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Joint Effect of HSD3B1 and HSD3B2 Genes Is Associated with Hereditary and Sporadic Prostate Cancer Susceptibility¹

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [B-l. C., S. L. Z., G. A. H., A. T., E. R. B., D. A. M., J. X.]; University of Maryland School of Medicine, Baltimore, Maryland 21201 [B-l. C.]; Department of Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287 [S. D. I., K. E. W., P. C. W., W. B. I.]; National Human Genome Research Institute, NIH, Bethesda, Maryland 20892 [J. D. C., J. M. T.]

	ABSTRACT

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3ß-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.

	INTRODUCTION

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Prostate cancer (MIM 176807) is the most frequently diagnosed cancer and the second leading cause of cancer mortality among men in many industrialized countries. Evidence for genetic susceptibility to prostate cancer is well documented from epidemiological studies (1) , twin studies (2, 3, 4) , and segregation analyses (5, 6, 7, 8) . Chromosomal regions that are likely to contain prostate cancer susceptibility genes have been identified including HPC1³ at 1q24–25 (9) , PCAP at 1q42–43 (10) , HPCX at Xq27–28 (11) , CAPB at 1p36 (12) , HPC20 at 20q13 (13) , HPC2 at 17p11 (14 , 15) , and 8p22–23 (16) .

Androgens have been hypothesized to be involved in prostate carcinogenesis because of their essential role in prostate development, growth, and maintenance. The enzyme HSD3B is a critical component of the androgen metabolism pathway because it catalyzes androstendione production in steroidogenic tissues and converts the active dihydrotestosterone into inactive metabolites in steroid target tissues. The HSD3B gene family has two genes and five pseudogenes, all of which map to chromosome 1p13 (17, 18, 19) . The HSD3B1 gene encodes the type I enzyme, which is exclusively expressed in the placenta and peripheral tissues, such as prostate, breast, and skin. The HSD3B2 gene encodes the type II enzyme, which is predominantly expressed in classical steroidogenic tissues, namely the adrenals, testis, and ovary (18 , 20, 21, 22, 23) . A number of mutations in HSD3B2 has been found to cause congenital adrenal hyperplasia, a rare Mendelian disease, manifested by salt-wasting and incomplete masculinization in males (24) .

Recent linkage findings at 1p13 significantly increase the likelihood that HSD3B genes play an important role in prostate cancer susceptibility. In a chromosome-wide linkage study to evaluate different prostate cancer susceptibility loci on chromosome 1 in 159 HPC families, our group reported evidence for linkage in a broad region from 1p13 to 1q32 (25) . The LOD score assuming heterogeneity was 1.31 (P = 0.01), and the allele-sharing LOD score was 1.34 (P = 0.01) at HSD3B2. The evidence for linkage was stronger in families with five or more affected men (allele-sharing LOD = 2.22, P = 0.001) and in families with mean age of onset > 65 years (allele-sharing LOD = 1.45, P = 0.01). In another genome-wide scan for prostate cancer susceptibility loci, Goddard et al. (26) reported a LOD score of 3.25 (P = 0.0001) at 1p13, near markers D1S534 and D1S1653, when the Gleason score was included as a covariate.

There are only a few studies on the sequence variants of HSD3B2 in prostate cancer. A complex (TG)_n (TA)_n(CA)_n repeat has been described and studied in intron 3 of HSD3B2 (27 , 28) . However, there is no published study that evaluates the association between this repeat and other sequence variants in HSD3B1 and prostate cancer risk. Considering the biological importance of the HSD3B genes and the evidence that these genes are located in a chromosomal region that is likely to contain prostate cancer susceptibility genes, a systematic study and evaluation of these genes in relationship to prostate cancer appears warranted.

We have two major goals in this study. The first one is to identify sequence variants in the HSD3B1 and HSD3B2 genes by directly sequencing the PCR products from the 500-bp promoter region, all exons, exon-intron junctions, and 3'-UTR of both genes in 96 subjects. The second goal is to test for association between prostate cancer and HSD3B genes by comparing the distributions of the four frequent SNPs in 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls.

