Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: HSD3B1 (cancer-related)
Sun Y, Wang W, Guo Y, et al.High copper levels in follicular fluid affect follicle development in polycystic ovary syndrome patients: Population-based and in vitro studies.
Toxicol Appl Pharmacol. 2019; 365:101-111 [PubMed
] Related Publications
Although the adverse effects of copper overexposure on the liver, kidney, spleen and intestinal organs are well known, information about the impact of copper toxicity on human reproduction is limited. A total of 348 infertile patients were enrolled in our present study, including 89 with polycystic ovary syndrome (PCOS), 145 with fallopian tube obstruction and 114 controls. The follicular fluid concentrations of 22 trace elements were measured by inductively coupled plasma mass spectrometry (ICP-MS). Principal component analysis was used to identify trace element profile alterations in different groups. The mRNA levels of steroidogenesis-related genes were measured by real-time PCR. Our results showed that the trace element profile in follicular fluid was obviously altered in PCOS patients. Copper concentrations were significantly (p < .05) higher in the PCOS group than in the other two groups. Increased copper levels in follicular fluid were associated with a higher number of retrievable oocytes in the PCOS group (B = 1.785, p = .001) but a lower rate of high-quality embryos (B = -6.360, p = .050). Moreover, follicular fluid copper levels were positively correlated with follicular fluid progesterone levels (r = 0.275, p = .010) and testosterone levels (r = 0.250, p = .022). Cultured human granulosa cells overexposed to copper showed significantly (p < .05) increased estradiol secretion and decreased testosterone levels. Real-time quantitative PCR revealed a significant (p < .05) increase in CYP19A1 and HSD3b mRNA expression. Our results indicate that increased copper levels in follicular fluid could affect follicle development in PCOS patients, and the mechanism may be related to copper-induced abnormalities in steroidogenesis.
Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (
3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation. Generally, it is thought that intratumoral androgen synthesis is upregulated after gonadal testosterone deprivation, enabling development of castration-resistant prostate cancer. Given its critical role in extragonadal androgen synthesis, we sought to directly interrogate the transcriptional regulation of HSD3B1 in multiple metastatic prostate cancer cell models. Surprisingly, we found that VCaP, CWR22Rv1, LNCaP, and LAPC4 models demonstrate induction of HSD3B1 upon androgen stimulation for approximately 72 hours, followed by attenuation around 120 hours. 3βHSD1 protein levels mirrored transcriptional changes in models harboring variant (LNCaP) and wild-type (LAPC4) HSD3B1, and in these models androgen induction of HSD3B1 is abrogated via enzalutamide treatment. Androgen treatment increased flux from [3H]-dehydroepiandrosterone to androstenedione and other downstream metabolites. HSD3B1 expression was reduced 72 hours after castration in the VCaP xenograft mouse model, suggesting androgen receptor (AR) regulation of HSD3B1 also occurs in vivo. Overall, these data suggest that HSD3B1 is unexpectedly positively regulated by androgens and ARs. These data may have implications for the development of treatment strategies tailored to HSD3B1 genotype status.
Hahn AW, Gill DM, Nussenzveig RH, et al.Germline Variant in HSD3B1 (1245 A > C) and Response to Abiraterone Acetate Plus Prednisone in Men With New-Onset Metastatic Castration-Resistant Prostate Cancer.
Clin Genitourin Cancer. 2018; 16(4):288-292 [PubMed
] Related Publications
BACKGROUND: The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. Recently, the HSD3B1 (1245C) variant was shown to predict shorter duration of response to androgen deprivation therapy with medical or surgical castration in the setting of castration-sensitive prostate cancer (CSPC). The HSD3B1 (1245C) variant also predicts longer duration of response to ketoconazole in men with castration-resistant prostate cancer (CRPC). We hypothesized that the HSD3B1 (1245C) variant predicts response to treatment with abiraterone acetate (AA) and can help personalize treatment in men with advanced prostate cancer.
METHODS: Clinical data and samples were from a prospectively maintained prostate cancer registry at the University of Utah. Genotyping was performed. The primary study end point was progression-free survival in first-line AA in men with metastatic CRPC. We performed prespecified multivariate analyses to assess the independent predictive value of HSD3B1 genotype on progression-free survival on AA.
