No association of the 5' promoter region polymorphism of CYP17 gene with prostate cancer risk

CYP17 gene encodes the enzyme cytochrome p450c17alpha, which mediates two steps in the steroid biosynthesis pathway. Steroid hormones are believed to play a key role in the etiology of prostate cancer. A polymorphic T-->C transition in the 5(') promoter region of CYP17 creates an additional Sp1-type (CCACC box) promoter site (allele A2). We have evaluated the genotypic and allelic distribution of this polymorphism among 92 prostate cancer patients in order to assess risk by comparison with a population-based series of 200 healthy individuals from Brazil. Our results provide no evidence for an association between prostate cancer risk and CYP17 T/C polymorphism.     

Polymorphism of cytochrome P450 2B6 and prostate cancer risk: A significant association in a Japanese population

Objectives:   To explore whether Lys262Arg polymorphism of the Cytochrome P450 2B6 (CYP2B6) gene could act as a genetic marker for prostate cancer risk among Japanese men.
Methods:   A total of 350 patients with sporadic prostate cancer and 328 controls were examined. A single nucleotide polymorphism with non-synonymous amino acid change located at Lys262Arg of the CYP2B6 gene was genotyped using a TaqMan assay.
Results:   The frequency of the Arg/Arg genotype among prostate cancer patients was significantly higher than that among the controls ( P  = 0.027). The frequency of the G allele of the Lys262Arg polymorphism was also significantly higher in prostate cancer patients than in the controls (30.4% vs 24.8%, P  = 0.025). Patients with the Lys/Arg plus Arg/Arg genotypes carried a low Gleason score more frequently than those with the Lys/Lys genotype ( P  = 0.042). The frequency of the G allele of the Lys262Arg polymorphism was significantly higher in the low Gleason score group than that in the high Gleason score group (34.3% vs 26.8%, P  = 0.038).
Conclusions:   Lys262Arg polymorphism of the CYP2B6 gene may be a genetic marker for evaluating the risk of sporadic prostate cancer in native Japanese men.     

老年男性CYP17基因多态性与血性激素水平的关系

目的:探讨CYP17基因多态性与老年男性血性激素水平的关系。方法:83例正常男性平均年龄66.7岁,分为<66.7岁组(36例)和>66.7岁组(47例),分别提取他们的血DNA标本。设计引物通过PCR技术扩增出包括CYP17基因多态位点的片段,用限制性内切酶MspA1Ⅰ进行酶切,确定出CYP17基因的3种基因型,即A1/A1、A1/A2、A2/A2,并经测序证实。同时测定血清中睾酮(T)和雌二醇(E2)水平。结果:3种基因型之间的T和E2水平差异均无显著性;年龄>66.7岁组与<66.7岁组比较,T和E2水平差异无显著性,但T/E2比值显著升高(P<0.05)。结论:CYP17基因的多态性并未使男性体内的性激素水平发生显著性差异,随着年龄增加,T水平虽有所下降,但T/E2比值却有显著增加,这可能与老年男性前列腺增生和前列腺癌的发生有密切关系。     

Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease

Growth factor-related genes regulate cell growth, differentiation and apoptosis in the kidney in response to cellular injury. One of the theories of stone formation is that cellular injury, and thus growth factors, play a role. We therefore investigated the association between growth factor genes and calcium oxalate stone disease. The most frequently seen polymorphism of the vascular endothelial growth factor (VEGF) gene is Bst U I C/T, which is located upstream at the -460th nucleotide. Other growth factor-related gene polymorphisms include the cytochrome P450c17alpha enzyme (CYP17) gene MspA I C/T polymorphism at the 5'-UTR promoter region, the epidermal growth factor receptor (EGFR) gene Bsr I polymorphism (A to T) at position 2,073, and the insulin-like growth factor-2 (IGF-2) gene Apa I A/G at exon 9. All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes. A normal control group of 230 healthy people, and 230 patients with calcium oxalate stone, were examined. The polymorphism was seen following polymerase chain reaction based restriction analysis. The result revealed a significant difference between normal individuals and stone patients (P=0.0003, Fisher's exact test) in the distribution of the VEGF gene polymorphism as well as an odds ratio of 1.30 (95% confidence interval=0.993-1.715) per copy of the "T" allele. Whereas, the IGF-2, EGFR and CYP17 gene polymorphisms did not reveal a significant association with stone disease. We conclude that the VEGF gene Bst U I polymorphism is a suitable genetic marker of urolithiasis.     