	MATERIALS AND METHODS

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Subjects.
A detailed description of the study sample was presented elsewhere (25) . HPC probands (n = 159) were ascertained at the Brady Urology Institute at Johns Hopkins Hospital (Baltimore, MD) through referrals, review of medical records for patients seen at Johns Hopkins Hospital for treatment of prostate cancer, and respondents to various lay publications describing our studies. Each proband had at least two first-degree relatives affected with prostate cancer. The diagnosis of prostate cancer was verified by medical records. The mean age at prostate cancer diagnosis for these probands was 61 years; 133 (84%) were Caucasian, and 14 (8.8%) were African-American.

All 245 unrelated prostate cancer cases were recruited from patients who underwent treatment for prostate cancer at the Johns Hopkins Hospital and did not have first-degree relatives affected with prostate cancer. For each subject, the diagnosis of prostate cancer was confirmed by pathology reports. Preoperative PSA levels, Gleason score, and pathological stages were available for 202, 240, and 241 cases, respectively. Mean age at diagnosis for these cases was 58.7 years. Over 93% of the cases were Caucasian, and 3.2% were African-American.

Nonprostate cancer controls (222) were selected from men participating in screening programs for prostate cancer. By applying the exclusion criteria of abnormal digital rectal examination and abnormal PSA level (i.e., 4 ng/ml), 211 were eligible for the study. The mean age at examination was 58 years. Over 86% of the eligible controls were Caucasian, and 7.1% were African-American. On the basis of interview of the subjects, 5.6% of the eligible controls had brothers or their father affected with prostate cancer.

The Institutional Review Board of Johns Hopkins University approved the protocols for subject recruitment. After each participant was guided through an informed consent process, they completed a signed consent form as a record of this process.

Sequencing Methods and SNP Genotyping.
The HSD3B1 and HSD3B2 genes are structurally very similar, with 85% homology (17 , 20 , 29 , 30) . Both genes span 7.8 kb and contain 4 exons. To identify SNPs in HSD3B1 and HSD3B2, we directly sequenced the PCR products of the putative promoter region, all exons, exon-intron junctions, and the 3'-UTR of both genes in 96 subjects. These subjects include 72 Caucasians and 24 African-Americans, with equal numbers of HPC cases, sporadic cases, and unaffected controls in each racial group. Table 1 lists the primers used to amplify the PCR products, the sizes of amplified PCR fragments, and the annealing temperatures for each pair of primers. All PCR reactions were performed in a 30-µl volume consisting of 30 ng of genomic DNA, 0.2 µM each primer, 0.2 mM each deoxynucleotide triphosphate, 1.5 mM MgCl_2, 20 mM Tris-HCl, 50 mM KCl, and 0.5 units of Taq polymerase (Life Technologies, Inc.). PCR cycling conditions were as follows: a 94°C hotstart for 4 min, followed by 33 cycles of 94°C for 30 s, specified annealing temperature for 30 s, and 72°C for 30 s, with a final extension of 72°C for 6 min. All PCR products were purified using the QuickStep PCR purification Kit (Edge BioSystems, Gaithersburg, MD) to remove deoxynucleotide triphosphates and excess primers. All sequencing reactions were performed using dye-terminator chemistry (BigDye; ABI, Foster City, CA) and then precipitated using 63 +/- 5% ethanol. Samples were loaded onto an ABI 3700 DNA Analyzer after adding 10 µl of formamide. SNPs were identified using Sequencher software version 4.0.5 (Gene Codes Corp.). For the four frequent SNPs, additional genotyping of 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls was performed using the same sequencing method.

