Identify SNPs and Polymorphisms Involved in the Development of Prostate Cancer

鉴定参与前列腺癌发展的 SNP 和多态性

• 批准号: 7733039
• 负责人: William Douglas Figg
• 金额: $ 58.26万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7733039
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; 5 Alpha-Reductase Inhibitor; ABCG2 gene; ATP-Binding Cassette Transporters; Achievement; Adenocarcinoma; Adrenal Glands; Affect; Alleles; Am 80; Androgen Receptor; Androgens; Base Sequence; Benign; Biochemical; Biological; Biological Assay; Biology; Biopsy; COL18A1 gene; CYP17A1 gene; CYP19A1 gene; CYP1B1 gene; CYP3A4 gene; Candidate Disease Gene; Carcinogens; Caucasians; Caucasoid Race; Cells; Chemopreventive Agent; Cholesterol; Clinical; Collaborations; Collagen XVIII (Alpha 1); Count; DNA; Development; Disease; Drug Transport; Endostatins; Enrollment; Evaluation; Exposure to; Failure; Finasteride; Fluorescence Microscopy; Flutamide; Gene Chips; Genes; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Heterocyclic Amines; High Prevalence; Hormones; Hyperplasia; In Vitro; Individual; LOX gene; Ligand Binding Domain; Malignant Neoplasms; Malignant neoplasm of prostate; Metabolic; Metabolism; Molecular; Molecular Profiling; Mutation; New Agents; Organic Anion Transporters; Patients; Pharmacogenomics; Pharmacology; Play; Polymorphic Microsatellite Marker; Population; Prevalence; Production; Prostate; Prostate Cancer Prevention Trial; Prostate-Specific Antigen; Prostatic Tissue; Protein-Lysine 6-Oxidase; Purpose; Regulator Genes; Reporting; Risk; Role; SRD5A2 gene; Screening procedure; Serum; Single Nucleotide Polymorphism; Staging; Statistically Significant; Steroids; Testosterone; Testosterone 5-alpha-Reductase; Therapeutic; Time; Tissue Sample; Tissues; Translational Research; Treatment Efficacy; Treatment Protocols; Upper arm; Variant; Withdrawal; androgen independent prostate cancer; base; cancer risk; cell type; cytochrome P450 3A; design; drug metabolism; genetic variant; improved; inhibitor/antagonist; interest; irinotecan; laser capture microdissection; men; neoplastic cell; prostate cancer prevention; response; steroid hormone; treatment duration; treatment planning; uptake

