 3700 capillary machine (Harvard School of Public Health), and the ABI GeneMapper 3.0 (National Cancer Institute).
Plasma steroid hormone levels
Data on prediagnostic blood levels of androstanediol (n = 4851), testosterone (n = 4753), estradiol (n = 2076), and SHBG (n = 4796) were available in five of seven BPC3 cohorts (HPFS, PHS, ATBC, EPIC, and PLCO). The hormonal analysis was performed at different points in time as a part of individual studies for each cohort, i.e. the number of included cohorts for one plasma hormone indicates the number of laboratories used. Mean intrabatch coefficients of variation ranged between 4.1 and 18% for each lab (23). Methods for steroid hormones and SHBG have been published elsewhere (24,25,26,27,28).
Statistical methods
We tested the association between AR variants and prostate cancer risk using Wald tests from conditional logistic regression (stratified by study and age at diagnosis or selection as a control in 5-yr intervals). The CAG repeat was coded either continuously as 10-repeat units or categorically according to approximate quintiles in controls (≤19, 20–21, 22, 23–24, ≥25). To test association between AR SNPs or CAG repeats and plasma biomarker levels, we used Wald tests from standard multiple linear regression, adjusting for laboratory batch (nested within study), age at blood draw in 5-yr intervals, and case-control status. To ensure approximate normality and homoscedacticity across cohorts, hormone levels were log-transformed before analysis, and outliers were removed using Rosner’s procedure (29). For all haplotype analyses, we included expected haplotype counts in the appropriate regression analyses and used the most common haplotype as the referent. Expected haplotype counts were calculated separately for each study to account for differences in haplotype frequencies and minimize potential for population stratification bias. All haplotypes with frequency less than 5% were combined in a single category. For subjects with no missing data, haplotyping was straightforward (because men are haploid on the X chromosome); for subjects with missing data, we used the expectation-maximization algorithm to calculate expected haplotype counts. Global tests of association between multiple haplotypes spanning AR and each outcome were calculated using likelihood ratios (30). All reported P values are two-sided and uncorrected for multiple hypothesis testing. We used the Cochran’s Q statistic to assess effect measure heterogeneity across cohorts for individual SNPs, individual haplotypes, and the CAG repeat.
Results
A total of seven AR polymorphisms (one microsatellite and six SNPs) were genotyped in 6058 cases and 6725 controls. Characteristics of the seven nested case-control study populations are reported in Table 1. We performed association analyses across multiple phenotypes, including overall risk, tumor stage, grade, and hormone levels. Results are presented for the entire population, adjusted for age and cohort. Study-specific results are presented in Supplemental Tables 1–9 (published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org).
Table 1.
Means and sd values for age, AR CAG repeats, and plasma hormone measurements by cohort and case-control status