E-cadherin gene 3'-UTR C/T polymorphism is associated with prostate cancer

INTRODUCTION: E-cadherin (CDH-1) is a cell-cell adhesive molecule which maintains cell integrity and communication between the intracellular and extracellular world. CDH-1 may therefore be related to carcinogenesis. A polymorphism located at the 3'-UTR of the CDH-1 gene is associated with stone disease; however, its relationship to prostate cancer has not been reported. We aimed to study whether there is an association between the 3'-UTR polymorphism and prostate cancer. MATERIALS AND METHODS: We collected 96 patients with prostate cancer and 114 normal controls for this study. The polymorphism of the CDH-1 gene was studied by polymerase chain reaction-based restriction analysis. RESULTS: There was a significant difference in genotype distribution of the CDH-1 gene polymorphism between cancer patients and normal controls (p < 0.001). The distribution of the CDH-1 gene CC genotype in prostate cancer patients (51.0%) was higher than in the controls (10.5%). The odds ratio for the CDH-1 'C' allele was 2.896 (95% CI = 1.908-4.396). There was no significant difference according to age, pathological grading, clinical staging, and responsiveness to hormonal therapy among patients. Only 3 patients (3.1%) had a history of urolithiasis. CONCLUSIONS: The CDH-1 gene 3'-UTR C/T polymorphism is associated with prostate cancer. The 'CC' homozygote indicates a relatively higher risk for developing prostate cancer than other genotypes.     

前列腺癌发生风险与CYP3A5基因多态性的关系

目的 探讨CYP3A5基因多态性与前列腺癌发生风险和病理特点的关系。方法 采用限制性片段多态性分析法对356例前列腺癌患者和306个男性对照中CYP3A5基因第3内含子多态性进行了研究。结果 在前列腺癌和对照组之间CYP3A5基因型分布差异无显著性(P=0．063)，但两组间CYP3A5*1等位基因的分布差异存在显著性(P=0．025)；与携带CYP3A5*3*3基因型者相比，携带CYP3A5*1等位基因的男性患前列腺癌的风险降低了30％(P=0．026)。在不同分期和分级的前列腺癌患者之间CYP3A5基因型分布差异无显著性(P=0．904和0．986)。结论 CYP3A5基因中的CYP3A5*1等位基因可能与前列腺癌的患病风险降低有关。     

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.     

中国维吾尔族男性CYP17基因多态性与前列腺癌发生的关系

目的:探讨维吾尔族男性CYP17基因多态性与前列腺癌发生危险性的关系。方法:收集31例前列腺癌患者和104例对照组的血液标本并提取DNA,设计引物,通过PCR扩增包括基因多态位点的片段,用限制性内切酶M spA1 I进行酶切,产物在2%琼脂糖凝胶上电泳,确定CYP17基因的3种基因型,即A1/A1、A1/A2、A2/A2,并经测序证实,同时测定血清标本中前列腺特异性抗原(PSA)含量。结果:基因型A1/A2、A2/A2频数与A1/A1比较,A1/A2和A2/A2在前列腺癌中的频数与对照组相比,其OR值分别为1.49和2.87,P值分别为0.321和0.052,肿瘤组3种基因型间的PSA值差异无显著性。而对照组中A1/A2组的PSA值高于A1/A1组,但差异无显著性(P=0.062),而A2/A2组显著高于A1/A1组(P=0.018)。结论:A2/A2基因型在前列腺癌中的频数有显著高于对照组的趋势,提示A2/A2基因型可能与维吾尔族男性前列腺癌发生危险性之间有密切关系,而对照组中A2/A2基因型组的PSA值的显著增高也支持了这一观点。     

Genotyp des GNB3-C825T-Polymorphismus

Background

G protein-mediated signal transduction plays a key role in pathways of metastasis. A C/T polymorphism (dbSNP rs5443) at position 825 of the GNB3 gene has been described. Previous studies demonstrated an association between the GNB3 C825T genotype and different cancer entities.

Patients and methods

In this report genotyping for this marker was performed in 235 prostate cancer patients and 111 healthy control subjects. Clinical follow-up data were available for a subset of 197 patients.

