Unexpected biochemical and pharmacogenetic consequences of SNPs and haplotypes: a cautionary tale for human molecular genetics and epidemiology.
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Genetics, Medical↗
Biomedical subjects
Juergen K V Reichardt
Publications and source records attributed to Juergen K V Reichardt.
Genomics in breast and prostate cancer: assessment of the current state and future perspectives.
Genomic approaches to cancer are beginning to have an important impact in unraveling the complex etiologies of this disease, as well as allowing us to rationally treat afflicted patients. In this article, we will focus largely on genomic approaches to breast and prostate cancer susceptibility, as well as pharmacogenomic approaches to treatment. Current genomic approaches to cancer susceptibility have led to some significant, if not spectacular, successes which include breast cancer. More modest achievements, if not outright failures, such as in prostate cancer, are also notable and will be discussed further. We propose interdisciplinary approaches involving basic, clinical and population scientists to vigorously attack the cancer problem scientifically and with more organization. We highlight recent successes and suggest new approaches with a personal, if not provocative, perspective.
Biomarkers, Tumor↗
Androgen metabolic genes in prostate cancer predisposition and progression.
Significant evidence implicates androgens in prostate cancer etiology. We review recent data with regard to the association between several allelic variants of specific androgen-metabolic genes and the predisposition to prostate cancer. We also review the emerging evidence regarding the role of genetic variants of these genes as well as the androgen receptor in prostate cancer progression. Based on the prostate cancer paradigm, we propose that a multidisciplinary attack on the problem--involving biochemistry, genetics, pharmacogenetics, endocrinology and molecular epidemiology--may be important for the understanding and successful treatment of complex (in terms of etiology) human diseases.
Androgens↗
Robustness of gene expression profiling in glioma specimen samplings and derived cell lines.
One of the most promising applications of microarrays is class distinction through gene expression profiling as a diagnostic tool. However, as there is apparent spatial heterogeneity in the morphology of cancer cells within a tumor, it is unclear if tumor sampling can be applied and yield consistent signals. In this report, we examined six brain tumors, four glioblastoma, and two oligodendroglioma biopsies. The six brain tumor tissues from two distinct different classes were dissected in four distinct areas and gene expression was profiled using microarrays. We used hierarchical clustering to compare the variability of gene expression profiles between spatially distinct biopsies of the same tumor as compared to the variability between tumors of the same histologic group. We conclude that, in general, repeat spatially distinct samples are not needed for microarray experiments and the gene expression signatures are robust across the tumor. Predominantly, variation was much greater between samples from different patients than from the multiple samplings of given tumor. Further, we compared biopsy expression profiles to the cell lines derived from those tissues. In general, the tumor cell lines vary greatly from the parental tissues and cluster more strongly with each other than the parental tissue. We select and examine the set of genes altered in expression to allow adaptation to cell culture.
Brain Neoplasms↗
Pharmacogenetic analysis of human steroid 5 alpha reductase type II: comparison of finasteride and dutasteride.
Human steroid 5 alpha-reductase type II is a prostate-specific, membrane-associated enzyme that catalyzes the conversion of testosterone to dihydrotestosterone, the most potent androgen in the prostate gland. Genetic variants of this enzyme have been associated with both the development and the progression of prostate cancer. Both finasteride and dutasteride are competitive inhibitors of the type II steroid 5 alpha-reductase that have been effectively used for the treatment of benign prostatic hyperplasia. Finasteride has also been successfully utilized for prostate cancer chemoprevention. We here investigate 5 alpha-reductase inhibition assays in vitro to measure the effect of incubation time on the apparent inhibition constant (Ki) for both constitutional and somatic (prostate cancer) enzyme variants. Our systematic pharmacogenetic analysis shows that both finasteride and dutasteride are slow, time-dependent inhibitors of steroid 5 alpha-reductase type II, and that the inhibition kinetics depend on the 5 alpha-reductase genotype. We also show that, overall, dutasteride is a more efficient steroid 5 alpha-reductase inhibitor than finasteride. Based on our data, we are able to map areas of the enzyme that are responsible for this time-dependent inhibition for either (or both) enzyme inhibitor(s). This comprehensive pharmacogenetic analysis of steroid 5 alpha-reductase variants unveiled significant pharmacogenetic variation for both finasteride and dutasteride and thus should be taken into account when designing protocols for treatment and/or chemoprevention of prostatic diseases with either one of these 5 alpha-reductase inhibitors since there is considerable pharmacogenetic variation for both drugs.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue.
Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5alpha-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5alpha-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5alpha-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5alpha-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5alpha-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5alpha-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5alpha-reductase inhibitors.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Molecular epidemiology of androgen-metabolic loci in prostate cancer: predisposition and progression.
PURPOSE: We review recent molecular epidemiological data with regard to the association between several allelic variants of certain androgen-metabolic genes and the predisposition to and progression of prostate cancer. MATERIALS AND METHODS: We review recent data dealing with genetic variations in androgens and the etiology of prostate cancer. RESULTS: Recent molecular epidemiological data support an association between several allelic variants of certain androgen-metabolic genes and the predisposition to and progression of prostate cancer. While some of the allelic variants examined are consistently shown to be associated with increased prostate cancer risk, most of the variants show significant variability in risk. CONCLUSIONS: A multidisciplinary attack on this problem, involving biochemistry, molecular genetics, pharmacogenetics, endocrinology and epidemiology, may be a useful paradigm in the analysis of prostate cancer and other complex human diseases. Based on the reviewed literature, we propose a guide on how and which single nucleotide polymorphisms to use in linkage and association studies of multifactorial phenotypes.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Pharmacogenetics of human androgens and prostate cancer--an update.
Prostate cancer is the most common non-skin cancer in the US; it is the second leading cause of death from cancer among US men, and the seventh leading cause of death in the US. This review examines the recent biochemical and pharmacogenetic literature related to prostate cancer, specifically that which focused on constitutional ('germline') single nucleotide polymorphisms at 'functional candidate' genes for prostate cancer. The investigations summarized in this review demonstrate the need to study the molecular genetics at these loci to rationally develop personalized medicine. In addition, the identification of somatic pharmacogenetic alterations in one of these loci suggests that this may also be a fruitful field of investigations with important clinical applications. Pharmacogenomic investigations of constitutional and tumor DNA may lead to significant advances in chemoprevention, presymptomatic diagnosis and improved treatment of prostate cancer.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Screening of nine SLC25A13 mutations: their frequency in patients with citrin deficiency and high carrier rates in Asian populations.
Deficiency of citrin encoded by SLC25A13 causes adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). So far we have diagnosed 126 (3) CTLN2 and 103 (4) NICCD patients in Japan (and other countries). From preliminary population analysis of the known nine SLC25A13 mutations, we found that the carrier frequency is high in China (1/79), Taiwan (1/98), and Korea (1/50) as well as Japan (1/69), suggesting that many patients with citrin deficiency exist in East Asia.
Adolescent↗
Association between two polymorphisms in the SRD5A2 gene and serum androgen concentrations in British men.
Androgens are essential for the growth of the prostate gland and have been implicated in the development of prostate cancer. Little is known about the determinants of androgen levels in men, although observed ethnic differences suggest they may have a genetic basis. Several polymorphisms have been identified in the steroid 5 alpha-reductase type II gene (SRD5A2), which encodes an enzyme that catalyzes the conversion of testosterone to its more potent metabolite, dihydrotestosterone. Although some of these polymorphisms have been associated with increased prostate cancer risk, the association with circulating androgen levels remains unclear. The purpose of this study is to investigate the association between the (TA)(n) dinucleotide repeat polymorphism in the 3' untranslated region and the A49T polymorphism (which replaces the normal alanine with threonine at codon 49) in the SRD5A2 gene and serum androgen concentrations in 604 British men. In particular, we wanted to test the hypotheses that the variant alleles are associated with an increased serum concentration of androstanediol glucuronide, a direct metabolite of dihydrotestosterone and a serum marker of 5 alpha-reductase activity. Mean hormone concentrations were evaluated in each genotype, and adjusted for age and other relevant factors. We found no evidence that the SRD5A2 (TA)(n) repeat polymorphism was associated with androgen levels. Men who possessed one or two copies of the variant T allele in the A49T polymorphism had a significantly 24% lower androstanediol glucuronide concentration than men who were homozygous for the wild-type allele (P = 0.0003). Because of the rarity of this variant allele, larger studies are needed to additionally clarify the role of the A49T polymorphism in androgen metabolism.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Association of galactose-1-phosphate uridyltransferase activity and N314D genotype with the risk of ovarian cancer.
