Additional upstream coding sequences of MAGE-11.
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Antigens, Neoplasm↗
Biomedical subjects
G A Coetzee
Publications and source records attributed to G A Coetzee.
Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins.
Members of the 160-kDa nuclear receptor coactivator family (p160 coactivators) bind to the conserved AF-2 activation function found in the hormone binding domains of nuclear receptors (NR) and are potent transcriptional coactivators for NRs. Here we report that the C-terminal region of p160 coactivators glucocorticoid receptor interacting protein 1 (GRIP1), steroid receptor coactivator 1 (SRC-1a), and SRC-1e binds the N-terminal AF-1 activation function of the androgen receptor (AR), and p160 coactivators can thereby enhance transcriptional activation by AR. While they all interact efficiently with AR AF-1, these same coactivators have vastly different binding strengths with and coactivator effects on AR AF-2. p160 activation domain AD1, which binds secondary coactivators CREB binding protein (CBP) and p300, was previously implicated as the principal domain for transmitting the activating signal to the transcription machinery. We identified a new highly conserved motif in the AD1 region which is important for CBP/p300 binding. Deletion of AD1 only partially reduced p160 coactivator function, due to signaling through AD2, another activation domain located at the C-terminal end of p160 coactivators. C-terminal coactivator fragments lacking AD1 but containing AD2 and the AR AF-1 binding site served as efficient coactivators for full-length AR and AR AF-1. The two signal input domains (one that binds NR AF-2 domains and one that binds AF-1 domains of some but not all NRs) and the two signal output domains (AD1 and AD2) of p160 coactivators played different relative roles for two different NRs: AR and thyroid hormone receptor.
Animals↗
Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility.
The prostate is an androgen-regulated organ, which has led to longstanding interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that genetic factors play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis, focused around a series of genes involved in androgen biosynthesis, transport and metabolism. We have begun to develop this model by utilizing sequence variants to study how polymorphic markers in two genes (SRD5A2 and AR) are related to prostate cancer risk within and between racial-ethnic groups. We are now collaborating with the Whitehead Institute/MIT, Center for Genome Research, to screen for single nucleotide polymorphisms in additional genes relevant to the androgen pathway and prostate cell growth. The model when fully developed can potentially provide a basis for targeting populations for screening interventions and for implementing primary preventive strategies.
Androgens↗
Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility.
The prostate is an androgen-regulated organ, which has led to long-standing interest in the role of androgens in prostate carcinogenesis. Although evidence of a hormonal etiology for prostate cancer is strong, it is almost entirely circumstantial. Much of the problem in proving a causal relationship relates to the continued difficulties in reliably measuring human tissue-specific exposure to endogenous steroid hormones. The international and racial-ethnic variations in prostate cancer incidence, combined with the effects of migration on risk patterns, have suggested that whereas environmental factors are likely to be important, genetic factors might also play a central role in determining prostate cancer risk. We are developing a polygenic model of prostate carcinogenesis focused around a series of genes involved in androgen biosynthesis and androgen activation, transport, and metabolism in the prostate. In this developing model, we have initially targeted four genes based on three main criteria: (a) all encode products that play important roles in inducing androgen stimulation in the prostate; (b) all are polymorphic; and (c) all show substantial allelic variation in the polymorphic marker among the racial-ethnic groups of greatest interest in terms of prostate cancer risk. In addition to studying how the polymorphic markers of interest are related to prostate cancer development within and between racial-ethnic groups, we are concurrently evaluating whether genotypic variations correlate in the anticipated direction with biochemical parameters in vitro and in vivo. We summarize the development of this model and the state of knowledge related to each of the genes comprising the current model. We discuss the extent to which the current model can explain demographic variation in prostate cancer risk as well as the potential for future expansion of the model to incorporate environmental risk factors as well as additional genes. The model, when fully developed, can potentially provide a basis for targeting populations for screening interventions and/or preventive strategies aimed at the multigene products or at the genes themselves.
3-Hydroxysteroid Dehydrogenases↗
Association of prostate cancer with vitamin D receptor haplotypes in African-Americans.
In previous studies, allelic variation in the 3' end of the vitamin D receptor gene was associated with increased risk of prostate cancer in white men. Several polymorphisms, including a BsmI restriction site and a poly(A) microsatellite, can be used interchangeably to mark the unidentified locus in whites. In African-Americans, however, these markers are not interchangeable, due to weaker linkage disequilibrium in this genomic region in this population. Here, we genotyped both the BsmI and poly(A) markers for 151 African-American prostate cancer cases (102 localized and 49 advanced) and 174 African-American male controls from a large epidemiological cohort. A direct haplotyping procedure was devised to determine BsmI/poly(A) haplotypes for double heterozygotes so that haplotypes could be used as allelic markers in standard logistic regression analyses. Using BsmI alone, b alleles were associated with a 2-fold decrease in risk of advanced prostate cancer. The association was, however, confined to haplotypes carrying a long (L) allele of the poly(A) microsatellite. BL and bL haplotypes were associated with increased and decreased risk, respectively, whereas neither BS nor bS haplotypes were associated with prostate cancer risk. An allelic variant that confers increased risk of advanced prostate cancer appears to be associated with the BsmI/poly(A) BL haplotype in African-Americans.
Aged↗
Cytochrome P450c17alpha gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations.
An increased level of serum estrogen is one marker of breast cancer risk. We have recently reported that increased risk of advanced breast cancer is associated with a common allele of the cytochrome P450c17alpha gene (CYP17), designated A2. We now show that CYP17 genotype is associated with serum hormone levels among 83 young, nulliparous women. Serum estradiol (E2) levels measured around day 11 of the menstrual cycle were 11 and 57% higher (P = 0.04), respectively, among women hetero- and homozygous for the CYP17 A2 allele compared to A1/A1 women. Similarly, around cycle day 22, E2 levels were 7 and 28% higher (P = 0.06), and progesterone levels were 24 and 30% higher (P = 0.04), respectively. These data provide direct evidence of genetic control of serum hormone levels.
Adult↗
Polymorphic exonic CAG microsatellites in the gene amplified in breast cancer (AIB1 gene).
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Alleles↗
Sex steroid hormones and genetic susceptibility to breast and prostate cancer.
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Animals↗
A 3-basepair deletion in repeat 1 of the LDL receptor promoter reduces transcriptional activity in a South African Pedi.
We have examined a naturally occurring mutation in the promoter region of the low density lipoprotein receptor (LDLR) gene of a South African Black patient with a clinical diagnosis of familial hypercholesterolemia (FH). The mutation constitutes a 3-bp deletion at nucleotide position -92 (FH Pedi-2) in the distal Sp1 binding site in repeat 1 of the LDLR promoter. The patient carries a second mutant LDLR allele containing a 1-bp deletion in exon 2 (FH Pedi-1) that gives rise to a frameshift mutation. Consistent with low receptor activity previously observed in cultured fibroblasts from the patient (5-15%), the rate of LDL receptor synthesis was markedly reduced to less than 20% of normal. DNase I footprint analysis indicated that the -92 mutation abolished binding of Sp1 to repeat 1 in the LDLR promoter. Transcription studies in transfected cells using normal and mutant promoter fragments linked to a luciferase reporter gene demonstrated that the promoter fragment containing the -92 mutation had approximately 10% of normal promoter activity. These findings indicate that the distal Sp1 binding site is essential for maximal activity of the normal intact LDLR promoter.
Arteriosclerosis↗
Absence of the glutathione S-transferase M1 gene increases cytochrome P4501A2 activity among frequent consumers of cruciferous vegetables in a Caucasian population.
The cancer protective effect of cruciferous vegetables has been attributed to induction of phase II enzymes. But cruciferous vegetables also induce cytochrome P4501A2 (CYP1A2), which catalyzes the metabolic activation of various procarcinogens, including aromatic amines in tobacco. Thus, frequent intake of cruciferous vegetables could also result in cancer-enhancing effects. GSTM1 is involved in the detoxification of various carcinogens, but it also enhances the excretion of isothiocyanates and possibly other enzyme inducers in cruciferous vegetables. We, therefore, hypothesized that GSTM1 null genotype might be associated with increased CYP1A2 activity among frequent consumers of cruciferous vegetables because the excretion of CYP1A2 inducers contained in these vegetables may be partially inhibited in the absence of the GSTM1 enzyme. Three hundred twenty-eight non-Hispanic white residents of Los Angeles County (265 males and 63 females) were genotyped for the presence or absence of GSTM1 alleles and phenotyped for CYP1A2 activity. Information on usual dietary habits was obtained from these subjects through in-person interviews. Among frequent (at least once a week) consumers of broccoli, GSTM1 null individuals exhibited a 21% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.24 versus 4.32, two-sided P = 0.01). No such difference was observed in subjects who consumed broccoli less frequently (two-sided P = 0.39). This interactive effect of GSTM1 genotype and vegetable intake on CYP1A2 activity also was observed when overall intake of the five cruciferous vegetables under study (broccoli, cabbage, cauliflower, Brussels sprouts, and mustard greens) was examined. Among weekly consumers of cruciferous vegetables, GSTM1 null individuals showed a 16% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.03 versus 4.33, two-sided P = 0.02), whereas no difference was evident among those who consumed cruciferous vegetables less frequently (two-sided P = 0.35). Our results suggest that cruciferous vegetables contain CYP1A2 inducers, which are deactivated in the presence of GSTM1.