Results

Neither significant evidence for differences in genotype distributions between the prostate cancer cases and controls (odds ratio CT/TT=0.94, 95% CI 0.58?C1.51, p=.82) nor evidence for genotype differences in e.g. progression-free survival in the subset of patients was observable (hazard ratio CT/TT=0.77, 95% CI 0.44?C1.37, p=.38). Similar results were obtained in the subgroup of patients with primary tumor stage ?? pT2 N0 M0 undergoing radical prostatectomy.

Conclusion

Our data do not support an association between prostate cancer and the genotype of the GNB3 C825T polymorphism. This finding might either indicate a much smaller genetic effect undetectable with the given sample size or a possible hormone dependence of the disease superimposed on the potential effect of the GNB3 C825T genotype.     

Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway

BACKGROUND: Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS: We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS: We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1 gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS: Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.     

Breast cancer risk associated with CYP1A1 genetic polymorphisms in Japanese women

Although several reports are available on the association between CYP1A1 polymorphisms and breast cancer risk in Caucasian women, it has never been reported in Japanese women. Since breast cancer incidence and clinicopathologic features of breast cancers are different between Japanese and Caucasian women, it is conceivable that the risk factors of breast cancer might also differ. In addition, a preliminary study has shown that the frequencies of the variant allele in the CYP1A1 gene are different among ethnic groups. Therefore, in the present study, we investigated the association of CYP1A1 polymorphisms with breast cancer risk in Japanese women. The association of two CYP1A1 polymorphisms, that is, 3' noncoding region (6235(T/C)) and codon 462 (Ile/Val), with breast cancer risk was analyzed by a case-control study (195 cases and 272 controls). Variant allele 6235C carriers at the 3' noncoding region polymorphism showed a significantly ( p < 0.01) reduced breast cancer risk (odds ratio 0.60; 95% CI 0.41–0.88) as compared with noncarriers, and variant allele 462Val carriers at the codon 462 polymorphism also showed a significantly ( p < 0.05) reduced risk (odds ratio 0.66; 95% CI 0.45–0.96) as compared with noncarriers. The relationship between the genetic polymorphisms and clinicopathologic characteristics of breast cancers was also investigated. Variant allele 6235C carriers showed a significantly ( p < 0.02) higher positivity of lymph node metastasis than noncarriers (54% versus 36%), and tumors measuring less than 2 cm were significantly ( p < 0.03) more frequently observed in variant allele 462Val carriers than noncarriers (50% versus 33%). These results suggest that the CYP1A1 polymorphisms would be useful for predicting breast cancer risk as well as some tumor characteristics in Japanese women.     

Osteocalcin gene HindIII C/T polymorphism is a biomarker for prostate cancer and responsiveness to hormone therapy

OBJECTIVES: Osteocalcin is a vitamin-K dependent protein which is related to the metabolism of bone and calcium. The formation or progression of prostate cancer is presumed to be associated with the osteocalcin gene. The most frequently seen polymorphism is HindIII which is located at the promoter region. HindIII is therefore a possible genetic marker in the search for the association between prostate cancer and normal control subjects. METHODS: In our study, a normal control group of 132 healthy people and 96 patients with prostate cancer were examined. The polymorphism was seen following polymerase chain reaction (PCR) based restriction analysis. RESULTS: The result revealed significant differences between normal individuals and cancer patients (p=0.034) and the distribution of the "CC" homozygote in the control group was higher than that in the patient group. No statistical differences were found in clinical staging and grading. The 54 patients who received hormone therapy were further categorized into response and non-response groups, statistical differences between these two groups were revealed (p=0.007, Fisher's exact test). CONCLUSIONS: Based on our results, we conclude that the HindIII polymorphism of the osteocalcin gene is a suitable genetic marker of prostate cancer which can be used in the prediction of the outcome of patients who receive hormone therapy.     

Incidence of genetic polymorphisms involved in lipid metabolism among Chinese patients with osteonecrosis of the femoral head