Deficiency in the galactose-1-phosphate uridyltransferase (GALT) enzyme results in accumulation of galactose and its metabolites in the ovary (Am J Epidemiol 1989;130:904-10). Galactose may raise gonadotropin levels, resulting in proliferation of ovarian epithelium. In 1993-1999, the authors conducted a population-based case-control study of ovarian cancer in Hawaii and Los Angeles, California, to examine the hypothesis that reduced GALT activity is associated with an increased risk of ovarian cancer. A total of 239 ovarian cancer cases and 244 population controls were interviewed. A blood sample was collected to measure levels of GALT and to assay for the N314D (A940G) polymorphism of the GALT gene. Covariate-adjusted mean GALT activity was similar between cases (23.8 micro mol per hour/g hemoglobin (Hb)) and controls (23.7 micro mol per hour/g Hb) (p = 0.83). No evidence was found for a dose-response relation between the odds ratios for ovarian cancer and GALT activity or the ratio of lactose intake to GALT activity. The risk associated with the presence of at least one variant Asp314 allele was 0.77 (95% confidence interval: 0.42, 1.41). This study did not support the hypothesis that reduced galactose metabolism is a risk factor for ovarian cancer, although increased GALT activity attenuated the inverse association of oral contraceptive pill use with risk.
Adult↗
Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men.
BACKGROUND: Prostate cancer is a significant public health problem in this country. Substantial data support a plausible role for androgens in the etiology of this disease. The human HSD17B3 gene encodes the testicular (or type III) 17 beta-hydroxysteroid dehydrogenase enzyme, which catalyzes testosterone biosynthesis in men. METHODS: We have investigated the G289S (glycine at codon 289 replaced by serine) polymorphism at the HSD17B3 locus as a candidate single nucleotide polymorphism (SNP) for prostate cancer risk in constitutional DNA from 103 Italian prostate cancer patients and 109 Italian disease-free centenarians to assess the role of this SNP in susceptibility to prostate cancer. RESULTS: The G289S polymorphism confers a significant increase in risk for prostate cancer (odds ratio = 2.5; 95% confidence interval, 1.03-6.07) in our study population. CONCLUSION: Our data are consistent with a plausible role of the G289S SNP in prostate cancer susceptibility. Therefore, the HSD17B3 gene may be a plausible candidate gene for prostate cancer risk.
17-Hydroxysteroid Dehydrogenases↗
Hormones and prostate cancer: current perspectives and future directions.
Prostate cancer is the most commonly diagnosed non-skin cancer in men in most western countries. Despite the high morbidity and mortality from prostate cancer, its etiology remains obscure. Although compelling laboratory data suggest a role for androgens in prostate carcinogenesis, most epidemiologic data on humans are inconclusive. To provide insights and directions for future epidemiologic research on hormones and prostate cancer, this review focuses on current perspectives of serum-based studies and polymorphisms in relevant hormone-related genes. We highlight the importance of methodologic studies and investigations of hormone levels in the prostatic tissue to help clarify the often-contradictory data on serologic studies. We recommend careful analysis and cautious interpretation of studies of genetic markers, including repeats and single nucleotide polymorphisms (SNPs), as false positive and negative results may arise in many current and future studies with limited statistical power and non-representative samples from the population. The review also highlights the reasons to perform functional analyses of SNPs, a critical and often under-appreciated component of molecular epidemiologic investigations. The time is ripe for large-scale multidisciplinary investigations that incorporate molecular genetics, biochemistry, histopathology, and endocrinology into traditional epidemiologic studies. Such collaboration will lead to a deeper understanding of the etiologic pathways of prostate cancer, ultimately yielding better preventive, diagnostic, and therapeutic strategies.
Androgens↗
Galactose-1-phosphate uridyl transferase (GALT) genotype and phenotype, galactose consumption, and the risk of borderline and invasive ovarian cancer (United States).
