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Clinical Cancer Research Vol. 12, 1936-1941, March 2006
© 2006 American Association for Cancer Research

Cancer Prevention

Estrogen Receptor ß Polymorphism Is Associated with Prostate Cancer Risk

Camilla Thellenberg-Karlsson1, Sara Lindström1, Beatrice Malmer1, Fredrik Wiklund1, Katarina Augustsson-Bälter3, Hans-Olov Adami3, Par Stattin2, Maria Nilsson4, Karin Dahlman-Wright4, Jan-Åke Gustafsson4 and Henrik Grönberg1

Authors' Affiliations: Departments of 1 Radiation Sciences/Oncology, and 2 Surgical and Perioperative Sciences, University of Umeå, Umeå, 3 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and 4 Department of Medical Nutrition and Biosciences, Karolinska Institutet, Novum, Huddinge, Sweden

Requests for reprints: Henrik Grönberg, Department of Radiation Sciences/Oncology, Umeå University, S-901 87 Umeå, Sweden. Phone: 46-90-785-1982; Fax: 46-90-127-464; E-mail: Henrik.Gronberg{at}oc.umu.se.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: After cloning of the second estrogen receptor, estrogen receptor ß (ERß) in 1996, increasing evidence of its importance in prostate cancer development has been obtained. ERß is thought to exert an antiproliferative and proapoptotic effect. We examined whether sequence variants in the ERß gene are associated with prostate cancer risk.

Experimental Design: We conducted a large population-based case-control study (CAncer Prostate in Sweden, CAPS) consisting of 1,415 incident cases of prostate cancer and 801 controls. We evaluated 28 single nucleotide polymorphisms (SNP) spanning the entire ERß gene from the promoter to the 3'-untranslated region in 94 subjects of the control group. From this, we constructed gene-specific haplotypes and selected four haplotype-tagging SNPs (htSNP: rs2987983, rs1887994, rs1256040, and rs1256062). These four htSNPs were then genotyped in the total study population of 2,216 subjects.

Results: There was a statistically significant difference in allele frequency between cases and controls for one of the typed htSNPs (rs2987983), 27% in cases and 24% in controls (P = 0.03). Unconditional logistics regression showed an odds ratio of 1.22 (95% confidence interval, 1.02-1.46) for men carrying the variant allele TC or CC versus the wild-type TT, and an odds ratio of 1.33 (95% confidence interval, 1.08-1.64) for localized cancer. No association of prostate cancer risk with any of the other SNPs or with any haplotypes were seen.

Conclusion: We found an association with a SNP located in the promoter region of the ERß gene and risk of developing prostate cancer. The biological significance of this finding is unclear, but it supports the hypothesis that sequence variation in the promoter region of ERß is of importance for risk of prostate cancer.

Prostate cancer is a large global health problem with as many as half a million new cases each year (1). Genetic susceptibility is of major importance in the etiology of prostate cancer and may account for as much as 40% of all cases (2). A recent segregation analysis (3) suggests that multiple low-penetrant genes account for a major part of the genetic susceptibility of prostate cancer and that only a small fraction can be explained by dominant inheritance of highly penetrant genes.

The estrogen receptor ß (ERß) gene is highly expressed in the prostate epithelium, suggesting a direct effect of estrogen on the prostate (4, 5). Deletion of ERß in mice lead to hyperplasia in the ventral prostate, indicating that ERß has an antiproliferative role in this tissue (6), a notion that was later confirmed (7). A number of studies on the expression pattern of ERß in both normal and malignant prostate tissue have been done. In most studies of cancer, expression of ERß diminishes with increasing Gleason score but may reappear in metastatic lesions (8–11).

Epigenetic regulation, for example, methylation of the promoter region seems to cause down-regulation of downstream genes. It also seems to be a reversible event in tumor progression because methylation is more common in high-grade compared with low-grade prostate cancer and normal prostate tissue, and then decreases again in metastatic lesions compared with localized high-grade tumors (9, 12, 13). Intense staining with Ki-67 in the prostate of ERß knockout mice, together with high expression of the androgen receptor, suggests the regulatory role of ERß in the androgen receptor. A proposed ligand to ERß, 5{alpha}-androstane 3ß, 17ß-diol (3ßAdiol) inhibits the growth of prostate epithelium in wild-type mice but not in ERß knockout mice, via down-regulation of androgen receptor (6, 14). Other studies of prostate cancer cell lines have shown the antiproliferative and anti-invasion properties of ERß as reintroduction of the gene inhibits growth and invasion and triggers apoptosis (15).