Brassicaceae↗
Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione S-transferase M1/T1/P1 genotypes.
Isothiocyanates (ITCs), degradation products of glucosinolates (which occur naturally in a variety of cruciferous vegetables), have been shown to exhibit chemopreventive activity. These compounds are metabolized in vivo to form the corresponding dithiocarbamates, which are the major urinary metabolites of ITCs, by a pathway involving the glutathione S-transferase (GST) class of enzymes. Using a newly developed assay that measures total ITC (primarily ITC conjugates) in urine, we examined the relationships between cruciferous vegetable intake (obtained from a food frequency/portion size questionnaire administered in person); dietary total ITC level; GSTM1, GSTT1, and GSTP1 genotypes; and levels of total ITC in spot urine samples collected from 246 Singapore Chinese (111 men and 135 women), ages 45-74 years, who are participants of the Singapore Cohort Study on diet and cancer. Consumption level of cruciferous vegetables was high in study subjects (mean consumption = 345 times per year, mean daily intake = 40.6 g), which was >3 times the comparable level of intake in the United States. Mean daily intake of total ITC among study subjects was 9.1 micromol, and there was a 2.5-fold difference between the 25th and 75th percentile values. Seventy-three % of study subjects tested positive for ITC in urine, and there was a 4-fold difference between the 25th and 75th percentile values among the positive subjects. There was a highly significant positive association between dietary intake and urinary excretion levels of total ITC (two-sided P = 0.0003) that was stronger than the association between overall cruciferous vegetable intake and urinary ITC level, which also was statistically significant (P = 0.0004). There was no difference in urinary ITC levels between GSTM1-null and GSTM1-positive study subjects (P = 0.61) or between subjects with differing GSTP1 genotypes (P = 0.77), but urinary excretion of ITC was significantly higher among GSTT1-positive subjects, relative to GSTT1-null subjects (P = 0.006). The strength of the association between GSTT1 genotype and urinary total ITC level was highly dependent on the level of cruciferous vegetable consumption (or dietary ITC level) in study subjects. Among subjects in the lowest tertile of cruciferous vegetable intake, there was little evidence of an association between GSTT1 genotype and urinary total ITC level (P = 0.67). In contrast, there was a strong and statistically significant association between GSTT1 genotype and urinary total ITC among subjects in the highest tertile of cruciferous vegetable intake (P = 0.02), whereas those in the middle tertile of cruciferous vegetable consumption exhibited an association of intermediate strength (P = 0.04). These results suggest the presence of GSTT1 inducers in cruciferous vegetables.
Age Factors↗
A polymorphism in the CYP17 gene increases the risk of breast cancer.
We conducted a case-control study to determine whether a polymorphism in the CYP17 gene was associated with risk of breast cancer. We found an increased risk of advanced breast cancer in women carrying an A2 allele. The odds ratio was 2.5 [95% confidence interval (CI), 1.07-5.94] for regional or metastatic disease. Among controls, the A1/A1 genotype was associated with a later age at menarche. The reduced risk of breast cancer associated with a later age of menarche was largely limited to A1/A1 women: odds ratio, 0.47 (CI, 0.22-0.98) for breast cancer and later age at menarche among A1 homozygotes compared with 0.80 (CI, 0.51-1.27) for A1/A2 and A2/A2 genotypes. These findings suggest that the CYP17 genotype may be a biomarker for the onset of ovulation and advanced breast cancer risk.
Aged↗
Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor.
BACKGROUND: Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility. PURPOSE: We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer. METHODS: Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatellite (CAG repeats) in the AR gene and for a newly discovered poly-A microsatellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests. RESULTS: Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A18 to A22) VDR poly-A allele versus two short (A14 to A17) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. CONCLUSIONS: In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer. IMPLICATIONS: These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.
Alleles↗
A polymorphism in intron 6 of the CYP17 gene.