| Controls
|
Cases
|
|||||
|---|---|---|---|---|---|---|
| n | Mean | sd | n | Mean | sd | |
| Age | ||||||
| CPS-II | 1177 | 71.9 | 5.14 | 1168 | 71.8 | 5.11 |
| ATBC | 1054 | 58.7 | 5.08 | 1048 | 59.2 | 5.25 |
| EPIC | 1115 | 61.5 | 6.19 | 734 | 60.9 | 5.95 |
| HPFS | 654 | 65.6 | 7.39 | 659 | 65.7 | 7.45 |
| MEC | 452 | 67.9 | 7.12 | 457 | 69.8 | 7.1 |
| PHS | 981 | 60.9 | 7.44 | 825 | 60.2 | 7.76 |
| PLCO | 1292 | 65.1 | 4.99 | 1167 | 65.4 | 4.95 |
| CAG repeats | ||||||
| CPS-II | 1150 | 21.9 | 3.04 | 1147 | 21.8 | 2.84 |
| ATBC | 994 | 22.3 | 2.86 | 990 | 22.3 | 2.91 |
| EPIC | 1029 | 21.8 | 2.94 | 689 | 22 | 2.93 |
| HPFS | 616 | 21.9 | 2.94 | 617 | 21.8 | 2.97 |
| MEC | 426 | 22 | 2.94 | 408 | 21.7 | 3.05 |
| PHS | 915 | 21.9 | 3.01 | 782 | 21.9 | 3.01 |
| PLCO | 1272 | 21.8 | 2.93 | 1144 | 21.8 | 3 |
| Androstanediol (ng/ml) | ||||||
| Total | 2566 | 7.11 | 5.02 | 2275 | 7.17 | 4.94 |
| ATBC | 96 | 3.09 | 1.83 | 68 | 3.67 | 3.01 |
| EPIC | 639 | 7.23 | 4.50 | 616 | 7.15 | 4.33 |
| HPFS | 648 | 6.33 | 5.40 | 653 | 6.60 | 5.47 |
| PHS | 363 | 7.03 | 3.25 | 235 | 7.37 | 3.18 |
| PLCO | 820 | 8.12 | 5.62 | 703 | 8.00 | 5.33 |
| Estradiol (ng/ml) | ||||||
| Total | 1118 | 32.5 | 10.3 | 958 | 32.6 | 11.0 |
| ATBC | 104 | 28.8 | 8.83 | 68 | 29.7 | 9.25 |
| HPFS | 651 | 31.6 | 9.09 | 655 | 32.2 | 9.68 |
| PHS | 363 | 35.1 | 12.2 | 235 | 34.6 | 14.2 |
| SHBG (nmol/liter) | ||||||
| Total | 2549 | 52.5 | 35.9 | 2247 | 53.5 | 37.3 |
| ATBC | 108 | 90.1 | 32.4 | 71 | 88.5 | 29.9 |
| EPIC | 604 | 46.6 | 20.3 | 582 | 44.7 | 19.1 |
| HPFS | 651 | 73.2 | 50.8 | 656 | 74.8 | 51.7 |
| PHS | 364 | 24.1 | 13.4 | 235 | 22.4 | 12.1 |
| PLCO | 822 | 48.2 | 22.5 | 703 | 47.6 | 23.4 |
| Testosterone (ng/ml) | ||||||
| Total | 2529 | 5.00 | 2.09 | 2224 | 5.03 | 2.06 |
| ATBC | 106 | 6.22 | 1.96 | 71 | 6.44 | 2.40 |
| EPIC | 593 | 4.90 | 2.03 | 561 | 4.98 | 2.12 |
| HPFS | 650 | 4.82 | 1.71 | 655 | 4.88 | 1.80 |
| PHS | 363 | 4.90 | 1.74 | 234 | 4.84 | 1.58 |
| PLCO | 817 | 5.11 | 2.49 | 703 | 5.12 | 2.28 |
We tested associations between the CAG repeat and hormone levels (androstanediol, estradiol, SHBG, and testosterone). Both estradiol and testosterone levels were significantly elevated in men with greater CAG repeat length (estradiol, P = 0.0002; testosterone, P = 4.73 × 10−5) (Table 2). For both estradiol and testosterone, a 10 CAG repeat increment was associated with approximately 8% higher hormone levels. Three SNPs (rs6152, rs1204038, and rs1337080) were nominally associated with estradiol levels (Supplemental Table 4); however, given the number of tests performed, we cannot rule out the possibility of chance findings.
Table 2.
Association between AR CAG repeats and plasma hormone levels
| Hormone | Controls | Cases | Mean difference (95% CI)a | r2 (%)b | P valuec |
|---|---|---|---|---|---|
| Androstanediol | 2452 | 2167 | 1.86 (−3.84, 7.89) | 0.0089 | 0.52 |
| Estradiol | 1059 | 898 | 8.89 (3.99, 13.8) | 0.7167 | 0.0002 |
| SHBG | 2435 | 2142 | 3.51 (−0.68, 8.14) | 0.0616 | 0.10 |
| Testosterone | 2419 | 2121 | 8.39 (4.23, 12.7) | 0.3725 | 4.73 × 10−5 |
Percentage increase in levels per 10 repeat increase in CAG length.
Percentage variance in trait explained by CAG repeat length.