RESULTS: Seventy-six men with metastatic CRPC treated with first-line AA were included. In multivariate analysis, the HSD3B1 (1245C) variant did not predict response to first-line AA.
CONCLUSION: The HSD3B1 (1245C) variant does not predict response to first-line AA in metastatic CRPC. This finding could be due to the ability of AA metabolites to act as both agonist (3-keto-5α-abiraterone) and antagonist (Δ4-abiraterone) on androgen signaling.
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ
A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.
Some epidemiological studies observed a positive association between dietary acrylamide intake and ovarian cancer risk but the causality needs to be substantiated. By analyzing gene-acrylamide interactions for ovarian cancer risk for the first time, we aimed to contribute to this. The prospective Netherlands Cohort Study on diet and cancer includes 62,573 women, aged 55-69 years. At baseline in 1986, a random subcohort of 2589 women was sampled from the total cohort for a case cohort analysis approach. Dietary acrylamide intake of subcohort members and ovarian cancer cases (n = 252, based on 20.3 years of follow-up) was assessed with a food frequency questionnaire. We selected single nucleotide polymorphisms (SNPs) in genes in acrylamide metabolism and in genes involved in the possible mechanisms of acrylamide-induced carcinogenesis (effects on sex steroid systems, oxidative stress and DNA damage). Genotyping was done on DNA from toenails through Agena's MassARRAY iPLEX platform. Multiplicative interaction between acrylamide intake and SNPs was assessed with Cox proportional hazards analysis. Among the results for 57 SNPs and 2 gene deletions, there were no statistically significant interactions between acrylamide and gene variants after adjustment for multiple testing. However, there were several nominally statistically significant interactions between acrylamide intake and SNPs in the HSD3B1/B2 gene cluster: (rs4659175 (p interaction = 0.04), rs10923823 (p interaction = 0.06) and its proxy rs7546652 (p interaction = 0.05), rs1047303 (p interaction = 0.005), and rs6428830 (p interaction = 0.05). Although in need of confirmation, results of this study suggest that acrylamide may cause ovarian cancer through effects on sex hormones.
Androgens, estrogens, progesterone and related signals are reported to be involved in the pathology of gastric cancer. However, varied conclusions exist based on serum hormone levels, receptor expressions, and in vitro or in vivo studies. This report used a web-based gene survival analyzer to evaluate biochemical processes, including cholesterol importing via lipoprotein/receptors (L/R route), steroidogenic enzymes, and steroid receptors, in gastric cancer patients prognosis. The sex hormone receptors (androgen receptor, progesterone receptor, and estrogen receptor ESR1 or ESR2), L/R route (low/high-density lipoprotein receptors, LDLR/LRP6/SR-B1 and lipoprotein lipase, LPL) and steroidogenic enzymes (CYP11A1, HSD3B1, CYP17, HSD17B1, HSD3B1, CYP19A1 and SRD5A1) were associated with 5-year survival of gastric cancer patients. The AR, PR, ESR1 and ESR2 are progression promoters, as are the L/R route LDLR, LRP6, SR-B1 and LPL. It was found that CYP11A1, HSD3B1, CYP17, HSD17B1 and CYP19A1 promote progression, but dihydrotestosterone (DHT) converting enzyme SRD5A1 suppresses progression. Analyzing steroidogenic lipidome with a hazard ratio score algorithm found that CYP19A1 is the progression confounder in surgery, HER2 positive or negative patients. Finally, in the other patient cohort from TCGA, CYP19A1 was expressed higher in the tumor compared to that in normal counterparts, and also promoted progression. Lastly, exemestrane (type II aromatase inhibitor) dramatically suppress GCa cell growth in pharmacological tolerable doses in vitro. This work depicts a route-specific outside-in delivery of cholesterol to promote disease progression, implicating a host-to-tumor macroenvironmental regulation. The result indicating lipoprotein-mediated cholesterol entry and steroidogenesis are GCa progression biosignatures. And the exemestrane clinical trial in GCa patients of unmet medical needs is suggested.
Kubota-Nakayama F, Nakamura Y, Konosu-Fukaya S, et al.Expression of steroidogenic enzymes and their transcription factors in cortisol-producing adrenocortical adenomas: immunohistochemical analysis and quantitative real-time polymerase chain reaction studies.