Our hypothesis is that genetic variation in the ERß gene might alter the expression of the gene and thus affect the risk of prostate cancer. We tested this hypothesis in a large population-based epidemiologic study.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Briefly, the cases and controls studied came from a large-scale, population-based case-control study (CAncer Prostate in Sweden, CAPS). A detailed description of the CAPS study is presented elsewhere (16). The study population consisted of 1,415 patients with prostate cancer and 801 control subjects. The case participants were recruited from four of the six regional cancer registries that cover the entire population of Sweden. Each of these registries serves one health care region (Northern, Central, Stockholm, and Southeastern) and altogether encompasses ~6 million inhabitants (67% of Sweden's population). The cases were linked to the National Prostate Cancer Registry and clinical information such as Gleason sum, PSA level at the time of diagnosis, tumor-node-metastasis stage, means of diagnosis and primary treatment were obtained for 95.3% of the cases. The cases were thereafter classified as either localized (n = 772); (T1-2 and N0/NX and M0/MX and grades 1-2/Gleason sum 2-7, and PSA <100) or advanced (n = 568; prone to progressive disease); (T3/4 or N+ or M+ or grade 3 or Gleason sum 8-10 or PSA >100). For cases and controls who reported at least one family member with prostate cancer, a more detailed family history of prostate cancer was obtained through additional questionnaires and record linkage to the Swedish Cancer Registry or through medical records. After retrieving these supplementary data, a total of 177 cases were classified as familial prostate cancer. Control subjects were randomly selected from the continuously updated Swedish Population Registry, frequency-matched according to the expected age distribution (within 5 years) and geographic origin of the cases. Mean age (age at diagnosis for case patients and age at inclusion for control subjects) for the cases and controls were 66.6 and 67.9 years, respectively.

The study was approved by the Ethical Committees at the two participating academic institutions, Umeå University and Karolinska Institutet. Written informed consent was obtained from each subject.

Selection of ER-ß single nucleotide polymorphisms. To make a thorough evaluation of sequence variation in the ERß gene, we used a haplotype-tagging single nucleotide polymorphisms (htSNP) method. The ER-ß gene is located on chromosome 14 q23.2, and is ~61.2 kb including eight exons, together with two untranslated first exons, ON and OK (Fig. 1 ). Five isoforms are presently known (17) and even more mRNA splice variants of unknown importance seem to exist (18). We conducted a search for known SNPs in the data bases http://snpper.chip.org/ and http://www.ncbi.nih.gov/SNP/ and selected a subset of SNPs from the promoter region (15 kb), introns, exons, and 3'-untranslated region (UTR) covering a total length of 68.5 kb. There are three SNPs in the coding regions, all synonymous. At the time of selection, not many SNPs in ERß were validated and even fewer had frequency data, so the main criteria for selection were that the SNPs were evenly spread throughout the gene.


Figure 1
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  		Fig. 1. Structure of ERß gene. Position of htSNPs. Shaded boxes, exons; thin line, introns, promotor, 3'-UTR.

 
In total, 37 SNPs were chosen with a mean distance between SNPs of 1,800 bp (Table 1 ). The SNP genotyping assays were designed by using the Assay-by-Design and Assay-on-Demand service (Applied Biosystems, Foster City, CA). The 37 SNPs were then genotyped in 94 randomly selected control subjects using a 5'-nuclease TaqMan assay together with fluorescently labeled Minor Groove Binders probes. All reactions were done in a 25 µL volume consisting of 10 ng of genomic DNA, 900 nmol/L of each primer, 200 nmol/L of each probe and 12.5 µL of TaqMan universal master mix. PCR cycling conditions were: 50°C for 2 minutes, 95°C for 10 minutes followed by 40 cycles of 92°C for 15 seconds, and 60°C for 1 minute. The samples were analyzed on an ABI 7700 sequence detection system. Five of the genotyped SNPs were monomorphic in the 94 randomly selected subjects and therefore excluded from further analysis, as were 10 SNPs with assay failure. From the remaining 22 SNPs, haplotypes were estimated using a Markov Chain Monte Carlo approach as implemented in the PHASE software package (http://www.stats.ox.ac.uk/mathgen/software.html).


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  		Table 1. Initially selected 37 SNPs for genotyping and construction of haplotypes