P value from linear regression, adjusted for cohort, batch (within cohort), prostate cancer case-control status, and age in 5-yr intervals.
The range of CAG repeats was 9 to 36 in controls and 8 to 35 in cases. We found no association between the CAG repeat and prostate cancer risk based on a continuous model [odds ratio, 0.96; 95% confidence interval (CI), 0.85–1.08; P(trend) = 0.46, per 10 CAG repeat increment] (Table 3). Similarly, the categorical analysis did not reveal an association (Supplemental Table 6). Furthermore, the CAG repeat was not associated with either advanced-stage or high-grade cancer (P = 0.10 and P = 0.63) using either case-control analysis (Table 3 and Supplemental Table 6) or case-only analysis (P = 0.52 for high-grade vs. low-grade cancer and P = 0.12 for high-stage vs. low-stage cancer). None of the six genotyped SNPs was associated with overall prostate cancer risk or aggressive disease (Table 4). Haplotype analysis showed similar null results (data not shown). We did not observe any evidence for effect-measure heterogeneity at the 0.05 level.
Table 3.
Association between AR CAG repeats and prostate cancer
| Outcome | Controls | Cases | Odds ratio (95% CI)a | P value |
|---|---|---|---|---|
| All prostate cancer cases (vs. controls) | 6402 | 5777 | 0.96 (0.85, 1.08) | 0.46 |
| High-grade cases (vs. controls)b | 6402 | 611 | 1.07 (0.81, 1.42) | 0.63 |
| Advanced-stage cases (vs. controls)c | 6402 | 900 | 0.82 (0.65, 1.04) | 0.10 |
Odds ratios, CI, and P value are from conditional logistic regression, stratified on age in 5-yr intervals and study.
Multiplicative change in odds of prostate cancer per 10 repeat increase in CAG length.
Gleason grade 8 or greater.
Stage C or D at diagnosis or death due to prostate cancer.
Table 4.
Association between AR tag-SNPs and prostate cancer
| SNP | Major/minor allele | n
|
Minor allele Frequency (%)
|
Odds ratio (95% CI) | P value | ||
|---|---|---|---|---|---|---|---|
| Controls | Cases | Controls | Cases | ||||
| All cases (vs. controls) | |||||||
| RS962458 | A/G | 6603 | 5967 | 7.04 | 6.90 | 0.98 (0.86, 1.13) | 0.80 |
| RS6152 | G/A | 6552 | 5966 | 15.1 | 14.6 | 0.97 (0.88, 1.07) | 0.51 |
| RS1204038 | G/A | 6644 | 5992 | 15.0 | 14.6 | 0.97 (0.88, 1.07) | 0.51 |
| RS2361634 | A/G | 6581 | 5949 | 6.53 | 6.86 | 1.06 (0.92, 1.21) | 0.45 |
| RS1337080 | A/G | 6652 | 5986 | 7.35 | 7.03 | 0.96 (0.84, 1.09) | 0.52 |
| RS1337082 | A/G | 6650 | 5996 | 19.9 | 19.5 | 0.97 (0.89, 1.06) | 0.54 |
| High-grade cases (vs. controls)a | |||||||
| RS962458 | A/G | 6603 | 647 | 7.04 | 5.87 | 0.83 (0.59, 1.17) | 0.29 |
| RS6152 | G/A | 6552 | 647 | 15.1 | 14.2 | 0.93 (0.74, 1.18) | 0.55 |
| RS1204038 | G/A | 6644 | 647 | 15.0 | 14.4 | 0.95 (0.75, 1.19) | 0.63 |
| RS2361634 | A/G | 6581 | 640 | 6.53 | 6.56 | 1.01 (0.73, 1.40) | 0.96 |
| RS1337080 | A/G | 6652 | 649 | 7.35 | 6.32 | 0.85 (0.61, 1.19) | 0.35 |
| RS1337082 | A/G | 6650 | 649 | 19.9 | 18.8 | 0.93 (0.75, 1.14) | 0.46 |
| Advanced stage cases (vs. controls)b | |||||||
| RS962458 | A/G | 6603 | 930 | 7.04 | 7.31 | 1.04 (0.79, 1.35) | 0.80 |
| RS6152 | G/A | 6552 | 926 | 15.1 | 15.3 | 1.02 (0.84, 1.24) | 0.84 |
| RS1204038 | G/A | 6644 | 933 | 15.0 | 15.1 | 1.00 (0.83, 1.22) | 0.96 |
| RS2361634 | A/G | 6581 | 930 | 6.53 | 6.34 | 0.97 (0.73, 1.28) | 0.82 |
| RS1337080 | A/G | 6652 | 934 | 7.35 | 7.71 | 1.05 (0.81, 1.36) | 0.72 |
| RS1337082 | A/G | 6650 | 931 | 19.9 | 19.0 | 0.94 (0.79, 1.12) | 0.51 |
Odds ratios, CI, and P value from conditional logistic regression, stratified on age in 5-yr intervals and study. Odds ratio compares risk in carriers of minor allele to risk in carriers of major allele.