Hum Pathol. 2016; 54:165-73 [PubMed
] Related Publications
Adrenal Cushing syndrome (CS) is caused by the overproduction of cortisol in adrenocortical tumors including adrenal cortisol-producing adenoma (CPA). In CS, steroidogenic enzymes such as 17α-hydroxylase/17, 20-lase (CYP17A1), 3β-hydroxysteroid dehydrogenase (HSD3B), and 11β-hydroxylase (CYP11B1) are abundantly expressed in tumor cells. In addition, several transcriptional factors have been reported to play pivotal roles in the regulation of these enzymes in CPA, but their correlations with those enzymes above have still remained largely unknown. Therefore, in this study, we examined the status of steroidogenic enzymes and their transcriptional factors in 78 and 15 CPA cases by using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR), respectively. Immunoreactivity of HSD3B2, CYP11B1, CYP17A1, steroidogenic factor-1 (SF1[NR5A1]), GATA6, and nerve growth factor induced-B (NGFIB[NR4A1]) was detected in tumor cells. Results of qPCR analysis revealed that expression of HSD3B2 mRNA was significantly higher than that of HSD3B1, and CYP11B1 mRNA was significantly higher than CYP11B2. In addition, the expression of CYP11B1 mRNA was positively correlated with those of NR5A1, GATA6, and NR4A1. These results all indicated that HSD3B2 but not HSD3B1 was mainly involved in cortisol overproduction in CPA. In addition, NR5A1, GATA6, and NR4A1 were all considered to play important roles in cortisol overproduction through regulating CYP11B1 gene transcription.
Sakai M, Martinez-Arguelles DB, Aprikian AG, et al.De novo steroid biosynthesis in human prostate cell lines and biopsies.
Prostate. 2016; 76(6):575-87 [PubMed
] Related Publications
BACKGROUND: Intratumoral androgen formation may be a factor in the development of prostate cancer (PCa), particularly castration-resistant prostate cancer (CRPC). To evaluate the ability of the human prostate to synthesize de novo steroids, we examined the expression of key enzymes and proteins involved in steroid biosynthesis and metabolism.
METHODS: Using TissueScan™ Cancer qPCR Arrays and quantitative RT-PCR, we performed comparative gene expression analyses between various prostate cell lines and biopsies, including normal, hyperplastic, cancerous, and androgen-deprived prostate cells lines, as well as normal, benign prostate hyperplasia (BPH), PCa, and CRPC human specimens. These studies were complemented with steroid biosynthesis studies in normal and BPH cells.
RESULTS: Normal human prostate WPMY-1 and WPE1-NA22, benign prostate hyperplasia BPH-1, and cancer PC-3, LNCaP, and VCaP cell lines, as well as normal, BPH, PCa, and CRPC specimens, were used. Although all cell lines express mRNA encoding for hydroxymethylglutaryl-CoA reductase (HMGCR), the mitochondrial translocator protein TSPO and cholesterol side chain cleavage enzyme CYP11A1 were only observed in WPMY-1, BPH-1, and LNCaP cells. HSD3B1, HSD3B2, and CYP17A1 are involved in androgen formation and were not found in most cell lines. WPE1-NA22 and BPH-1 cells were unable to synthesize de novo steroids from mevalonate. Moreover, androgen-deprived cells did not have alterations in the expression of enzymes that could lead to de novo steroid formation. All prostate specimens expressed TSPO and CYP11A1. HSD3B1/2, CYP17A1, HSD17B5, and CYP19A1 mRNA expression was distinct to the profile observed in cells lines. The majority of BPH (90.9%) and PCa (83.1%) specimens contained CYP17A1, compared to control (normal) specimens (46.7%). BPH (82%), PCa (59%), normal (40%), and CRPC (34%) specimens expressed the four key enzymes that metabolize cholesterol to androgens.
CONCLUSION: These studies question the use of prostate cell lines to study steroid biosynthesis and demonstrate that human prostate samples contain transcripts encoding for key steroidogenic enzymes and proteins indicating that they have the potential to synthesize de novo steroids. We propose CYP17A1 as a candidate enzyme that can be used for patient stratification and treatment in BPH and PCa.
Hagberg Thulin M, Nilsson ME, Thulin P, et al.Osteoblasts promote castration-resistant prostate cancer by altering intratumoral steroidogenesis.
Mol Cell Endocrinol. 2016; 422:182-191 [PubMed
] Related Publications
The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP-19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches.