 
Four SNPs (rs2987983, rs1887994, rs1256040, and rs1256062), which captured 99.6% of the haplotype variation among the 94 controls, were selected as htSNPs using the htSNP2 package (http://www.gene.cimr.cam.ac.uk/clayton/software/stata) for the STATA software. These four htSNPs were genotyped under the same conditions and with the same equipment as described above for all 1,415 cases and 801 control subjects. For all of the htSNPs, three htSNPs in each group of homozygous and heterozygous subjects were sequenced to produce internal controls. The primer sequences used to amplify the target DNA are available on request. PCR conditions were as follows: deoxynucleotide triphosphate 200 µmol/L, 10x PCR buffer, 3 mmol/L MgCl2, 0.5 µmol/L primer, 1 unit Taq Gold enzyme, 50 ng of DNA, cycling at 94°C for 20 seconds, 50°C for 30 seconds, 72°C for 30 seconds, repeated 35 cycles. For optimizing the PCR for SNP rs1256040, the following changes were made: increased MgCl2 to 4.5 mmol/L and addition of 5% DMSO, annealing temperature 50°C -> 43°C for 14 cycles and 40°C for 20 cycles. Sequencing was carried out using the ABI Prism Big dye terminator kit v1.1/3.1 from Applied Biosystems and following the manufacturer's instructions. When genotyping the whole study group, we placed two positive controls for each genotype and two negative controls on each plate. In addition, 29 blind duplicates were spread among the plates.

Statistical analysis. Hardy-Weinberg Equilibrium tests for each sequence variant and pair-wise linkage disequilibrium tests for all sequence variants were done using a replication method as implemented in the GENETICS package (http://lib.stat.cmu.edu/R/CRAN/index.html) for the R programming language. For each test, 10,000 permutations were done. Associations between genotypes and prostate cancer were assessed by the score test in unconditional logistic regression assuming a dominant genetic model. Genotype-specific risks were estimated as odds ratios with associated 95% confidence intervals by unconditional logistic regression. When testing for association and estimating odds ratios, the unconditional logistic regression was stratified by each combination of age (5-year age groups) and geographic region to adjust for the matching conducted in collecting control subjects.

Tests for association between haplotypes and prostate cancer risk were done using a score test developed by Schaid et al. (19), using the HAPLO.STAT program (http://www.mayo.edu/hsr/Sfunc.html) for the R programming language. This method, based on the generalized linear model framework, allows adjustment for possible confounding variables and provides both global tests and haplotype-specific tests. In these analyses, age and geographic region were adjusted for through indicator variables representing each combination of age category (5-year age groups) and geographic region (northern and central part of Sweden versus southeastern part of Sweden and the area of Stockholm). Haplotypes with estimated frequencies <0.005 were pooled into a single group. Empirical P values were based on randomly permuting the trait and covariates and computing haplotype statistics adjusted for the covariates as described in ref. (20). Precision criteria for the P values were set to a sample SE of one fourth of the estimated P values but at least 1,000 permutations were run for each simulation. All P values are two-sided.


   Results
Top
 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Four selected htSNPs (rs2987983, rs1887994, rs1256040, and rs1256060) were genotyped in all study subjects, 1,415 cases and 801 controls. All SNPs were in Hardy-Weinberg equilibrium among both cases and controls (P > 0.05). The pair-wise linkage disequilibrium between these SNPs was 0.05 between rs2987983 and rs1256062 and 0.61 to 0.99 for the other SNP combinations. No genotyping error was detected among the duplicates, corresponding to an estimated error rate of 0.0%.

The promoter SNP C/T –13950 (rs2987983) differed significantly in genotype frequency among cases and controls (P = 0.03). The genotype frequency of TC or CC was 47.6% in cases and 42.2% in controls. The difference was more pronounced among heterozygous carriers. The frequency for the C allele was 27% in cases and 24% in controls. For the other three htSNPs, no significant difference was found in genotype frequencies. Logistic regression analyses revealed a 23% increased risk of prostate cancer (odds ratios, 1.23; 95% confidence interval, 1.02-1.49) among men with the TC or CC compared with the genotype TT (adjusted for age and geographic region).

Subgroup analysis based on localized or advanced cancer revealed an increased risk of 35% (odds ratios, 1.35; 95% confidence interval, 1.09-1.68) for being diagnosed with localized cancer (Table 2 ). Subgroup analysis by age (<65 or ≥65 years) or family history did not indicate any heterogeneity (data not shown). No significant association was found for the three other analyzed htSNPs and risk of prostate cancer in subgroup analyses. Seven haplotypes with a frequency of ≥1% were found in this population, based on the four htSNPs. We found no evidence of association with any of the haplotypes. The overall global test gave P = 0.10 (Table 3 ).


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  		Table 2. Genotype frequencies and odds ratios for prostate cancer among ERß SNPs

 

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  		Table 3. Haplotypes in prostate cancer cases and controls

 

   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
To test our hypothesis that sequence variation in the ERß gene is associated with prostate cancer risk, we did a systematic and comprehensive analysis of the promoter, introns, exon, and 3'-UTR region of the gene in a large population-based study. To our knowledge, this is the first study evaluating sequence variations in ERß and risk of prostate cancer. In a previous study on ERß and risk of breast cancer, we found no significant association (21), whereas a larger study found an association with sequence variants in ERß (22). Our finding that one SNP in the promoter region (–13950 C/T) is associated with prostate cancer risk, suggests that genetic variation in the promoter of ERß plays a part in the etiology of prostate cancer.