Gleason grade 8 or greater.
Stage C or D at diagnosis or death due to prostate cancer.
Discussion
Given the importance of androgens in prostate cancer growth, key genes in the androgen pathway have been proposed to be involved in prostate cancer initiation. Over the past decade, a large number of studies have investigated the role of the AR CAG microsatellite polymorphism in prostate cancer development, but no consensus has been reached. The formation of the BPC3 provided a unique opportunity to uniformly study this hypothesis in the largest set of prospectively collected prostate cancer cases and controls to date. We found strong evidence that the number of CAG repeats does not alter prostate cancer risk in populations of European ancestry. Based on the literature, we tested different models (e.g. continuous vs. cut-point for the CAG repeat) as well as various phenotypic traits (disease aggressiveness), but it did not alter the results. The tagSNPs chosen to capture additional genetic variation in AR were also not associated with prostate cancer risk.
Our assessment of the relationship between circulating levels of sex steroids and CAG repeat length based on up to 4500 men showed longer CAG repeat lengths to be associated with significantly higher levels of estradiol and testosterone in agreement with a recent large study (11). These findings are further supported by the observation that individuals with Kennedy’s disease, a disease caused by dramatic expansion of CAG repeats, typically have elevated testosterone levels (31). Because longer CAG repeats have been associated with decreased AR activity (3,4,5), it is plausible that men with longer repeats have elevated testosterone and estradiol levels to maintain sufficient androgen action. The association between the CAG repeat and testosterone levels has long been debated, and data have been inconclusive. However, negative studies have been 4-fold to 10-fold smaller in sample size and might therefore lack statistical power to find a true correlation. That longer CAG repeats are associated with increased circulating testosterone and estradiol concentrations in this study, but not with prostate cancer, argues against an important direct role for circulating androgen levels in prostate cancer etiology. This is supported by a recent analysis from the BPC3 (23) as well as a recent pooled analysis of 18 cohorts (2). Whether circulating levels adequately reflect androgen action in prostate tissue levels requires further study, however.
The BPC3 includes participants from seven cohorts and is the largest investigation of the association between genetic variants in the sex steroid hormone pathway and the risk of prostate cancer to date, with 37 genes studied (15). A next important step is to jointly analyze these genes with respect to prostate cancer risk.
We have demonstrated that inherited variation at the AR locus is not associated with prostate cancer risk. The most likely explanation for earlier significant findings is statistical chance due to smaller sample sizes. We recognize that characteristics of prostate cancer cases have changed over time with the introduction of prostate-specific antigen testing, and with screening practices varying widely across cohorts within BPC3, we did not specifically test this hypothesis. However, our findings regarding cases with high-grade and high-stage disease (i.e. less likely to have been screen-detected) were in line with our overall results. Also, detailed treatment data were not included for these individuals, which prevented us from testing whether AR germline variants altered prostate cancer progression. A recent study, for example, observed that prostate cancer cases that received hormonal therapy and carried the variant allele of an AR promoter SNP, rs17302090, had an increased risk of dying from prostate cancer (32). Given the latter results and the importance of androgens in prostate cancer treatment, it will be of interest to further test AR polymorphisms in the context of clinical factors, such as response to androgen ablation therapy and time to progression after failure of hormonal treatment.
