CYP1A2基因多态性与前列腺癌的相关性研究

目的:评价CYP1A2基因单核苷酸多态性(SNPs)与前列腺癌分期分级的相关性。方法:对253例良性前列腺增生(BPH)患者与206例去势前列腺癌患者CYP1A2基因中rs2069514-3859(A>G)位点及rs2069525-1707(C>T)位点进行基因测序,并对各基因表型与前列腺癌的分期分级相关性进行统计学分析。结果:BPH及去势前列腺癌患者的两种CYP1A2单核苷酸多态性的发生率无明显差异(P>0.05),其基因多态性与前列腺癌的病理分期均无相关性(P>0.05);但rs2069525-1707(C>T)中含C等位基因型的前列腺癌Gleason评分多在7分以下(P=0.030,OR=4.658,95%CI:1.222～17.754)。结论:CYP1A2基因的SNPs与前列腺癌的病理分级之间可能有一定的相关性,但其发生机制及临床意义有待进一步证实及研究。     

细胞色素P450 2D6*10基因多态性对曲马多药代动力学的影响

目的 探讨细胞色素P450 2D6*10(CYP2D6*10)基因多态性对曲马多药代动力学的影响.方法 辽宁籍汉族健康志愿者,性别不限,年龄22～45岁,体重50～82 kg,身高161～179 cm,经左肘静脉采血2 ml,采用酚/氯仿抽提法提取全血DNA,采用聚合酶链反应.限制性片段长度多态性进行CYP2D6*10基因分型,分为野生型纯合子组(w/w组,n=5)、杂合子组(m/w组,n=8)和突变型纯合子组(m/m组,n=6).右上肢静脉经3 min注射曲马多1.5 ms/kg.分别于注射前、注射后0.25、0.5、1、1.5、2、3、4、6、8、12、16、24、32 h时取血3 ml,测定血浆曲马多及O-去甲基曲马多浓度.采用非房室模型方法计算曲马多曲线下面积(AUG0→∞)、血浆清除率(CL)、血浆消除半衰期(t1/2)、平均滞留时间(MRT)、血浆代谢率(MR)和0-去甲基曲马多峰浓度(Cmax)、达峰时间(Tmax)、AUc..、MRT.结果 与w/w组比较,m/m组曲马多t..和MRT延长,MR降低,O.去甲基曲马多AUC0→∞减少,m/w组曲马多MR降低(P<0.05或0.01);与m/m组比较,m/w组曲马多MR降低(P<0.01).结论 CYP2D6*10基因多态性是引起曲马多药代动力学个体差异的重要遗传因素之一.     

单核苷酸多态性与前列腺癌的研究进展

前列腺癌是影响西方国家男性健康的常见恶性肿瘤,而单核苷酸多态性(SNPs)作为第3代遗传标记可以影响到前列腺癌的发生、发展及预后。相同SNPs在不同种族间和前列腺癌的关系可能存在差异;本文就与前列腺癌相关的基因进行分类,描述不同SNPs与前列腺癌的关系。SNPs可以预测前列腺癌治疗过程中可能的不良反应,同时也可预测前列腺癌的患病风险,但目前仍存在一定的局限。     

1667例汉族前列腺癌人群前列腺癌易感性基因多态性验证分析

目的:前列腺癌在工业化国家发病率居男性恶性肿瘤首位,在我国前列腺癌近年发病率不断上升,成为泌尿系统常见恶性肿瘤。本文通过前列腺癌基因多态性分析研究汉族人群前列腺癌易感性危险位点。方法:取1 667例前列腺癌患者与1 525例对照组外周血样双盲利用Sequenom技术进行40个前列腺癌危险位点的SNP分析。结果:40个公认的前列腺癌位点检测结果有16个位点与前列腺癌明显相关(P<0.05);同时发现在不同人种中位于8q24的1、2、5位点与10q11的MSMB编码区及22q13.2编码TTLL1/BIK区域共同决定前列腺癌易感性。结论:汉族前列腺癌人群前列腺癌基因多态性分析结果显示:rs1465618、rs721048、rs12621278、rs7679673、rs12653946、rs339331、rs1512268、rs10086908、rs16901979、rs1447295、rs10993994、rs10896449、rs902774、rs9600079、rs11649743、rs5759167与前列腺癌易感性明显相关。     

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.     