Plaza-Parrochia F, Poblete C, Gabler F, et al.Expression of steroid sulfated transporters and 3β-HSD activity in endometrium of women having polycystic ovary syndrome.
Steroids. 2015; 104:189-95 [PubMed
] Related Publications
Intracrinology mechanism involves the metabolism of steroids in peripheral tissues, such as DHEA, to molecules with estrogenic or androgenic activity. Proliferation rate of endometria from Polycystic Ovary Syndrome women (PCOS) is increased, favoring hyperplasia development. Besides, in endometria from PCOS-women the synthesis of androst-5-ene-3β,17β-diol (androstenediol), an estrogenic molecule, is enhanced concomitantly to increased cellular proliferation. DHEA, the major intracrinological precursor, circulates mainly in its sulfated form and requires transporters for cell intake, that belong to the families of organic anion transporting polypeptides (OATP) and organic anion transporters (OAT). The aim of this study was to determine protein levels and activity of sulfated steroid transporters OATP2B1, OATP3A1, OATP4A1 and OAT4 in endometria from control and PCOS-women and to evaluate the activity of the enzyme 3β-HSD. Levels of transporters were done by RT-PCR (OAT4 only) and Western-blot (WB). Additionally, in primary culture cells stimulated with steroids, protein levels by WB and uptake of tritiated DHEAS, were evaluated; 3β-HSD activity was assessed using radiolabel substrate. PCOS-endometrium had higher levels of OATP2B1 and OATP4A1 than CE (p<0.05); decreased OATP4A1 levels were found in androstenediol or testosterone-stimulated cells. Accordingly, the entry of DHEAS to cells was lower in cells stimulated with testosterone (p<0.05); 3β-HSD-activity was similar in control and PCOS-endometria. Therefore, this study describes that steroids can modulate the expression and activity of transporters of OATPs-family in human endometria and that some transporter levels are increased in PCOS-endometria, suggesting a potential role in the pathogenesis of endometrial hyperplasia of these patients.
Assinder SJ, Davies K, Surija J, Liu-Fu FOxytocin differentially effects 3β-hydroxysteroid dehydrogenase and 5α-reductase activities in prostate cancer cell lines.
Peptides. 2015; 71:149-55 [PubMed
] Related Publications
It is known that oxytocin stimulates steroidogenesis in several organs by modulating activity of 3β-hydroxysteroid dehydrogenases (HSD3B) and steroid 5α-reductases (SRD5A). However, this has not been established in prostate cancer where these enzymes, key to local production of androgens, are increased. Analysis of both HSD3B and SRD5A activities using a live cell in situ colourimetric assay demonstrated that in PC-3 cells HSD3B activity was significantly increased by oxytocin whilst SRD5A activity was unchanged. This was confirmed in ELISA based assays of conversion of pregnenolone to progesterone and testosterone to dihydrotestosterone in cell lysates following treatment. In contrast, oxytocin significantly inhibited HSD3B activity in LNCaPs, but significantly increased activity of SRD5A, as confirmed by ELISA assays. Analysis of both cell lines by microarray and qRT-PCR determined that these changes were not due to altered gene transcription. This study demonstrates differential effects of oxytocin on the activities of key de novo steroidogenic enzymes in prostate cancer cells.
Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.
BACKGROUND: 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (DHT), may be a promising target for treating castration-resistant prostate cancer (CRPC).
METHODS: From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen-deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause-specific mortality rates were determined during the 3-10 years follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time.
RESULTS: Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs. 64.7%, respectively; P = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence were different between the variant and wild-type groups.
CONCLUSION: Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk.
Lottrup G, Nielsen JE, Skakkebæk NE, et al.Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours.
Eur J Endocrinol. 2015; 172(4):491-9 [PubMed
] Related Publications
OBJECTIVE: Testicular adrenal rest tumours (TARTs) are a common finding in patients with congenital adrenal hyperplasia (CAH). These tumours constitute a diagnostic and management conundrum and may lead to infertility. TART cells share many functional and morphological similarities with Leydig cells (LCs), and masses consisting of such cells are occasionally misclassified as malignant testicular tumours, which may lead to erroneous orchiectomy in these patients.
DESIGN: In this study, we aimed to investigate the potential of LC developmental markers and adrenal steroidogenic markers in the differential diagnosis of TARTs and malignant LC tumours (LCTs).