Association tests between the SNPs and prostate cancer were performed by comparing allele and genotype frequencies between cases and controls for each SNP. Allele frequencies were estimated by a direct count. The hypotheses of differences in allele frequencies between cases and controls were tested using standard contingency ² tests, and Ps were determined via ² approximation (33) . Differences in genotype frequencies (variant alleles were assumed to be dominant or recessive) between cases and controls were tested using unconditional logistic regression and were adjusted for potential confounders, such as age.

	RESULTS

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SNP Identification.
A total of five SNPs in HSD3B1 and six SNPs in HSD3B2 were identified in the screening panel of 96 subjects. The frequency of the SNPs by race and prostate cancer status are presented in Table 2 . There were four SNPs in the coding region of HSD3B1 (exon 4) and two of which are nonsynonymous changes. SNP B1-F286L causes an amino acid change from phenylalanine to leucine, and B1-N367T results in an amino acid change from asparagine to threonine. The possible effects of these two SNPs on the functional enzymatic activities of HSD3B1 protein remain to be determined. Although no SNPs were identified in the coding region of HSD3B2, two common SNPs (B2-c7474t and B2-c7519g) were found in the 3'-UTR region.

To test the main hypothesis, that HSD3B genes are associated with prostate cancer risk, we compared the allele and genotype frequencies for each of the four SNPs in HPC probands, sporadic cases, and unaffected controls (Table 3) . Although variant alleles of three SNPs were observed at higher frequencies in cases than in controls, only one of them (the missense change, B1-N367T) reached nominal significance. The frequency of allele "C " of B1-N367T was higher in the HPC probands (34%) and in the sporadic cases (33%), compared with the unaffected controls (26%). The differences were significant between HPC probands and controls (P = 0.03), sporadic cases and controls (P = 0.04), and either type of prostate cancer and controls (P = 0.02). When the genotype frequencies of the four SNPs were compared, similar findings were observed (Table 4) . The frequencies of the variant genotypes (C/A and C/C) of B1-N367T were higher in both HPC cases (55%) and sporadic cases (54%) than in the controls (43%). Compared with men with the wild-type genotype at B1-N367T (A/A), men with the variant genotypes at B1-N367T (C/A or C/C) were at increased risk for prostate cancer. After adjustment for age, the point estimate of the RR was 1.52 (95% CI = 0.95–2.45) for HPC, 1.5 (95% CI = 1.01–2.24) for sporadic prostate cancer, and 1.5 (95% CI = 1.04–2.17, P = 0.03) for either type of prostate cancer. In HSD3B2, the frequencies of the variant genotypes at B2-c7474g and B2-c7519g were also slightly higher in both the HPC cases and sporadic cases, compared with the controls, although the differences were not statistically significant.

Considering that the younger controls may have a higher chance of developing prostate cancer later in their life than older controls because of the age-dependent penetrance of the disease, and that the evidence for linkage at 1p13 is provided primarily by families with older mean age of onset, we performed an analysis in subjects who were age 60 years (age of diagnosis for affected or age at examination for unaffected). Larger differences in the proportion of men with either variant genotype of the two SNPs were observed among HPC probands (76%), sporadic cases (74%), and unaffected controls (51%). After adjustment for age, the differences were statistically significant between HPC probands and controls (P = 0.002), sporadic cases and controls (P = 0.005), and all cases and controls (P = 0.0005).

Association between Characteristics of Prostate Cancer and the SNPs.
The relationships between the four frequent polymorphisms in HSD3B genes and Gleason scores or pathological stages in sporadic prostate cancer cases were also examined. No statistically significant differences in the genotypic frequencies of these SNPs were found between the groups with low (6) or high (7) Gleason scores or between the groups with disease confined to the prostate versus nonlocalized disease (Table 6) .