The increased risk of 23% overall and 35% for localized cancer may seem modest but is not unexpected, in a complex disease such as prostate cancer. Multiple genes in different pathways are probably involved and each contributes to a small increase in risk. Our view is consistent with metaanalysis of association studies in other complex diseases (23). For most of the diseases (seven of eight) where genetic associations were replicated, the excess risk was in the range of 7% to 76%. The strengths of our study include its large size and strictly population-based design. In addition, the population in Sweden is genetically homogenous, reducing the risk of confounding due to population stratification. The multiple testing problems are common in genetic association studies and is difficult to adjust for when SNPs are in strong linkage disequilibrium. Using false-positive report probability is one approach to accommodate this problem (24). In our study, the prior probability must be considered high for the ERß gene due to its documented importance in the progression of prostate cancer and in the regulation of proliferation (12, 15). Assuming a prior probability of 0.05 to 0.1, the false-positive report probability is 0.24 to 0.40 if the ERß confers an odds ratio of 1.5 to prostate cancer risk. The range of false-positive report probability is then below the suggested criterion of 0.5.

The –13950 T/C polymorphism is located upstream in the promoter region and it might be disputed if it has any functional implication. Previous studies on methylation of ERß receptor have investigated CpG islands in the region of the untranslated exon 0N and the foregoing promoter (9, 12). There is no detailed study of the more distant region of the promoter 0K. However, that distant region harbors several potential transcription factor binding sites (25). As shown by Zhao et al. (26), the promoter 0K lies ~44 kb upstream from the ATG of exon 1 and gives another possible implication as the –13950 T/C polymorphism is then actually located within an intron and might be located at and affect the binding site for a transcription factor. The 0K promoter is GC-rich with ~65% GC and encompass several CpG sites but otherwise it is not yet well characterized. Alternatively, the polymorphism is a mere marker, which is in strong linkage disequilibrium with the functional polymorphism or even another gene. The gene closest upstream to the ERß located at a distance of 41.5 kb, is a hypothetical gene which has not been further characterized (hypothetical gene supported by BX247957). Recently, a study on lactase non-persistence found a segregating noncoding polymorphism, 13910 bp 5' of the initiation codon of the gene for lactase-phlorizin hydrolase (27). This promoter variant affected the binding site of a transcription factor. The lactase-phlorizin hydrolase variant is now used clinically for diagnosing the condition.

The HapMap project has just published haplotypes and haplotype blocks together with frequency data of a substantial number of SNPs in the ERß region (http://www.hapmap.org/index.html.en). Three of the four htSNPs we identified seem to belong to one haplotype block. The first one (rs2987983) located in the promoter, lies in a breaking point, between two blocks (Fig. 2 ). This may explain why we do not see any significant association with our haplotypes in the ERß gene and prostate cancer. The weak linkage disequilibrium (0.05) between rs2987983 and the other genotyped htSNPs further supports this interpretation. The ERß gene is a strong candidate with respect to the proposed function. With the results that we now present, genetic variation in the intron and exon regions of ERß is unlikely to be of importance for the risk of prostate cancer. In contrast, the promoter region and the region further upstream need more evaluation.


Figure 2
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  		Fig. 2. Haplotype blocks over ERß region spanning 200 kb, from the HapMap project. Position of ERß outlined. Vertical arrow, location of rs2987983 in the breaking point between haplotype blocks. Blocks are constructed by the confidence interval method according to ref. (28).

 
In summary, we found an association between prostate cancer and a SNP located –13950 from the initiating codon of ERß with unknown functional implications. Additional genetic analysis of this region is necessary, with more densely positioned markers as well as further characterization of the upstream region with respect to its function. Preferentially, functional/expression studies in cell lines with the variant allele versus the common one should be done. Also, more studies in independent populations that could replicate our findings are warranted.


   Acknowledgments
 
We thank all study participants in the CAPS study, Ulrika Lund for skillfully coordinating the study center at Karolinska Institute, all urologists including their patients in the CAPS study, and all urologists providing clinical data to the national registry of prostate cancer; Karin Andersson, Susan Lindh, Gabriella Thorén, and Margareta Åswärd at the Regional Cancer Registries; and Sören Holmgren and the personnel at the Medical Biobank in Umeå for skillfully handling the blood samples.


   Footnotes
 
Grant support: Lion's Cancer Research Foundation (Umeå, Sweden), Swedish Cancer Society, and Spear grant from the Umeå University Hospital (Umeå, Sweden).

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.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

Received 2/ 4/05; revised 11/ 8/05; accepted 12/15/05.


   References
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 Abstract
 Patients and Methods
 Results
 Discussion
 References
 

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