METHODS: We investigated mRNA and protein expression of testicular steroidogenic enzymes; CYP11A1 and HSD3B1/2, markers of adrenal steroidogenesis; CYP11B1, CYP21A2 and ACTH receptor/melanocortin 2 receptor (MC2R), and markers of LC maturation; and delta-like 1 homolog (DLK1) and insulin-like 3 (INSL3) in testicular biopsies with TART, orchiectomy specimens with LCTs and samples from human fetal adrenals.
RESULTS: Expression of testicular steroidogenic enzymes was observed in all specimens. All investigated adrenal steroidogenic markers were expressed in TART, and weak reactions for CYP11B1 and MC2R were observed at the protein level in LTCs. TART and fetal adrenals had identical expression profiles. DLK1 was highly expressed and INSL3 not detectable in TART, whereas INSL3 was highly expressed in LCTs.
CONCLUSIONS: The similar expression profiles in TART and fetal adrenals as well as the presence of classical markers of adrenal steroidogenesis lend support to the hypothesis that TART develops from a displaced adrenal cell type. Malignant LCTs seem to have lost DLK1 expression and do not resemble immature LCs. The different expression pattern of DLK1, INSL3 and most adrenocortical markers adds to the elucidation of the histogenesis of testicular interstitial tumours and may facilitate histopathological diagnosis.
It has become important to evaluate the possible involvement of 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) and 2 (HSD3B2) isoforms in aldosterone-producing adenoma (APA). In this study, we studied 67 and 100 APA cases using real-time quantitative PCR (qPCR) and immunohistochemistry, respectively. Results of qPCR analysis demonstrated that HSD3B2 mRNA was significantly more abundant than HSD3B1 mRNA (P < 0.0001), but only HSD3B1 mRNA significantly correlated with CYP11B2 (aldosterone synthase) mRNA (P <0.0001) and plasma aldosterone concentration (PAC) of the patients (P <0.0001). Results of immunohistochemistry subsequently revealed that HSD3B2 immunoreactivity was detected in the great majority of APA but a significant correlation was also detected between HSD3B1 and CYP11B2 (P <0.0001). In KCNJ5 mutated APA, CYP11B2 mRNA (P <0.0001) and HSD3B1 mRNA (P = 0.011) were significantly higher than those of wild type APA. These results suggest that HSD3B1 is involved in aldosterone production, despite its lower levels of expression compared with HSD3B2, and also possibly associated with KCNJ5 mutation in APA.
Nyante SJ, Gammon MD, Kaufman JS, et al.Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects.
Cancer Causes Control. 2015; 26(1):121-31 [PubMed
] Free Access to Full Article Related Publications
PURPOSE: To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina.
METHODS: Cases (n = 1,972) were women 20-74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r (2) statistic. Odds ratios (ORs) and 95 % confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values <3.3 × 10(-4) were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n = 679) and basal-like (n = 200), were based on the Wald statistic.
RESULTS: ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95 % CI 1.51-3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95 % CI 1.43-3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95 % CI 1.14-1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r (2) = 0.70; whites r (2) = 0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER-, and unclassified subtypes.
CONCLUSIONS: ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.
Khvostova EP, Otpuschennikov AA, Pustylnyak VO, Gulyaeva LFGene expression of androgen metabolising enzymes in benign and malignant prostatic tissues.
Horm Metab Res. 2015; 47(2):119-24 [PubMed
] Related Publications
Benign prostatic hyperplasia (BPH) as well as prostate cancer (CaP) are prevalent in the aging male population, and both the diseases display androgen-dependence when the circulating testosterone from the gonads decreases. This suggests that the local or intracrine production of androgens may drive these diseases. Both diseases are dependent on the conversion of androgen by the epithelial compartment to the ligand with higher affinity and can be treated by blocking synthesis of this androgen metabolite. For this approach to be effective, a detailed knowledge of androgen biosynthesis in both disease states is required. The aim of the present study was to investigate the gene expression levels of androgen metabolising enzymes in BPH compared to normal adjacent prostate tissues and CaP. Expression of the genes HSD3B1, HSD17B3, and SRD5A2 was significantly increased in BPH tissues compared to normal adjacent prostate tissues. In contrast to BPH, CaP demonstrated significant decrease in the expression of HSD17B3, AKR1C2, and SRD5A2 compared to normal adjacent prostate tissues. HSD17B2 expression was significantly decreased in all samples. Moreover, HSD3B1 and SRD5A2 mRNA levels were upregulated in BPH compared with CaP. These results suggest that a change in androgen metabolism may be an important step in the pathogenesis of BPH, leading to increased cell proliferation due to in situ androgen synthesis. These features can be used to develop differential treatment strategies for BPH. HSD3B1 and SRD5A2 could be used as therapeutic target for BPH.