Background and purpose Corticosteroid treatment is associated with osteonecrosis of the femoral head (ON) in certain patients. The degree of drug sensitivity in general is governed by genetic variation between individuals. We investigated the relationship between ON and the presence of different alleles of the cytochrome P450 gene (CYP3A4), the product of which metabolizes corticosteroids, and of the P-glycoprotein (P-gp) gene (ABCB1), the product of which modulates cellular uptake of corticosteroids, to determine whether patients with certain alleles may be at higher risk of ON after corticosteroid treatment.Methods We studied 31 patients from Guangdong, China who were both treated with corticosteroid therapy and developed ON, and 17 corticosteroid-therapy patients without ON. Patient DNA was screened for known polymorphisms in the CYP3A4 gene (CYP3A4*4, CYP3A4*5, CYP3A4*6) and the P-gp gene ABCB1 (mutations C3435T, G2677T/A).Results The majority (20/31) of the corticosteroid-treated patients who developed ON were heterozygous for ABCB1, whereas only 3/17 without ON were heterozygous. Statistical significance was observed between the ON and the control groups for the ABCB1 G2677T/A polymorphism. Analysis of haplotypic frequencies indicated significant linkage disequilibrium between the two ABCB1 polymorphisms, C3435T and G2677T/A (D'' = 0.034). No CYP3A4 polymorphisms were detected in any of the patients.Interpretation Patients carrying an ABCB1 polymorphism had a higher risk of having corticosteroid-associated ON than those with wild-type genotypes. This statistically significant association conflicts with previous studies, possibly due to different sampling methods. Knowing which genetic backgrounds are most strongly associated with corticosteroid-associated ON provides a method of screening for patients who are most at risk of developing ON.     

Association of Urokinase Gene 3'-UTR T/C polymorphism with bladder cancer

INTRODUCTION: Bladder cancer is a disease characterized by multiple recurrences. Some investigators assume urokinase to be involved in the causation of bladder cancer, although there is lack of genetic evidence. Our aim was to evaluate whether polymorphism of the urokinase gene is associated with transitional cell carcinoma (TCC) of the urinary bladder. MATERIALS AND METHODS: The study included 100 patients (mean age 62.5 +/- 10.2 years) with TCC of urinary bladder and 150 healthy controls (mean age 60 +/- 11.5 years) living in the same area. Polymerase chain reaction (PCR)-based restriction analysis was used to identify the C/T polymorphism of the urokinase gene. Genotyping distribution and allelic frequencies between patients and controls were compared. RESULTS AND CONCLUSION: There was a significant difference in the frequency distribution of the urokinase gene 3'-UTR C/T polymorphism in bladder cancer patients as compared to the normal control group (p < 0.05), but no significant difference in allelic frequencies or in carriage rates between bladder cancer patients and normal controls were observed. Our study suggests that urokinase gene polymorphism may be associated with bladder cancer and can thus serve as a potential genetic marker in screening for the possible causes of bladder cancer. Perhaps analysis of patients with superficial bladder TCC and mutated urokinase might help clarify this aspect in large cohort studies in different populations.     

Genetic impact on prostate anatomical variability during ageing: role of CYP17, SRD5A2 and androgen receptor genes polymorphisms

OBJECTIVES: To investigate the role of genetic determinism on individual variability in age-related prostate changes, as defining 'normal' anatomy in prostate gland ageing is a challenge because the variability of changes in prostate morphology increases with age. MATERIALS AND METHODS: We assessed the influence of androgen- and oestrogen-regulating genetic polymorphisms on age-related weight and stromal-ratio changes in the prostate, using an anatomical, autopsy-based study. We quantified weight and glandular/stromal ratio in 85 autopsy prostates from men aged > 50 years. We genotyped allelic variants of androgen-regulating genes [androgen receptor (CAG repeats) and type II 5-alpha reductase (TA repeat and V89L)] and an oestrogen-regulating gene (A1/A2 variants of the 17alpha-hydroxylase (CYP17)). RESULTS: There was a fair negative correlation between prostate weight and the number of CAG repeats (r = -0.32, P = 0.003); the group with < or = 19 CAG repeats had heavier prostates than the > or = 20 group (P = 0.015). The stromal ratio was higher in the group with 20-23 CAG repeats (P = 0.02) and in the A2A2 group of the CYP17 polymorphism (P = 0.016) compared with the other groups mixed together. CONCLUSION: A low number of CAG repeats is associated with higher prostate weights. The A2A2 genotype of CYP17 is associated with a higher stromal ratio.     

Incidence of genetic polymorphisms involved in lipid metabolism among Chinese patients with osteonecrosis of the femoral head

Background and purpose Corticosteroid treatment is associated with osteonecrosis of the femoral head (ON) in certain patients. The degree of drug sensitivity in general is governed by genetic variation between individuals. We investigated the relationship between ON and the presence of different alleles of the cytochrome P450 gene (CYP3A4), the product of which metabolizes corticosteroids, and of the P-glycoprotein (P-gp) gene (ABCB1), the product of which modulates cellular uptake of corticosteroids, to determine whether patients with certain alleles may be at higher risk of ON after corticosteroid treatment.