Supplementary Material
Footnotes
This work was supported by National Cancer Institute cooperative agreements UO1-CA98233, UO1-CA98710, UO1-CA98216, and UO1-CA98758, and by the Intramural Research Program of National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics. S.L. is supported by the Swedish Research Council (Vetenskapsrådet).
Disclosure Summary: The authors have nothing to disclose.
First Published Online June 9, 2010
Abbreviations: AR, Androgen receptor; CI, confidence interval; SNP, single nucleotide polymorphism.
Program in Molecular and Genetic Epidemiology (S.L., D.J.H., P.K.), Harvard School of Public Health, Boston, Massachusetts; Departments of Epidemiology (S.L., M.S., D.T., P.K.), Nutrition (E.G., M.S.), and Biostatistics (P.K.), Harvard School of Public Health, Boston, Massachusetts; Department of Medicine (J.M., D.J.H., M.S.), Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics (D.Alt.), Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts; Center for Human Genetic Research (D.Alt.), Massachusetts General Hospital, Boston, Massachusetts; Department of Molecular Biology (D.Alt.), Massachusetts General Hospital, Boston, Massachusetts; Department of Genetics (D.Alt.), Harvard Medical School, Boston, Massachusetts; Diabetes Unit (D.Alt.), Massachusetts General Hospital, Boston, Massachusetts; Department of Epidemiology and Public Health (E.R., A.S.), Faculty of Medicine, Imperial College, London, United Kingdom; Division of Cancer Epidemiology and Genetics (D.Alb., S.I.B., S.J.C., R.B.H., S.J.W.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland; Cancer Epidemiology Unit (N.E.A.), University of Oxford, Oxford, United Kingdom; German Institute of Human Nutrition Potsdam-Rehbrücke (H.B.), Nuthetal, Germany; National Institute for Public Health and the Environment (H.B.B.-d.-M.), Bilthoven, The Netherlands; Department of Oncology (A.M.D.), University of Cambridge, Cambridge, United Kingdom; Department of Epidemiology (H.S.F., M.J.T.), American Cancer Society, Atlanta, Georgia; Kaiser Permanente (H.S.F.), Denver, Colorado; Massachusetts Veterans Epidemiology and Research Information Center and Geriatric Research, Education, and Clinical Center (J.M.G.), Boston Veterans Affairs Healthcare System, Boston, Massachusetts; Division of Aging (J.M.G.), Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; Department of Preventive Medicine (C.A.H., B.E.H., D.O.S.), Keck School of Medicine, University of Southern California, Los Angeles, California; Division of Epidemiology (R.B.H.), New York University Langone Medical Center, New York, New York; Division of Cancer Epidemiology (R.K.), German Cancer Research Center, Heidelberg, Germany; Cancer Research Center (L.N.K., L.L.M.), University of Hawaii, Honolulu, Hawaii; Andalusian School of Public Health and Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (C.M.), Granada, Spain; Clinical Epidemiology and Cardiology (K.O.), Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; Surgical and Perioperative Sciences, Urology and Andrology (P.S.), Umeå University, Umeå, Sweden; Cancer Registry Azienda Ospedaliera “Civile M.P.Arezzo” (R.T.), Ragusa, Italy; Department of Chronic Disease Prevention (J.V.), National Institute for Health and Welfare, Helsinki, Finland; Core Genotyping Facility (M.Y.), Advanced Technology Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland; Department of Medical Oncology (M.L.F.), Dana-Farber Cancer Institute, Boston, Massachusetts; and The Broad Institute of Harvard and MIT (M.L.F.), Cambridge, Massachusetts
References
- Huggins C, Hodges C 1941 Studies on prostatic cancer: I. The effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1:293–297 [DOI] [PubMed] [Google Scholar]