Hogg K, Robinson WP, Beristain AGActivation of endocrine-related gene expression in placental choriocarcinoma cell lines following DNA methylation knock-down.
Mol Hum Reprod. 2014; 20(7):677-89 [PubMed
] Related Publications
Increasingly, placental DNA methylation is assessed as a factor in pregnancy-related complications, yet the transcriptional impact of such findings is not always clear. Using a proliferative in vitro placental model, the effect of DNA methylation loss on gene activation was evaluated at a number of genes selected for being differentially methylated in pre-eclampsia-associated placentae in vivo. We aimed to determine whether reduced DNA methylation at specific loci was associated with transcriptional changes at the corresponding gene, thus providing mechanistic underpinnings for previous clinical findings and to assess the degree of transcriptional response amongst our candidate genes. BeWo and JEG3 choriocarcinoma cells were exposed to 1 μM 5-Aza-2'-deoxycytidine (5-Aza-CdR) or vehicle control for 48 h, and re-plated and cultured for a further 72 h in normal media before cells were harvested for RNA and DNA. Bisulphite pyrosequencing confirmed that DNA methylation was reduced by ∼30-50% points at the selected loci studied in both cell lines. Gene activation, measured by qRT-PCR, was highly variable and transcript specific, indicating differential sensitivity to DNA methylation. Most notably, loss of DNA methylation at the leptin (LEP) promoter corresponded to a 200-fold and 40-fold increase in LEP expression in BeWo and JEG3 cells, respectively (P < 0.01). Transcripts of steroidogenic pathway enzymes CYP11A1 and HSD3B1 were up-regulated ∼40-fold in response to 5-Aza-CdR exposure in BeWo cells (P < 0.01). Other transcripts, including aromatase (CYP19), HSD11B2, inhibin (INHBA) and glucocorticoid receptor (NR3C1) were more moderately, although significantly, affected by loss of associated DNA methylation. These data present a mixed effect of DNA methylation changes at selected loci supporting cautionary interpretation of DNA methylation results in the absence of functional data.
Hanamura T, Niwa T, Gohno T, et al.Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.
Breast Cancer Res Treat. 2014; 143(1):69-80 [PubMed
] Related Publications
Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes to ER activation, especially postmenopause. These pathways might function as an alternative estrogenic steroid-producing, aromatase-independent pathways.
Szabó DR, Baghy K, Szabó PM, et al.Antitumoral effects of 9-cis retinoic acid in adrenocortical cancer.
Cell Mol Life Sci. 2014; 71(5):917-32 [PubMed
] Related Publications
The currently available medical treatment options of adrenocortical cancer (ACC) are limited. In our previous meta-analysis of adrenocortical tumor genomics data, ACC was associated with reduced retinoic acid production and retinoid X receptor-mediated signaling. Our objective has been to study the potential antitumoral effects of 9-cis retinoic acid (9-cisRA) on the ACC cell line NCI-H295R and in a xenograft model. Cell proliferation, hormone secretion, and gene expression have been studied in the NCI-H295R cell line. A complex bioinformatics approach involving pathway and network analysis has been performed. Selected genes have been validated by real-time qRT-PCR. Athymic nude mice xenografted with NCI-H295R have been used in a pilot in vivo xenograft model. 9-cisRA significantly decreased cell viability and steroid hormone secretion in a concentration- and time-dependent manner in the NCI-H295R cell line. Four major molecular pathways have been identified by the analysis of gene expression data. Ten genes have been successfully validated involved in: (1) steroid hormone secretion (HSD3B1, HSD3B2), (2) retinoic acid signaling (ABCA1, ABCG1, HMGCR), (3) cell-cycle damage (GADD45A, CCNE2, UHRF1), and the (4) immune response (MAP2K6, IL1R2). 9-cisRA appears to directly regulate the cell cycle by network analysis. 9-cisRA also reduced tumor growth in the in vivo xenograft model. In conclusion, 9-cisRA might represent a promising new candidate in the treatment of hormone-secreting adrenal tumors and adrenocortical cancer.