Methods We studied 31 patients from Guangdong, China who were both treated with corticosteroid therapy and developed ON, and 17 corticosteroid-therapy patients without ON. Patient DNA was screened for known polymorphisms in the CYP3A4 gene (CYP3A4*4, CYP3A4*5, CYP3A4*6) and the P-gp gene ABCB1 (mutations C3435T, G2677T/A).

Results The majority (20/31) of the corticosteroid-treated patients who developed ON were heterozygous for ABCB1, whereas only 3/17 without ON were heterozygous. Statistical significance was observed between the ON and the control groups for the ABCB1 G2677T/A polymorphism. Analysis of haplotypic frequencies indicated significant linkage disequilibrium between the two ABCB1 polymorphisms, C3435T and G2677T/A (D' = 0.034). No CYP3A4 polymorphisms were detected in any of the patients.

Interpretation Patients carrying an ABCB1 polymorphism had a higher risk of having corticosteroid-associated ON than those with wild-type genotypes. This statistically significant association conflicts with previous studies, possibly due to different sampling methods. Knowing which genetic backgrounds are most strongly associated with corticosteroid-associated ON provides a method of screening for patients who are most at risk of developing ON.     

激素性股骨头坏死的遗传易感性研究

目的以激素性骨坏死的遗传易感性学说评估候选基因多态性与股骨头坏死对激素易感性的相关性。方法2005年10月至2007年10月,收集48例使用激素治疗的患者,其中使用激素治疗后发生股骨头坏死的患者31例,设为实验组;使用激素治疗后未发生股骨头坏死的患者17例,设为对照组。分别从两组患者外周血淋巴细胞中获得基因组DNA并同时进行序列分析测定。结果实验组中分别有22．6％（7／31）和41．9％（13／31）出现C3435T-26和G2677T-21的单核苷酸多态性（single nucleotide polymorphisms,SNPs）。两组对比,ABCB1 G2677T-21的SNPs差异有统计学意义（P=0．0016）,而ABCB1 C3435T-26的SNPs差异无统计学意义（P=1．000）。单元型频率分析显示外显子C3435T和G2677T出现的连锁不平衡具有统计学意义（D＇=0．0343）。CYP3A4-4、CYP3A4-5和CYP3A4-6的测序结果与已发表的研究结果一致,未检测出多态性。结论C3435T-26和G2677T-21的SNPs与激素性股骨头坏死有高度相关性。     

Genetic polymorphisms in CYP17, CYP3A4, CYP19A1, SRD5A2, IGF-1, and IGFBP-3 and prostate cancer risk in African-American men: the Flint Men's Health Study

BACKGROUND: Association studies have examined the significance of several candidate genes based on biological pathways relevant to prostate carcinogenesis, including both the androgen and insulin-like growth factor pathways. Clinical and epidemiologic evidence suggest that androgens, specifically testosterone and dihydrotestosterone (DHT) are important not only in normal prostate growth but in the pathogenesis of prostate cancer. Similarly, the insulin-like growth factor-1 (IGF-1) signaling pathway regulates both cellular proliferation and apoptosis. Therefore, genes involved in the biosynthesis, activation, metabolism and degradation of androgens and the stimulation of mitogenic and antiapoptotic activities of prostate epithelial cells represent important candidates for affecting the development and progression of prostate cancer. METHODS: Using resources from the Flint Men's Health Study, a population-based case control study of African-American men aged 40-79, we evaluated the associations between selected single-nucleotide polymorphisms (SNPs) in the CYP17, CYP3A4, CYP19A1, SDR5A2, IGF1, and IGFBP3 genes and prostate cancer diagnosis in 473 men (131 prostate cancer cases and 342 disease-free controls). RESULTS: We found a significant association between prostate cancer and selected CYP17 SNP genotypes, with the heterozygous genotype conferring decreased risk. Suggestive evidence for association between IGF1 SNPs and prostate cancer were also found. No significant associations were observed between SNPs in the other genes and prostate cancer. CONCLUSIONS: These findings suggest that variation in or around CYP17 and/or IGF1 may be associated with prostate cancer development in the African-American population. Additional studies are needed to determine whether these polymorphisms are indeed associated with prostate cancer risk in African Americans.