	DISCUSSION

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Although these results are potentially important, caution should be taken when interpreting and generalizing these findings. Our case-control population has several potential limitations. First of all, the study subjects were recruited primarily for genetics studies rather than for a rigorously designed epidemiological study. Thus, it is difficult to interpret the point estimates of the RR in this study and to generalize these findings. However, this study does provide some valuable results. The SNPs identified in our studies can be used in the future to study prostate cancer and other diseases. The increased frequencies of the variant HSD3B SNPs in the cases (particularly HPC cases) should prompt additional studies. The second potential limitation is the source of our control subjects, which were recruited from a prostate cancer screening population. This control group may represent a higher risk population than the general population because of self-selection. This potential bias, however, is unlikely to be significant in our study. All control subjects were found to have normal digital rectal examination and PSA results at the time of screening. Three percent of the 182 personally interviewed controls reported a positive family history (defined as an affected father and/or brothers). Additional analyses excluding the individuals who reported positive family history produced similar results. The third potential limitation in our study is that the association is subject to potential population stratification. Differences in the allele frequencies between cases and controls could be attributable to the different genetic backgrounds in cases and controls. We attempted to limit the impact of this source of population stratification by limiting our analyses to Caucasian men only, although this approach might not fully remove the potential impact. On the other hand, based on a sample of 24 consecutive SNPs on chromosomes 1, 8, 11, 12, and X that were recently genotyped in this population, we found no evidence to suggest population stratification exists within our Caucasian case and control samples (data not shown). A family-based association test is an alternative study design to overcome the potential bias of population stratification. However, a family-based association study is inefficient in this population because most parents of affected men are deceased because of the late age of onset of prostate cancer. The fourth potential limitation is the multiple tests performed in our study. Not only were multiple SNPs genotyped, but multiple hypotheses (dominant or recessive and single SNP or joint effect) and multiple groups (HPC probands, sporadic cases, and unaffected controls) were also tested for each of the SNPs. Some of the tests are not independent, and appropriate methods are not available to adjust the significance level because of the multiple but related comparisons. However, using the commonly suggested Bonferoni test, we calculated adjusted significance levels by multiplying the nominal Ps by the total number of tests performed in the study (n = 44). After the adjustment, the only statistically significant finding was the association between prostate cancer risk and the joint effect of the two genes. With these caveats, we cautiously report our findings and call for large well-designed studies to rigorously evaluate these findings.

The hypothesis that sequence variants in either HSD3B1 or HSD3B2 may increase prostate cancer susceptibility is biologically plausible; however, the exact mechanism by which such an effect may be mediated is not defined. HSD3B genes encode membrane-bound microsomal proteins with two predicted transmembrane domains: (a) a 16-residue segment between residues 75 and 91; and (b) a COOH-terminal 26-residue segment between residues 283 and 308. The B1-N367T variant is located in the COOH-terminal extramembrane domain. This SNP results in an amino acid change from Asn to Thr and may have an effect on conformation, enzymatic activity, stability, or regulation of HSD3B1 protein. This amino acid change creates a new putative PKC phosphorylation site (the phosphorylation site pattern: [ST][.][RK]).⁴ PKC isozymes are a family of kinases in the signal transduction cascade and are involved in cell proliferation, antitumor resistance, and apoptosis. It has been shown that HSD3B1 gene expression is specifically induced by IL-4 and IL-13 in both human prostate cancer cell lines and primary prostatic epithelial cells (21) . In addition, the PKC activator phorbol-12-myristate-13-acetate further enhanced the stimulatory effect of IL-4 on HSD3B activity (34) . It is possible that HSD3B proteins are regulated through phosphorylation by PKC, and it is worth exploring whether the new PKC phosphorylation site in a variant HSD3B1 protein alters the regulation of HSD3B1 protein. Because SNP B2-c7519g is located in the 3'-UTR of HSD3B2, it has no effect on the amino acid sequence of HSD3B2 protein. However, the nucleotide change may result in a conformational change in the 3'-UTR of HSD3B2 mRNA and may affect the stability of this mRNA. Post-transcriptional regulation of mRNA stability can have a significant impact on mRNA abundance and subsequent protein expression. Several elements in the 3'-UTR region that are important to the stability of a variety of mRNA species have been identified, including the poly(A) site, arbitrary unit-rich elements, iron-responsive element, 3'-terminal stem-loop, long-range stem loop, exoribonuclease cleavage site, and endoribonuclease cleavage site. It is possible that the nucleotide change in the 3'-UTR of HSD3B2 mRNA alters the structure of a protein binding site and, hence, alters the stability of the mRNA and the quantity of the protein produced.