Hanamura T, Niwa T, Nishikawa S, et al.Androgen metabolite-dependent growth of hormone receptor-positive breast cancer as a possible aromatase inhibitor-resistance mechanism.
Breast Cancer Res Treat. 2013; 139(3):731-40 [PubMed
] Related Publications
Aromatase inhibitors (AIs) have been reported to exert their antiproliferative effects in postmenopausal women with hormone receptor-positive breast cancer not only by reducing estrogen production but also by unmasking the inhibitory effects of androgens such as testosterone (TS) and dihydrotestosterone (DHT). However, the role of androgens in AI-resistance mechanisms is not sufficiently understood. 5α-Androstane-3β,17β-diol (3β-diol) generated from DHT by 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1) shows androgenic and substantial estrogenic activities, representing a potential mechanism of AI resistance. Estrogen response element (ERE)-green fluorescent protein (GFP)-transfected MCF-7 breast cancer cells (E10 cells) were cultured for 3 months under steroid-depleted, TS-supplemented conditions. Among the surviving cells, two stable variants showing androgen metabolite-dependent ER activity were selected by monitoring GFP expression. We investigated the process of adaptation to androgen-abundant conditions and the role of androgens in AI-resistance mechanisms in these variant cell lines. The variant cell lines showed increased growth and induction of estrogen-responsive genes rather than androgen-responsive genes after stimulation with androgens or 3β-diol. Further analysis suggested that increased expression of HSD3B1 and reduced expression of androgen receptor (AR) promoted adaptation to androgen-abundant conditions, as indicated by the increased conversion of DHT into 3β-diol by HSD3B1 and AR signal reduction. Furthermore, in parental E10 cells, ectopic expression of HSD3B1 or inhibition of AR resulted in adaptation to androgen-abundant conditions. Coculture with stromal cells to mimic local estrogen production from androgens reduced cell sensitivity to AIs compared with parental E10 cells. These results suggest that increased expression of HSD3B1 and reduced expression of AR might reduce the sensitivity to AIs as demonstrated by enhanced androgen metabolite-induced ER activation and growth mechanisms. Androgen metabolite-dependent growth of breast cancer cells may therefore play a role in AI-resistance.
Huuskonen P, Myllynen P, Storvik M, Pasanen MThe effects of aflatoxin B1 on transporters and steroid metabolizing enzymes in JEG-3 cells.
Toxicol Lett. 2013; 218(3):200-6 [PubMed
] Related Publications
Effects of 96 h aflatoxin B1 (AFB1) exposure at concentrations from 0.2 μM to 6 μM on the mRNA and protein expression levels of the following transporters ABCB1/B4, ABCC1, ABCC2, ABCG2, OAT4 and the mRNA expression of steroid-metabolizing enzymes CYP1A1, CYP19A1, HSD3B1 and HSD17B1, and conjugating enzyme family UGT1A were evaluated in trophoblastic JEG-3 cells. Statistically significant dose-dependent five-fold increases in the expression levels with ABCC2 and OAT4 were recorded at 2 and 6μM AFB1. Protein expression of ABCG2 was decreased dose-dependently with 0.2-6 μM AFB1. With the other transporters, only a trend of increased expression was observed. Analogously, a three-fold increase in the expressions of CYP19A1, HSD3B1, HSD17B1 and UGT1A-family were observed at 0.3 μM AFB1. When an inhibitor of CYP19A1, finrozole, was dosed simultaneously with AFB1, no increases in the transcripts of transporters or steroid hydroxylases or CYP19A1 were observed. This delayed increase in the expression levels - only after 96h incubations - may indicate that the response is due to a secondary metabolite of AFB1 or other secondary controlling cascades rather than the parent compound itself. In conclusion, AFB1 affected the placental steroid synthesizing, metabolizing and conjugating enzymes as well as the expression levels of several transporter proteins in JEG-3 cells. These alterations may lead to anomalies in the foetoplacental hormonal homeostasis.
Bladder cancer is the 4(th) most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR) and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62). This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63). The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25) than females (OR 1.56 95%CI 0.83-2.95), (SNP-gender interaction P = 0.048). We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003). The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.