Cytochrome P450 3A and 2B6 in the developing kidney: implications for ifosfamide nephrotoxicity

Repeated administration of agents (e.g., cancer chemotherapy) that can cause drug-induced nephrotoxicity may lead to acute or chronic renal damage. This will adversely affect the health and well-being of children, especially when the developing kidney is exposed to toxic agents that may lead to acute glomerular, tubular or combined toxicity. We have previously shown that the cancer chemotherapeutic ifosfamide (IF) causes serious renal damage substantially more in younger children (less than 3 years of age) than among older children. The mechanism of the age-related IF-induced renal damage is not known. Our major hypothesis is that renal CYP P450 expression and activity are responsible for IF metabolism to the nephrotoxic chloroacetaldehyde. Presently, the ontogeny of these catalytic enzymes in the kidney is sparsely known. The presence of CYP3A4, 3A5 and 2B6 was investigated in human fetal, pediatric and adult kidney as was the metabolism of IF (both R-IF and S-IF enantiomers) by renal microsomes to 2-dechloroethylifosfamide (2-DCEIF) and 3-dechloroethylifosfamide (3-DCEIF). Our analysis shows that CYP 3A4 and 3A5 are present as early as 8 weeks of gestation. IF is metabolized in the kidney to its two enantiomers. This metabolism can be inhibited with CYP 3A4/5 and 2B6 specific monoclonal inhibitory antibodies, whereby the CYP3A4/5 inhibitory antibody decreased the production of R-3-DCEIF by 51%, while the inhibitory CYP2B6 antibody decreased the production of S-2-DCEIF and S-3-DCEIF by 44 and 43%, respectively, in patient samples. Total renal CYP content is approximately six-fold lower than in the liver.     

Cytochrome P450 2B6 is a growth-inhibitory and prognostic factor for prostate cancer

BACKGROUND: Cytochrome P450s (CYPs) influence the biological effects of carcinogens, drugs and hormones including testosterones. Among them, Cytochrome P450 2B6 (CYP2B6) plays a critical role in the deactivation of testosterone. In the present study, we examined CYP2B6 expression in human prostate tissues and prostate cancer. METHODS: Immunohistochemical analysis was performed in 98 benign and 106 malignant prostate tissues and patients' charts were reviewed for clinical, pathologic and survival data. We also investigated whether stable expression of CYP2B6 in LNCaP (human prostate cancer cell line) influences cellular proliferation. RESULTS: CYP2B6 was abundantly expressed in the normal epithelial cells compared to the prostate cancer cells. Significant immunostaining of CYP2B6 was found in 75 of 106 samples (71%), in the cytoplasm of cancerous tissue samples. CYP2B6 immunoreactivity was inversely correlated with high Gleason score (P < 0.001). Decreased immunoreactivity of CYP2B6 significantly correlated with poor prognosis (P < 0.0001). Univariate and multivariate hazard analyses revealed a significant correlation of decreased CYP2B6 expression with poor cancer-specific survival (P = 0.0028 and 0.0142, respectively). Furthermore, overexpression of CYP2B6 in LNCaP cells significantly decreased testosterone-induced proliferation. CONCLUSIONS: These results demonstrated that decreased expression of CYP2B6 might play a role in the development of prostate cancer, and be useful as the prognostic predictor for human prostate cancer.     

Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes

Tamoxifen has a key role in the management of women with hormone receptor (HR) positive breast cancer. It is the endocrine treatment of choice in premenopausal women with HR positive breast cancer and is also clinically indicated in significant numbers of post-menopausal women who have relative contraindications to aromatase inhibitors. Tamoxifen is a pro-drug that is metabolised to its active metabolites by the cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A, CYP2B6, and CYP2C19. The CYP genes are polymorphic resulting in variable enzyme activity.Retrospective clinical data suggests that specific single nucleotide polymorphisms (SNPs) of CYP2D6 can lead to null or reduced enzyme activity resulting in worse outcomes for those individuals when treated with tamoxifen for HR positive breast cancer. There is however a lack of robust prospective clinical data on this subject. Commercial tests are now available for the genotyping of CYP2D6 with the aim of individualisation of tamoxifen therapy for patients with HR positive breast cancer. Selective serotonin reuptake inhibitor antidepressant drugs such as paroxetine and fluoxetine have also been used to manage tamoxifen induced hot flushes. These drugs potently inhibit the metabolism of tamoxifen by CYP2D6 and thus potentially may lessen the efficacy of tamoxifen. The genetic variations in other enzymes involved in tamoxifen metabolism (CYP3A, CYP2B6, CYP2C19) do not appear to cause any meaningful difference in the efficacy of tamoxifen.This review article will summarize the available published breast cancer data on the interaction between the relevant SNPs for CYP2D6, CYP3A, CYP2B6, and CYP2C19 and the efficacy of tamoxifen, their role in individualisation of hormonal therapy and the role of the commercially available genotyping kits.     