We tested the secondary hypothesis that the joint effect of the two genes is associated with prostate cancer risk for the following two reasons: (a) even with the similarity in the structure and enzymatic function between HSD3B1 and HSD3B2 proteins, the differential expression patterns of HSD3B1 and HSD3B2 genes in different tissues implicate HSD3B1 and HSD3B2 as being involved in the regulation of androgen levels in different ways. HSD3B2, which is predominately expressed in steroidogenic tissues, may be more important for systematic androgen levels. On the other hand, HSD3B1, which is primarily expressed in peripheral tissues, including prostate, may play a more important role in local androgen levels; and (b) if either variant at HSD3B1 or HSD3B2 increases the risk for prostate cancer, a single SNP analysis would be a less powerful approach when the two genes are not in complete LD. This is because the genotypes at the other gene (SNP) may confound the effect of the genotypes at the gene (SNP) under study. This confounding effect can be decreased by studying the two genes (SNPs) simultaneously. Whereas the false positive rate is not increased when there is no association between a disease and either gene, these analyses do increase the total number of tests and, thus, affect the interpretation of significance level.

Consistent with the results of our previous linkage study, where families with late age of diagnosis of prostate cancer have the strongest evidence for linkage to the region of HSD3B genes (16) , the highest risk (odds ratio = 3.14) for HPC was observed in the men with late age of onset in the present study. Although the reason for this finding is unknown, genetic heterogeneity could partially explain this observation. Several other prostate cancer susceptibility genes have been reported, including HPC1 at 1q24–25 (9) , PCAP at 1q42–43 (10) , HPCX at Xq27–28 (11) , CAPB at 1p36 (12) , HPC20 at 20q13 (13) , and HPC2/ELAC2 on chromosome 17 (14) . Evidence for linkage to some of these regions has primarily been observed in prostate cancer families with early age of onset, e.g., the linkage study of chromosome 1 markers in our 159 HPC families only observed linkage at HPC1 in the 79 families with early age of onset, with a peak allele sharing LOD of 3.05 (P = 0.0002). However, the 80 families with late age of onset were not linked to HPC1.

The deviation from HWE for the two SNPs of HSD3B2 (B2-c7474t and B2-c7519g) in sporadic prostate cancer cases is an interesting result. This result is unlikely attributable to genotyping errors, because the SNPs were unambiguously scored by three experienced molecular geneticists (B-l. C., G. A. H., and S. L. Z), and the distributions of the two closely linked SNPs were very similar (Table 4) . Two other explanations are possible: (a) the deviation from HWE could be attributable to chance; the observed number of homozygotes of the rare alleles (9 and 10 in B2-c7474t and B2-c7519g, respectively) is only slightly more than the expected number of 6; and (b) the two sequence variants may be either causal changes or in strong LD with a causal change.

In summary, our study provides evidence for association between HSD3B genes and prostate cancer risk. Considering the importance of this gene family, the complexities of the genetics of prostate cancer, and the limitations of our study, additional studies at a functional level, as well as additional study populations, are warranted.

	ACKNOWLEDGMENTS

 
We thank all of the subjects who participated in this study.

	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 by PHS SPORE CA58236 and two grants from the Department of Defense (to W. B. I. and J. X.).

² To whom requests for reprints should be addressed, at Center for Human Genomics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: (336) 716-5700; Fax: (336) 716-7575; E-mail: jxu{at}wfubmc.edu

³ The abbreviations used are: HPC, hereditary prostate cancer; HSD3B, 3ß-hydroxysteroid dehydrogenase; SNP, single nucleotide polymorphism; LOD, log of odd; UTR, untranslated region; PSA, prostate specific antigen; HWE, Hardy-Weinberg equilibrium; LD, linkage disequilibrium; RR, relative risk; CI, confidence interval; PKC, protein kinase C; IL, interleukin.

⁴ Internet address: http://maple.bioc.columbia.edu/predictprotein/.

Received 8/31/01. Accepted 1/ 9/02.

	REFERENCES

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1. Isaacs W. B., Xu J., Walsh P. C. Hereditary prostate cancer Chung L. W. K. Isaacs W. B. Simons J. W. eds. . Prostate Cancer, Biology, Genetics, and the New Therapeutics, : Humana Press Totowa, NJ 2001.
2. Gronberg H., Damber L., Damber J. E. Studies of genetic factors in prostate cancer in a twin population. J. Urol., 152: 1484-1487, 1994.[Medline]
3. Page W. F., Braun M. M., Partin A. W., Caporaso N., Walsh P. Heredity and prostate cancer: a study of World War II veteran twins. Prostate, 33: 240-245, 1997.[Medline]
4. Lichtenstein P., Holm N. V., Verkasalo P. K., Iliadou A., Kaprio J., Koskenvuo M., Pukkala E., Skytthe A., Hemminki K. Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med., 343: 78-85, 2000.[Abstract/Free Full Text]
5. Carter B. S., Beaty T. H., Steinberg G. D., Childs B., Walsh P. C. Mendelian inheritance of familial prostate cancer. Proc. Natl. Acad. Sci. USA, 89: 3367-3371, 1992.[Abstract/Free Full Text]
6. Gronberg H., Damber L., Damber J. E., Iselius L. Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am. J. Epidemiol., 146: 552-557, 1997.[Abstract/Free Full Text]
7. Schaid D. J., McDonnell S. K., Blute M. L., Thibodeau S. N. Evidence for autosomal dominant inheritance of prostate cancer. Am. J. Hum. Genet., 62: 1425-1438, 1998.[Medline]
8. Cui J., Staples M. P., Hopper J. L., English D. R., McCredie M. R., Giles G. G. Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am. J. Hum. Genet., 68: 1207-1218, 2001.[Medline]
9. Smith J. R., Freije D., Carpten J. D., Gronberg H., Xu J., Isaacs S. D., Brownstein M. J., Bova G. S., Guo H., Bujnovszky P., Nusskern D. R., Damber J. E., Bergh A., Emanuelsson M., Kallioniemi O. P., Walker-Daniels J., Bailey-Wilson J. E., Beaty T. H., Meyers D. A., Walsh P. C., Collins F. S., Trent J. M., Isaacs W. B. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science (Wash. DC), 274: 1371-1374, 1996.[Abstract/Free Full Text]
10. Berthon P., Valeri A., Cohen-Akenine A., Drelon E., Paiss T., Wohr G., Latil A., Millasseau P., Mellah I., Cohen N., Blanche H., Bellane-Chantelot C., Demenais F., Teillac P., Le Duc A., de Petriconi R., Hautmann R., Chumakov I., Bachner L., Maitland N. J., Lidereau R., Vogel W., Fournier G., Mangin P., Cohen D., Cussenot O. Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am. J. Hum. Genet., 62: 1416-1424, 1998.[Medline]
11. Xu J., Meyers D., Freije D., Isaacs S., Wiley K., Nusskern D., Ewing C., Wilkens E., Bujnovszky P., Bova G. S., Walsh P., Isaacs W., Schleutker J., Matikainen M., Tammela T., Visakorpi T., Kallioniemi O. P., Berry R., Schaid D., French A., McDonnell S., Schroeder J., Blute M., Thibodeau S., Gronberg H., Emanuelsson M., Damber J., Bergh A., Jonsson B., Smith J., Bailey-Wilson J., Carpten J., Stephan D., Gillanders E., Amundson I., Kainu T., Freas-Lutz D., Baffoe-Bonnie A., Aucken A. V., Sood R., Collin F., Brounstein M., Trent J. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat. Genet., 20: 175-179, 1998.[Medline]
12. Gibbs M., Stanford J. L., McIndoe R. A., Jarvik G. P., Kolb S., Goode E. L., Chakrabarti L., Schuster E. F., Buckley V. A., Miller E. L., Brandzel S., Li S., Hood L., Ostrander E. A. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am. J. Hum. Genet., 64: 776-787, 1999.[Medline]
13. Berry R., Schroeder J. J., French A. J., McDonnell S. K., Peterson B. J., Cunningham J. M., Thibodeau S. N., Schaid D. J. Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am. J. Hum. Genet., 67: 82-91, 2000.[Medline]
14. Tavtigian S. V., Simard J., Teng D. H., Abtin V., Baumgard M., Beck A., Camp N. J., Carillo A. R., Chen Y., Dayananth P., Desrochers M., Dumont M., Farnham J. M., Frank D., Frye C., Ghaffari S., Gupte J. S., Hu R., Iliev D., Janecki T., Kort E. N., Laity K. E., Leavitt A., Leblanc G., McArthur-Morrison J., Pederson A., Penn B., Peterson K. T., Reid J. E., Richards S., Schroeder M., Smith R., Snyder S. C., Swedlund B., Swensen J., Thomas A., Tranchant M., Woodland A. M., Labrie F., Skolnick M. H., Neuhausen S., Rommens J., Cannon-Albright L. A. A candidate prostate cancer susceptibility gene at chromosome 17p. Nat. Genet., 27: 172-180, 2001.[Medline]
15. Rebbeck T. R., Walker A. H., Zeigler-Johnson C., Weisburg S., Martin A. M., Nathanson K. L., Wein A. J., Malkowicz S. B. Association of HPC2/ELAC2 genotypes and prostate cancer. Am. J. Hum. Genet., 67: 1014-1019, 2001.
16. Xu J., Zheng S. L., Hawkins G. A., Faith D. A., Kelly B., Isaacs S. D., Wiley K. E., Chang B., Ewing C. M., Bujnovszky P., Carpten J. D., Bleecker E. R., Walsh P. C., Trent J. M., Meyers D. A., Isaacs W. B. Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22–23. Am. J. Hum. Genet., 69: 341-350, 2001.[Medline]
17. Luu T., V., Lachance Y., Labrie C., Leblanc G., Thomas J. L., Strickler R. C., Labrie F. Full length cDNA structure and deduced amino acid sequence of human 3 ß-hydroxy-5-ene steroid dehydrogenase. Mol. Endocrinol., 3: 1310-1312, 1989.[Abstract/Free Full Text]
18. Rheaume E., Lachance Y., Zhao H. F., Breton N., Dumont M., de Launoit Y., Trudel C., Luu-The V., Simard J., Labrie F. Structure and expression of a new complementary DNA encoding the almost exclusive 3 ß-hydroxysteroid dehydrogenase/ 5- 4-isomerase in human adrenals and gonads. Mol. Endocrinol., 5: 1147-1157, 1991.[Abstract/Free Full Text]
19. McBride M. W., McVie A. J., Burridge S. M., Brintnell B., Craig N., Wallace A. M., Wilson R. H., Varley J., Sutcliffe R. G. Cloning, expression, and physical mapping of the 3ß-hydroxysteroid dehydrogenase gene cluster (HSD3BP1-HSD3BP5) in human. Genomics, 61: 277-284, 1999.[Medline]
20. Simard J., Durocher F., Mebarki F., Turgeon C., Sanchez R., Labrie Y., Couet J., Trudel C., Rheaume E., Morel Y., Luu-The V., Labrie F. Molecular biology and genetics of the 3 ß-hydroxysteroid dehydrogenase/5-4 isomerase gene family. J. Endocrinol., 150 (Suppl.): S189-S207, 1996.[Medline]
21. Gingras S., Simard J. Induction of 3ß-hydroxysteroid dehydrogenase/isomerase type 1 expression by interleukin-4 in human normal prostate epithelial cells, immortalized keratinocytes, colon, and cervix cancer cell lines. Endocrinology, 140: 4573-4584, 1999.[Abstract/Free Full Text]
22. Gingras S., Moriggl R., Groner B., Simard J. Induction of 3ß-hydroxysteroid dehydrogenase/5-4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. Mol. Endocrinol., 13: 66-81, 1999.[Abstract/Free Full Text]
23. El Alfy M., Luu-The V., Huang X. F., Berger L., Labrie F., Pelletier G. Localization of type 5 17ß-hydroxysteroid dehydrogenase, 3ß-hydroxysteroid dehydrogenase, and androgen receptor in the human prostate by in situ hybridization and immunocytochemistry. Endocrinology, 140: 1481-1491, 1999.[Abstract/Free Full Text]
24. Rheaume E., Simard J., Morel Y., Mebarki F., Zachmann M., Forest M. G., New M. I., Labrie F. Congenital adrenal hyperplasia due to point mutations in the type II 3 ß-hydroxysteroid dehydrogenase gene. Nat. Genet., 1: 239-245, 1992.[Medline]
25. Xu J., Zheng S. L., Chang B., Smith J. R., Carpten J. D., Stine O. C., Isaacs S. D., Wiley K. E., Henning L., Ewing C., Bujnovszky P., Bleeker E. R., Walsh P. C., Trent J. M., Meyers D. A., Isaacs W. B. Linkage of prostate cancer susceptibility loci to chromosome 1. Hum. Genet., 108: 335-345, 2001.[Medline]
26. Goddard K. A., Witte J. S., Suarez B. K., Catalona W. J., Olson J. M. Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am. J. Hum. Genet., 68: 1197-1206, 2001.[Medline]
27. Verreault H., Dufort I., Simard J., Labrie F., Luu-The V. Dinucleotide repeat polymorphisms in the HSD3B2 gene. Hum. Mol. Genet., 3: 384 1994.[Free Full Text]
28. Devgan S. A., Henderson B. E., Yu M. C., Shi C. Y., Pike M. C., Ross R. K., Reichardt J. K. Genetic variation of 3 ß-hydroxysteroid dehydrogenase type II in three racial/ethnic groups: implications for prostate cancer risk. Prostate, 33: 9-12, 1997.[Medline]
29. Lachance Y., Luu-The V., Verreault H., Dumont M., Rheaume E., Leblanc G., Labrie F. Structure of the human type II 3 ß-hydroxysteroid dehydrogenase/ 5- 4 isomerase (3 ß-HSD) gene: adrenal and gonadal specificity. DNA Cell Biol., 10: 701-711, 1991.[Medline]
30. Lachance Y., Luu-The V., Labrie C., Simard J., Dumont M., de Launoit Y., Guerin S., Leblanc G., Labrie F. Characterization of human 3 ß-hydroxysteroid dehydrogenase/ 5- 4-isomerase gene and its expression in mammalian cells. J. Biol. Chem., 267: 3551 1992.[Free Full Text]
31. Weir B. S. eds. . Genetic Data Analysis II: Methods for Discrete Population Genetic Data, : Sinauer Association, Inc. Publishers Sunderland, MA 1996.
32. Zaykin D., Zhivotovsky L., Weir B. S. Exact tests for association between alleles at arbitrary numbers of loci. Genetica, 96: 169-178, 1995.[Medline]
33. Schlesselman J. J. eds. . Case-control Studies, : Oxford University Press New York 1982.
34. Gingras S., Cote S., Simard J. Multiple signal transduction pathways mediate interleukin-4-induced 3ß-hydroxysteroid dehydrogenase/5-4 isomerase in normal and tumoral target tissues. J. Steroid Biochem. Mol. Biol., 76: 213-225, 2001.[Medline]

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