- Roddam AW, Allen NE, Appleby P, Key TJ 2008 Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 100:170–183 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beilin J, Ball EM, Favaloro JM, Zajac JD 2000 Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol 25:85–96 [DOI] [PubMed] [Google Scholar]
- Chamberlain NL, Driver ED, Miesfeld RL 1994 The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22:3181–3186 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mhatre AN, Trifiro MA, Kaufman M, Kazemi-Esfarjani P, Figlewicz D, Rouleau G, Pinsky L 1993 Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet 5:184–188 [DOI] [PubMed] [Google Scholar]
- Crabbe P, Bogaert V, De Bacquer D, Goemaere S, Zmierczak H, Kaufman JM 2007 Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism. J Clin Endocrinol Metab 92:3604–3610 [DOI] [PubMed] [Google Scholar]
- Krithivas K, Yurgalevitch SM, Mohr BA, Wilcox CJ, Batter SJ, Brown M, Longcope C, McKinlay JB, Kantoff PW 1999 Evidence that the CAG repeat in the androgen receptor gene is associated with the age-related decline in serum androgen levels in men. J Endocrinol 162:137–142 [DOI] [PubMed] [Google Scholar]
- Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichael C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M 2003 The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol (Oxf) 59:749–755 [DOI] [PubMed] [Google Scholar]
- Van Pottelbergh I, Lumbroso S, Goemaere S, Sultan C, Kaufman JM 2001 Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men. Clin Endocrinol (Oxf) 55:659–666 [DOI] [PubMed] [Google Scholar]
- Zitzmann M, Brune M, Kornmann B, Gromoll J, von Eckardstein S, von Eckardstein A, Nieschlag E 2001 The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. J Clin Endocrinol Metab 86:4867–4873 [DOI] [PubMed] [Google Scholar]
- Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O'Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC 2009 Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. J Clin Endocrinol Metab 94:277–284 [DOI] [PubMed] [Google Scholar]
- Freedman ML, Pearce CL, Penney KL, Hirschhorn JN, Kolonel LN, Henderson BE, Altshuler D 2005 Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. Am J Hum Genet 76:82–90 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zeegers MP, Kiemeney LA, Nieder AM, Ostrer H 2004 How strong is the association between CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate cancer risk? Cancer Epidemiol Biomarkers Prev 13:1765–1771 [PubMed] [Google Scholar]
- Lindström S, Wiklund F, Adami HO, Bälter KA, Adolfsson J, Grönberg H 2006 Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-α-reductase type 2 is important for prostate cancer development. Cancer Res 66:11077–11083 [DOI] [PubMed] [Google Scholar]
- Hunter DJ, Riboli E, Haiman CA, Albanes D, Altshuler D, Chanock SJ, Haynes RB, Henderson BE, Kaaks R, Stram DO, Thomas G, Thun MJ, Blanché H, Buring JE, Burtt NP, Calle EE, Cann H, Canzian F, Chen YC, Colditz GA, Cox DG, Dunning AM, Feigelson HS, Freedman ML, Gaziano JM, Giovannucci E, Hankinson SE, Hirschhorn JN, Hoover RN, Key T, Kolonel LN, Kraft P, Le Marchand L, Liu S, Ma J, Melnick S, Pharaoh P, Pike MC, Rodriguez C, Setiawan VW, Stampfer MJ, Trapido E, Travis R, Virtamo J, Wacholder S, Willett WC 2005 A candidate gene approach to searching for low-penetrance breast and prostate cancer genes. Nat Rev Cancer 5:977–985 [DOI] [PubMed] [Google Scholar]
- Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, McCullough ML, Feigelson HS, Thun MJ 2002 The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer 94:2490–2501 [DOI] [PubMed] [Google Scholar]
- 1994 The effect of vitamin E and β carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330:1029–1035 [DOI] [PubMed] [Google Scholar]
- Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, Fahey M, Charrondière UR, Hémon B, Casagrande C, Vignat J, Overvad K, Tjønneland A, Clavel-Chapelon F, Thiébaut A, Wahrendorf J, Boeing H, Trichopoulos D, Trichopoulou A, Vineis P, Palli D, Bueno-De-Mesquita HB, Peeters PH, Lund E, Engeset D, González CA, Barricarte A, Berglund G, Hallmans G, Day NE, Key TJ, Kaaks R, Saracci R 2002 European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5:1113–1124 [DOI] [PubMed] [Google Scholar]
- Giovannucci E, Pollak M, Liu Y, Platz EA, Majeed N, Rimm EB, Willett WC 2003 Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men. Cancer Epidemiol Biomarkers Prev 12:84–89 [PubMed] [Google Scholar]
- Kolonel LN, Altshuler D, Henderson BE 2004 The multiethnic cohort study: exploring genes, lifestyle and cancer risk. Nat Rev Cancer 4:519–527 [DOI] [PubMed] [Google Scholar]
- Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M, Giovannucci E 2002 Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 94:1099–1106 [DOI] [PubMed] [Google Scholar]
- Hayes RB, Reding D, Kopp W, Subar AF, Bhat N, Rothman N, Caporaso N, Ziegler RG, Johnson CC, Weissfeld JL, Hoover RN, Hartge P, Palace C, Gohagan JK 2000 Etiologic and early marker studies in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control Clin Trials 21:349S–355S [DOI] [PubMed] [Google Scholar]
- Ahn J, Schumacher FR, Berndt SI, Pfeiffer R, Albanes D, Andriole GL, Ardanaz E, Boeing H, Bueno-de-Mesquita B, Chanock SJ, Clavel-Chapelon F, Diver WR, Feigelson HS, Gaziano JM, Giovannucci E, Haiman CA, Henderson BE, Hoover RN, Kolonel LN, Kraft P, Ma J, Le Marchand L, Overvad K, Palli D, Stattin P, Stampfer M, Stram DO, Thomas G, Thun MJ, Travis RC, Trichopoulos D, Virtamo J, Weinstein SJ, Yeager M, Kaaks R, Hunter DJ, Hayes RB 2009 Quantitative trait loci predicting circulating sex steroid hormones in men from the NCI-Breast and Prostate Cancer Cohort Consortium (BPC3). Hum Mol Genet 18:3749–5377 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ 1996 Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 88:1118–1126 [DOI] [PubMed] [Google Scholar]
- Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D 2001 Effects of long-term α-tocopherol supplementation on serum hormones in older men. Prostate 46:33–38 [DOI] [PubMed] [Google Scholar]
- Platz EA, Leitzmann MF, Rifai N, Kantoff PW, Chen YC, Stampfer MJ, Willett WC, Giovannucci E 2005 Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol Biomarkers Prev 14:1262–1269 [DOI] [PubMed] [Google Scholar]
- Travis RC, Key TJ, Allen NE, Appleby PN, Roddam AW, Rinaldi S, Egevad L, Gann PH, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjønneland A, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Sieri S, Vineis P, Palli D, Quirós JR, Ardanaz E, Chirlaque MD, Larrañaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Bikou C, Trichopoulos D, Stattin P, Jenab M, Ferrari P, Slimani N, Riboli E, Kaaks R 2007 Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 121:1331–1338 [DOI] [PubMed] [Google Scholar]
- Weiss JM, Huang WY, Rinaldi S, Fears TR, Chatterjee N, Hsing AW, Crawford ED, Andriole GL, Kaaks R, Hayes RB 2008 Endogenous sex hormones and the risk of prostate cancer: a prospective study. Int J Cancer 122:2345–2350 [DOI] [PubMed] [Google Scholar]
- Rosner B 1983 Percentage points for a generalized ESD many-Outlier Procedure. Technometrics 25:165–172 [Google Scholar]
- Kraft P, Cox DG, Paynter RA, Hunter D, De Vivo I 2005 Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques. Genet Epidemiol 28:261–272 [DOI] [PubMed] [Google Scholar]
- Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, LeGuern E, Tardieu S, Chadarevian R, Giral P, Turpin G 2002 A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab 87:3893–3901 [DOI] [PubMed] [Google Scholar]
- Lindström S, Adami HO, Bälter KA, Xu J, Zheng SL, Stattin P, Grönberg H, Wiklund F 2007 Inherited variation in hormone-regulating genes and prostate cancer survival. Clin Cancer Res 13:5156–5161 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.