Genetic polymorphisms in the cytochrome P450 1A1 and 2E1 genes, smoking, drinking and prostate cancer susceptibility: A case-control study in a Han nationality population in Southern China

AIM: To investigate the association among the polymorphisms of the cytochrome P450 1A1 and 2E1 genes, smoking, drinking and the risk of prostate cancer (PCa) in a Han nationality population in Southern China. METHODS: A case-control study including 225 PCa patients and 250 age-matched controls was conducted. The six polymorphic sites of the CYP 1A1 and CYP2E1 genes were analysed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or allele-specific PCR technique using genomic DNA isolated from peripheral blood lymphocytes. RESULTS: We found that the CYP1A1 Val/Val genotype significantly increased the risk for PCa (OR, 2.26; 95% CI, 1.09-4.68). In contrast, the CYP2E1 C1/C2 (OR, 0.67; 95% CI, 0.46-0.99) or C2/C2 genotype (OR, 0.31; 95% CI, 0.10-1.00) significantly decreased the risk. Furthermore, the individuals carrying the CYP1A1 Val allele and the CYP2E1 C1/C1 genotype showed the highest risk (OR, 2.50; 95% CI, 1.45-4.29). Though there was no significant difference with smoking history (P = 0.237) or drinking habit (P = 0.499) between cases and controls, a deep smoking habit (OR, 2.02; 95% CI, 1.28-3.17) and heavy smoking history (OR, 1.61; 95% CI, 1.04-2.50) significantly increased the susceptibility of PCa after stratification by smoking method and accumulative smoking amount. Moreover, both the CYP1A1 Val allele (OR, 2.82; 95% CI, 1.49-5.35) and CYP2E1 C1/C1 genotype (OR, 2.57; 95% CI, 1.31-5.02) had obvious interaction with heavy smoking history that significantly raised the risk. We also discovered a significant interaction between the CYP2E1 C1/C1 genotype and drinking (OR, 1.85; 95% CI, 1.04-3.28). CONCLUSIONS: Individuals carrying the CYP1A1 Val allele or the CYP2E1 C1/C1 genotype with a smoking or drinking habit were at increased risk of PCa, which also showed a positive correlation with exposure dose of tobacco.     

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Men fail active surveillance for a variety of reasons; however, no single reliable biomarker has been found to date which will identify these men from the outset. We know that there are about 35 prostate cancer risk alleles which have been discovered to influence risk of prostate cancer, from large‐scale genome‐wide association studies. Some of these have been associated with aggressive prostate cancer. Nobody has examined the potential for these risk alleles to predict men who might fail active surveillance. This study adds to the growing evidence that single nucleotide polymorphisms may be able to identify men who have aggressive prostate cancers, and that this could be part of a risk algorithm used in active surveillance protocols.

OBJECTIVE

• ? To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance.

PATIENTS AND METHODS

• ? We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate‐specific antigen <10 ng/mL, biopsy Gleason ≤6, three or fewer positive cores, ≤50% tumour involvement/core) but instead underwent early radical prostatectomy.
• ? We genotyped these men for 35 CaP risk alleles. We defined ‘unfavourable’ pathological characteristics to be Gleason ≥7 and/or ≥ pT2b in their radical prostatectomy specimen.

RESULTS

• ? In all, 263 men (median age 60 [46–72] years) fulfilled our selection criteria for active surveillance, and 58 of 263 (22.1%) were found to have ‘unfavourable’ pathological characteristics.
• ? The frequencies of three CaP risk alleles (rs1447295 [8q24], P= 0.004; rs1571801 [9q33.2], P= 0.03; rs11228565 [11q13], P= 0.02) were significantly higher in men with ‘unfavourable’ pathological characteristics.
• ? Two other risk alleles were proportionately more frequent (rs10934853 [3q21], P= 0.06; rs1859962 [17q24], P= 0.07) but did not achieve nominal statistical significance.
• ? Carriers of any one of the significantly over‐represented risk alleles had twice the likelihood of unfavourable tumour features (P= 0.03), and carriers of any two had a sevenfold increased likelihood (P= 0.001).
• ? Receiver–operator curve analysis demonstrated an area under the curve of 0.66, suggesting that the number of single nucleotide polymorphisms carried provided discrimination between men with ‘favourable’ and ‘unfavourable’ tumour features in their prostatectomy specimen.

CONCLUSION

• ? In potential candidates for active surveillance, certain CaP risk alleles are more prevalent in patients with ‘unfavourable’ pathological characteristics in their radical prostatectomy specimen.

     

南京地区人群CYP2E1基因多态性及吸烟、饮酒与前列腺癌易感性

目的:探讨Ⅰ相代谢酶细胞色素P450 2E1(CYP2E1)基因RsaⅠ和PstⅠ位点多态性及吸烟、饮酒习惯与前列腺癌(PCa)发病风险的关系,并探讨基因与生活习惯在PCa发病中的联合作用。方法:采用PCR-RFLP技术检测109例原发性PCa患者及202例年龄匹配的男性非肿瘤患者外周血CYP2E1基因RsaⅠ和PstⅠ多态位点的基因型。结果:深吸烟(OR=2.29,95%CI:1.28～4.09)、重度吸烟史(OR=1.81,95%CI:1.02～3.22)等生活习惯为PCa易感因素。CYP2E1 C1/C1基因型与PCa易感性有显著相关(OR=1.71,95%CI:1.04～2.82),且与饮酒的联合作用明显与PCa易感性相关(OR=2.21,95%CI:1.06～4.59)。重度吸烟人群中,携带CYP2E1易感基因型(C1/C1)与不吸烟且携带非易感基因型(C1/C2或C2/C2)个体相比PCa的发病风险显著增高(OR=2.80,95%CI:1.20～6.56)。结论:携带CYP2E1易感基因型(C1/C1)并有烟酒嗜好者PCa的发病风险显著增高,且与烟草的暴露呈显著剂量反应关系。     

单核苷酸多态性与前列腺癌关系的研究进展

单核苷酸多态性(SNP)是第3代遗传标记,有许多显著的特性。近年来出现了许多新的检测SNP的研究方法,如TaqM an探针技术、基因芯片技术、变性高效液相色谱、基质辅助激光解吸附-电离飞行时间质谱和微测序技术等。SNP作为遗传标记在人类多种肿瘤的研究中取得了一定的进展,本文综述了与前列腺癌(PCa)相关的前列腺特异性抗原的应答元件、酶类、激素及其受体、细胞周期调节蛋白、细胞因子、粘附分子及维生素等基因的SNP与前列腺癌发生发展的关系,以探讨前列腺癌的发病机制。     

HPC2/ELAC2 polymorphism associated with Japanese sporadic prostate cancer

BACKGROUND: HPC2/ELAC2 gene was identified by linkage analysis from familial prostate cancer (Pca) patients in USA. To determine the association of HPC2/ELAC2 gene with Japanese sporadic Pca, we performed a case-control study focused on two missense polymorphisms. METHODS: We genotyped the two polymorphic sites of Ser217Leu and Ala541Thr in sporadic Japanese Pca patients (n = 285) and matched controls (n = 233). Controls were unrelated Japanese outpatients who had no history of any cancer and normal PSA level (less than 4.0 ng/ml). Statistical analyses were performed by Mann-Whitney's U-test, Fisher's exact test, and logistic regression analysis. RESULTS: We observed a significantly higher frequency of the Thr allele at 541 polymorphic site in Pca patients (8.4%) compared to the control group (2.1%) (P = 0.0030, Odds Ratio (OR) = 4.02, 95% CI = 1.50-10.8). However, this SNP does not correlate with clinical stage, PSA level, Gleason score of biopsies or age at diagnosis. No association was identified at Ser217Leu polymorphic site. CONCLUSIONS: Our results indicate that Thr allele at 541 in HPC2/ELAC2 has strong significance in the predisposition of sporadic Pca in Japan. This polymorphism can be useful to predict the personal Pca risk, which lead the effective screening of Pca.     

前列腺癌易感基因遗传多态性的研究进展

随着人类基因组研究计划(human genome project,HGP)DNA序列测定和分析研究工作的深入发展,单核苷酸多态性(single nucleotide polymorphism,SNP)作为第三代遗传标记已经广泛应用于人群复杂性疾病易感性机制和个体化治疗方案的设计方面的研究。本文就与前列腺癌相关的遗传易感基因SNP进行了综述,主要阐述了细胞因子、受体以及相关酶类遗传多态性与前列腺癌发生之间的关系并分析其在前列腺癌治疗等方面的作用。