OBJECTIVE: Previous studies have suggested that high levels of galactose consumption and/or low levels of galactose-I-phosphate uridyl transferase (GALT) activity may result in an increased risk of epithelial ovarian cancer. Similarly, some have reported that carriers of the N314D (asparagine at codon 314 replaced by aspartate) GALT polymorphism, which can be associated with low GALT activity, may have a higher risk of ovarian cancer. We examined these issues as part of a large case-control study of ovarian cancer conducted in Los Angeles between 1992 and 1998. METHODS: A total of 1,439 histologically confirmed borderline and invasive ovarian cancer cases among English-speaking non-Asian women were ascertained through the population-based cancer registry for Los Angeles County and completed in-person interviews were obtained from 689 of these (78% of cases approached). Controls consisted of 645 English-speaking non-Asian women with at least one intact ovary matched to cases on race/ethnicity (African-American, Latina, non-Latina White), date of birth (+/-3 years), and neighborhood of residence. Interviewer-administered questionnaires included information on reproductive factors, exogenous hormone use, medical history, and diet. Dietary information for the year before each case's diagnosis (and the same period for her matched control) was obtained using a self-administered food-frequency questionnaire. Blood samples were obtained from 452 controls, 136 cases with borderline ovarian cancer, and 312 cases with invasive ovarian cancer. The N314D polymorphism was characterized using PCR-RFLP and GALT enzyme activity, and was determined for a sample of the subjects with GALT genotype using an erythrocyte-based radioactive enzyme assay. RESULTS: We found no effect of N314D GALT genotype on the risk of borderline ovarian cancer (odds ratio (OR)=0.91; 95% confidence interval (CI)=0.54-1.6) or invasive ovarian cancer (OR=0.78; 95% CI= 0.53-1.2). Neither did we observe a relationship between GALT activity or lactose/galactose intake and risk of borderline or invasive ovarian cancer. Among N314D carriers, galactose consumption was associated with an increased risk of borderline (OR = 2.7, p = 0.01), but not invasive (OR = 1.2, p = 0.34), ovarian cancer; however, this result was based on only 24 N314D-positive borderline cases. CONCLUSIONS: Differences in galactose intake and GALT metabolism do not contribute significantly to the risk of ovarian cancer. There is some evidence that galactose intake may play a role in the development of borderline ovarian cancer among women who carry the uncommon GALT N314D polymorphism. More data are needed if this latter suggestion is to be definitively addressed.
Adult↗
Increasing PCR sensitivity for amplification from paraffin-embedded tissues.
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Cytological Techniques↗
Steroid 5-alpha reductase type II V89L substitution is not associated with risk of prostate cancer in a multiethnic population study.
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3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
Associations between polymorphisms in the steroid 5-alpha reductase type II (SRD5A2) gene and benign prostatic hyperplasia and prostate cancer.
The prostate gland is an androgen-dependent, and polymorphisms in androgen synthesis gene steroid 5-alpha reductase type II (SRD5A2) may be associated with benign prostatic hyperplasia (BPH) and prostate cancer. We evaluated the association between 3 polymorphisms in the SRD5A2 gene (2 single nucleotide polymorphism: alanine-49 to threonine [A49T] and valine-89 to leucine [V89L], and a (TA)n dinucleotide repeat in the 3' untranslated region), and BPH and prostate cancer within a multiethnic population. Men between 60 and 86 years of age were recruited from annual prostate cancer screening programs and from a large urology clinic. Unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (95% CI). We genotyped 606 men (412 Hispanic, 98 Caucasian, 73 African-American, and 23 Asian), of whom 100 had prostate cancer, 393 had BPH (280 symptomatic and 113 asymptomatic), and 113 had normal prostates. Overall, the V89L variant was associated with prostate cancer; the OR for men with the leucine-leucine (LL) genotype compared to men with the valine-valine (VV) genotype was 4.47 (95% CI, 1.24-16.18). This association was stronger in Hispanics (OR=7.26; 95% CI: 1.49-35.47). Although V89L was nonsignificantly associated with BPH in overall population, BPH risk increased significantly with the number of L alleles in Hispanics (P for trend=0.03). Prostate cancer and BPH were not associated with the alanine-49 to threonine single nucleotide polymorphism and the (TA)n repeat. These results suggest that the SRD5A2 gene may play an important role in both BPH and prostate cancer.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
A renaissance of "biochemical genetics"? SNPs, haplotypes, function, and complex diseases.
We have made remarkable progress in understanding the molecular bases of many Mendelian diseases over the past 2-3 decades. The current interest in discovering the molecular basis of complex diseases uses either linkage or candidate gene approaches. The latter often uses case/control (or case/cohort) study designs. We believe it is critically important to have a thorough understanding of SNP (single nucleotide) and haplotype function in such endeavors. Functionally neutral SNPs and haplotypes are probably best suited for linkage studies (far away from the locus of interest). Functionally relevant SNPs and haplotypes seem best suited for candidate gene approaches. The need for functional data may result in a renaissance of biochemical genetics with a new twist in the genomic era. We propose that the functional characterization of SNPs and haplotypes be advanced with great vigor for those genes with defined assayable phenotypes. These systematic investigations will involve classical biochemistry, modern genetics, and genomics and will probably also draw on newer technologies such as microarrays. In short, a renaissance of biochemical genetics will advance our understanding of complex diseases.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