Arai S, Shibata Y, Nakamura Y, et al.Development of prostate cancer in a patient with primary hypogonadism: intratumoural steroidogenesis in prostate cancer tissues.
Andrology. 2013; 1(1):169-74 [PubMed
] Related Publications
Intratumoural steroidogenesis may play a significant role in the progression of prostate cancer (PC) in the context of long-term ablation of circulating testosterone (T). To clarify the mechanism accounting for the progression of PC in a 74-year-old man who had undergone bilateral orchiectomy when he was 5 years old, we performed immunohistochemical studies of androgen receptor (AR) and steroidogenic enzymes in the prostate. We also measured steroid hormone levels in the serum and prostate, as well as mRNA levels of genes mediating androgen metabolism in the prostate. Positive nuclear staining of AR was detected in malignant epithelial cells. The levels of androstenedione (Adione), T, and 5-alpha dihydrotestosterone (DHT) in the serum of the patient were similar to those in PC patients receiving neoadjuvant androgen deprivation therapy (ADT), but were higher in the patient's prostate than in PC patients not receiving ADT. The gene expression of CYP17A1 and HSD3B1 was not detected, whereas that of STS, HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected. Moreover, cytoplasmic staining of HSD3B2, AKR1C3, SRD5A1, and SRD5A2 was detected in malignant epithelial cells. Hence, in the present case (a man with primary hypogonadism), steroidogenesis in PC tissues from adrenal androgens, especially dehydroepiandrosterone sulphate, was the mechanism accounting for progression of PC. This mechanism might help elucidate the development of castration-resistant PC.
Sinreih M, Hevir N, Rižner TLAltered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer.
Chem Biol Interact. 2013; 202(1-3):210-7 [PubMed
] Related Publications
Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. It is associated with prolonged exposure to estrogens that is unopposed by the protective effects of progesterone, which suggests that altered progesterone biosynthesis, metabolism and actions might be implicated in the development of EC. Our aim was to evaluate these processes through quantitative real-time PCR expression analysis in up to 47 pairs of EC tissue and adjacent control endometrium. First, we examined the expression of genes encoding proteins associated with progesterone biosynthesis: steroidogenic acute regulatory protein (STAR); a side chain cleavage enzyme (CYP11A1); and 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase (HSD3B). There were 1.9- and 10.0-fold decreased expression of STAR and CYP11A1, respectively, in EC versus adjacent control endometrium, with no significant differences in the expression of HSD3B1 and HSD3B2. Next, we examined expression of genes encoding five progesterone metabolizing enzymes: the 3-keto and 20-ketosteroid reductases (AKR1C1-AKR1C3) and 5α-reductases (SRD5A1 and SRD5A2); and the opposing 20α-hydroxysteroid dehydrogenase (HSD17B2). These genes are expressed in EC and adjacent control endometrium. No statistically significant differences were seen in mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1. Expression of HSD17B2 was 3.0-fold increased, and expression of SRD5A2 was 3.7-fold decreased, in EC versus adjacent control endometrium. We also examined mRNA levels of progesterone receptors A and B (PGR), and separately the expression of progesterone receptor B (PR-B). Here we saw 1.8- and 2.0-fold lower mRNA levels of PGR and PR-B, respectively, in EC versus adjacent control endometrium. This down-regulation of STAR, CYP11A1 and PGR in endometrial cancer may lead to decreased progesterone biosynthesis and actions although the effects on progesterone levels should be further studied.
Lévesque É, Huang SP, Audet-Walsh É, et al.Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression.
Clin Cancer Res. 2013; 19(3):699-709 [PubMed
] Related Publications
PURPOSE: Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression.
EXPERIMENTAL DESIGN: The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen-deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry-based methods.
RESULTS: After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29-4.10; P = 0.0014-2 × 10(-7)) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71-8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05).
CONCLUSION: This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression.
Lichtenauer UD, Shapiro I, Osswald A, et al.Characterization of NCI-H295R cells as an in vitro model of hyperaldosteronism.
Horm Metab Res. 2013; 45(2):124-9 [PubMed
] Related Publications
In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3βHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line.
BACKGROUND: The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study.
METHODS: In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results.
RESULTS: Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI] = 1.22 [1.01-1.48], 1.31 [1.03-1.66], 3.03 [1.12-8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk.
CONCLUSIONS: Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility.