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5-alpha-reductase 2 polymorphisms as risk factors in prostate cancer.

https://arctichealth.org/en/permalink/ahliterature19112
Source
Pharmacogenetics. 2002 Jun;12(4):307-12
Publication Type
Article
Date
Jun-2002
Author
Söderström T
Wadelius M
Andersson S-O
Johansson J-E
Johansson S
Granath F
Rane A
Author Affiliation
Department of Medical Sciences, Clinical Pharmacology, University Hospital, S-751 85 Uppsala, Sweden. torbjorn.soderstrom@lmk.ck.lul.se
Source
Pharmacogenetics. 2002 Jun;12(4):307-12
Date
Jun-2002
Language
English
Publication Type
Article
Keywords
Age Factors
Aged
Alleles
Case-Control Studies
Cell Differentiation
DNA - blood - metabolism
DNA Primers - chemistry
European Continental Ancestry Group
Genotype
Heterozygote
Humans
Male
Middle Aged
Neoplasm Staging
Odds Ratio
Polymerase Chain Reaction
Polymorphism, Genetic
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms - enzymology - etiology - genetics
Research Support, Non-U.S. Gov't
Risk factors
Sweden - epidemiology
Testosterone 5-alpha-Reductase - genetics
Abstract
Prostate cancer is a significant cause of death in Western countries and is under the strong influence of androgens. The steroid 5alpha-reductase 2 catalyzes the metabolism of testosterone into the more potent androgen dihydrotestosterone in the prostate gland. The enzyme is a target in pharmacological treatment of benign prostatic hyperplasia using specific inhibitors such as finasteride. Makridakis et al. have characterized the V89L and A49T polymorphisms in recombinant expression systems. The L allelic variant has a lower Vmax/Km ratio than the V variant. In the A49T polymorphism, the T variant has an increased Vmax/Km ratio. We performed a population-based case-control study of the impact of the SRD5A2 V89L and A49T polymorphisms on the risk of prostate cancer. We also studied the relation between the genotypes and age at diagnosis, tumor, node, metastasis stage, differentiation grade, prostate specific antigen and heredity. The study included 175 prostate cancer patients and 159 healthy controls that were matched for age. There was an association with SRD5A2 V89L LL genotype and metastases at the time of diagnosis, OR 5.67 (95% CI 1.44-22.30) when adjusted for age, differentiation grade, T-stage and prostate specific antigen. Heterozygous prostate cancer cases that carried the SRD5A2 A49T AT genotype were significantly younger than cases that carried the AA genotype, (mean age 66 years vs 71, P = 0.038). The SRD5A2 V89L and A49T polymorphisms were, however, not associated with altered prostate cancer risk. Further studies of the V89L polymorphism may lead to better understanding of the etiology of prostate cancer metastases.
PubMed ID
12042668 View in PubMed
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Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: results from two Australian studies and an additional validation set.

https://arctichealth.org/en/permalink/ahliterature93836
Source
Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2557-65
Publication Type
Article
Date
Dec-2007
Author
Beesley Jonathan
Jordan Susan J
Spurdle Amanda B
Song Honglin
Ramus Susan J
Kjaer Suzanne Kruger
Hogdall Estrid
DiCioccio Richard A
McGuire Valerie
Whittemore Alice S
Gayther Simon A
Pharoah Paul D P
Webb Penelope M
Chenevix-Trench Georgia
Author Affiliation
Queensland Institute of Medical Research, Herston, Queensland, Australia.
Source
Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2557-65
Date
Dec-2007
Language
English
Publication Type
Article
Keywords
Australia
Case-Control Studies
DNA Repair - genetics
DNA Repair Enzymes - genetics
Female
Genetic Predisposition to Disease
Genotype
Gonadal Steroid Hormones - genetics - metabolism
Humans
Neoplasms, Glandular and Epithelial - genetics - metabolism
Ovarian Neoplasms - genetics - metabolism
Polymorphism, Single Nucleotide
Reproducibility of Results
Risk factors
Testosterone 5-alpha-Reductase - genetics
Abstract
Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r(2) = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition.
PubMed ID
18086758 View in PubMed
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Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development.

https://arctichealth.org/en/permalink/ahliterature79804
Source
Cancer Res. 2006 Nov 15;66(22):11077-83
Publication Type
Article
Date
Nov-15-2006
Author
Lindström Sara
Wiklund Fredrik
Adami Hans-Olov
Bälter Katarina Augustsson
Adolfsson Jan
Grönberg Henrik
Author Affiliation
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden. sara.lindstrom@oc.umu.se
Source
Cancer Res. 2006 Nov 15;66(22):11077-83
Date
Nov-15-2006
Language
English
Publication Type
Article
Keywords
Aged
Case-Control Studies
Cytochrome P-450 Enzyme System - genetics
Haplotypes
Humans
Male
Middle Aged
Neoplasm Staging
Polymorphism, Single Nucleotide
Prostatic Neoplasms - genetics - pathology
Receptors, Androgen - genetics
Testosterone 5-alpha-Reductase - genetics
Variation (Genetics)
Abstract
Prostate cancer risk may be influenced by single genetic variants in the hormone-regulating genes androgen receptor (AR), cytochrome P450 (CYP17), and steroid-5-alpha-reductase type 2 (SRD5A2). In this study, we comprehensively investigated polymorphisms in these three loci and their joint effect in a large population-based study. We selected 23 haplotype-tagging single-nucleotide polymorphisms (htSNP) that could uniquely describe >95% of the haplotypes (6 in AR, 6 in CYP17, and 11 in SRD5A2). These htSNPs were then genotyped in the Cancer Prostate in Sweden population (2,826 case subjects and 1,705 controls). We observed significant association for several SNPs in the AR gene (P = 0.004-0.02) and CYP17 (P = 0.009-0.05) and one SNP in SRD5A2 (P = 0.02). Carriers of the most common AR haplotype had a significant excess risk to develop prostate cancer [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.1-1.5; P = 0.002], yielding an estimated population attributable risk of 16% (95% CI, 0.06-0.25). Combining risk alleles from these genes yielded a 12% risk increase for each additional high-risk allele carried (95% CI, 1.1-1.2; P for trend = 9.2 x 10(-5)), with an overall OR of 1.87 (95% CI, 1.0-3.4) for carriers of all five included risk alleles, an OR of 2.13 (P for trend = 8 x 10(-4)) for advanced disease, and an OR of 4.35 (P for trend = 7 x 10(-5)) for disease onset before age 65 years. Genetic variation in key genes in the androgen pathway is important for development of prostate cancer and may account for a considerable proportion of all prostate cancers. Carriers of five high-risk alleles in the AR, CYP17, and SRD5A2 genes are at approximately 2-fold excess risk to develop prostate cancer.
PubMed ID
17108148 View in PubMed
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Messenger ribonucleic acid levels of steroid 5 alpha-reductase 2 in human prostate predict the enzyme activity.

https://arctichealth.org/en/permalink/ahliterature20049
Source
J Clin Endocrinol Metab. 2001 Feb;86(2):855-8
Publication Type
Article
Date
Feb-2001
Author
T G Söderström
C. Bjelfman
E. Brekkan
B. Ask
L. Egevad
B J Norlén
A. Rane
Author Affiliation
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Division of Clinical Pharmacology, Huddinge University Hospital, SE-14186, Huddinge, Sweden. torbjorn.soderstrom@medsci.uu.se
Source
J Clin Endocrinol Metab. 2001 Feb;86(2):855-8
Date
Feb-2001
Language
English
Publication Type
Article
Keywords
Adult
Aged
Aged, 80 and over
European Continental Ancestry Group
Humans
Hydrogen-Ion Concentration
Kinetics
Male
Middle Aged
Prostate - enzymology
Prostatic Hyperplasia - enzymology - genetics
Prostatic Neoplasms - enzymology - genetics
RNA, Messenger - metabolism
Research Support, Non-U.S. Gov't
Sweden
Testosterone 5-alpha-Reductase - genetics - metabolism
Abstract
Testosterone is converted to dihydrotestosterone by 5 alpha-reductase2 in the prostate. Dihydrotestosterone controls cell division, and interindividual differences in prostatic 5 alpha-reductase 2 expression and activity may be a determinant of the risk of developing prostate cancer. However, little is known about interindividual differences in intraprostatic hormonal activity in vivo. To determine whether 5 alpha-reductase-specific messenger RNA (mRNA) is predictive of 5 alpha-reductase activity in prostatic tissue, we analyzed 30 prostatic tissue specimens from 15 Caucasian patients, 47--82 yr old. The mRNA was measured by RT-PCR. Five specimens consisted of cancer, whereas the remaining 25 were derived from benign prostate hyperplasia (BPH). We found a strong association between enzyme activity at pH 5.5 and the 5 alpha-reductase 2-specific mRNA expression when expressed on the basis of beta-actin [Spearman's rank-correlation coefficient (r(s)) = 0.81; 95% confidence interval, 0.64-0.91; P
PubMed ID
11158057 View in PubMed
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