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Asian↗
The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance.
Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C-->T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.
Adolescent↗
Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies.
Markers in the 3' end of the vitamin D receptor gene have recently been associated with prostate cancer risk. To evaluate the adequacy of the commonly used BsmI restriction fragment length polymorphism as a marker of this locus, we genotyped 627 individuals from five ethnic groups for this marker, as well as for a polymorphic site in the 3' untranslated region of this gene. At the latter site, we identified 12 alleles, A13 to A24, of a poly(A) microsatellite. Allele size followed a bimodal distribution with distinct short (A13-A17) and long (A18-A24) allele populations. Poly(A) allele frequency differed by ethnicity, with the frequency of short alleles being highest in non-Hispanic whites (41%), intermediate in Hispanics and African-Americans (31 and 29%, respectively), and lowest in Japanese-Americans and Chinese (8 and 9%, respectively). In each of the ethnic groups, some degree of coupling was observed between BsmI B and short poly(A) alleles and between BsmI b and long poly(A) alleles. However, the strength of the linkage disequilibrium varied by ethnicity, with departures from complete disequilibrium producing disagreement between the BsmI and poly(A) genotypes. Genotypic disagreement was lowest in Japanese-Americans and non-Hispanic whites (6 and 7%, respectively), intermediate in Chinese and Hispanics (11 and 19%, respectively), and highest among African-Americans (37%), indicating that BsmI is not a good marker for the vitamin D receptor 3' untranslated region genotype in all populations. This finding may explain contradictory results from recent association studies using the BsmI marker.
Asian↗
Identification of two germline point mutations in the 5'UTR of the androgen receptor gene in men with prostate cancer.
PURPOSE: As part of an ongoing study to identify germline mutations and/or polymorphisms in the androgen receptor (AR) gene which might be associated with prostate cancer, the 5'-untranslated region (5'UTR) of the AR gene was screened in genomic DNA of prostate cancer cases. This region, which is > 1 kb in length, might modulate AR expression by affecting transcription and/or translation rates. A life-time exposure to enhanced AR expression, in turn, could potentially predispose to prostate cancer. MATERIALS AND METHODS: Genomic DNA samples from 38 prostate cancer cases were analyzed for mutations in the 5'UTR of the AR gene. RESULTS: Two mutations were identified. One mutation, G2T, is located within the AR transcription initiation site 1 (AR-TIS I), and the second, C214A, within a GC rich region of the 5'UTR. CONCLUSIONS: Although 5'UTR mutations in the AR gene might only rarely occur in men with prostate cancer, the occasional mutation in this area may contribute to the disease by altering rates of transcription and/or translation of this gene.
Humans↗
Genetic susceptibility to cancer from exogenous and endogenous exposures.
The past four decades of epidemiological research have yielded valuable information on the risks of populations to environmental exposures such as tobacco, asbestos, and dietary components. Prevention efforts have been focused on large-scale population-based interventions to minimize exposure to such external carcinogens. While some cancers are beginning to show a decline from changing environmental exposures, hormone-related cancers, such as breast and prostate, are becoming more prevalent. The development of these cancers appears to be closely related to endogenous exposures to circulating steroid hormones. Although prevention trials using antihormone agents are proving successful in some instances, the long-term control of these cancers necessitates a clearer understanding of the metabolism and transport of the relevant hormone in vivo. The revolution in molecular biology has provided powerful genetic tools for evaluating mechanisms of cancer causation as well as the potential to better define individual susceptibility. Using tobacco exposure as an example, we and others have demonstrated that polymorphisms in genes controlling aromatic amine metabolism provide at least a partial explanation for ethnic and individual susceptibility to bladder cancer. Similar studies have examined genetic polymorphisms in the metabolism of tobacco smoke and lung cancer risk, red meat and colorectal cancer, and aflatoxin and liver cancer. Our current studies have pursued a similar paradigm of genetic polymorphism and individual cancer susceptibility in prostate and breast carcinogenesis. We are evaluating polymorphisms in the steroid 5 alpha-reductase type II and androgen receptor genes in relation to prostate cancer based on the evidence that intracellular dihydrotestosterone is the critical "carcinogen." We are pursuing genetic polymorphisms affecting estradiol metabolism, including those in the 17 beta-hydroxysteroid dehydrogenase 2 and estrogen receptor genes as they relate to susceptibility to breast cancer. The potential role of a polymorphism in the cytochrome P450c 17 alpha gene in both breast and prostate cancers is also being examined.
Adult↗