The purpose of this project is to perform translational research to develop new agents, and/or therapeutic maneuvers, that appear to have antitumor activity in prostate cancer, and to develop molecular profiles of patients with prostate cancer to tailor an individualized treatment plan. To achieve this goal, we have become extensively involved in the efforts to understand the biology of prostate cancer. Currently, we are attempting to correlate biological variables associated with prostate cancer and response to therapy (e.g., important polymorphic markers, and microvessel counts). One early achievement by the Molecular Pharmacology Section was to report the first confirmation of the therapeutic efficacy of flutamide withdrawal, as well as the enhanced activity of simultaneous adrenal suppression. It has been hypothesized that the clinical improvement associated with flutamide is a result of the presence of a mutation within the ligand-binding domain of the androgen receptor. We remain interested in analyzing candidate genes at the genomic level for genetic variations that may predispose individuals to increased risk of prostate cancer. We have completed the analysis of genes involved in the natural production of endostatin (COL18A1, no statistical difference), a gene directly involved in the synthesis of testosterone from cholesterol (CYP17, the results suggest that the polymorphism is associated with overall survival in patients with androgen independent prostate cancer), a gene involved in the toxic metabolic breakdown of testosterone (CYP1B1, an association with decreased survival was observed), drug metabolism (CYP3A4 &5, the studied genetic variants are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer), and a gene involved in cellular transport and conjugation (UGT1A9, functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens). The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and progression of prostate cancer is unknown. SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, while testosterone transport was analyzed in Cos-7 cells transfected with wild-type (WT), 334G and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy and the relationship between SLCO1B3 haplotypes and survival was examined in patients. Our recent study showed that prostate cancer over-expresses OATP1B3 compared to normal or benign hyperplastic tissue, and the common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostate cancer. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 (P = 0.11) and D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele (P = 0.048). Thus, a polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT. Due to the expression of ABCG2 in the prostate, together with the purported role of dietary carcinogens and steroids in the development and progression of prostate cancer, we determined if the C421A single nucleotide polymorphism (SNP) in the ATP-binding cassette transporter ABCG2 increases prostate cancer risk or affects survival. We also evaluated the effect of this SNP on the intracellular accumulation of the carcinogenic heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a known substrate of the ABCG2, and testosterone in vitro. While there were no significant differences in the prevalence of prostate cancer based on ABCG2 genetic variation in this population, survival was significantly longer for individuals with wild-type ABCG2, as compared with those hetero- or homozygous for the C421A SNP (7.4 years vs 5.3 years, P = 0.044). Intracellular accumulation of PhIP was 80% higher in HEK293 cells transfected with Q141K ABCG2 than in wild-type cells, confirming that this SNP decreases transport of PhIP. In contrast, testosterone was not transported by either wild-type or variant transfected cells, nor did it act as in inhibitor of ABCG2 in subsequent transport assays. Increased exposure to PhIP may decrease survival, but the ABCG2 C421A polymorphism does not appear to increase the risk of prostate cancer. Furthermore, the analysis of other genes (SRD5A1&2, LOX, CYP19, ER) which have shown preliminary evidence that suggests that they may play important roles are ongoing and at various stages of completion. Other polymorphic containing genes of interest have been recently identified after screening the DNA from patients with prostate cancer against a gene chip designed to screen genes involved in metabolism and drug transport. These important genes will be added to the ongoing goal of a molecular fingerprint of prostate cancer. Some of the overall goals of this project are: (a) to better understand associations between important androgen regulatory gene polymorphisms and prostate cancer risk and (b) to evaluate the effects of these polymorphisms and serum hormone concentrations on the use of finasteride as a chemopreventive agent for prostate cancer. The recently completed Prostate Cancer Prevention Trial (PCPT) investigated the prevention of prostate cancer using the steroid 5 alpha-reductase inhibitor finasteride over a seven year treatment period. Through a longstanding collaboration we have access to tissue samples of the 18,800 men enrolled in this study. We are currently focusing on hormone-related factors that are associated with prostate cancer risk, which may help explain the findings of the PCPT (i.e., decreased overall occurrence of adenocarcinoma, but increased prevalence of high-grade disease in the finasteride treatment arm). We hypothesize that men with polymorphisms within genes that positively impact androgen levels will have a higher risk of developing prostate cancer and high grade disease than those with the wild-type alleles. In addition, long-term exposure to finasteride may select for somatic alterations and increase serum levels of testosterone and potentially harmful testosterone breakdown products. The evaluation of whether the polymorphic variations in the AR, SRD5A2 and HSD3B2 genes are associated with the risk of biopsy-detected prostate cancer in the PCPT are underway. We are identifying by laser-capture microdissection and direct nucleotide sequencing somatic alterati [summary truncated at 7800 characters]

该项目的目的是进行转化研究，以开发新的药物和/或治疗性动作，这些动作似乎在前列腺癌中具有抗肿瘤活性，并开发前列腺癌患者的分子特征以量身定制个性化治疗计划。为了实现这一目标，我们已经广泛参与了了解前列腺癌生物学的努力。目前，我们正在尝试将与前列腺癌和对治疗的反应相关的生物学变量（例如，重要的多态标记物和微血管计数）相关联。分子药理学部门的一个早期成就是报告首次证实氟他胺戒断的治疗功效，以及同时肾上腺抑制的活性增强。已经假设，与氟丁酰胺相关的临床改善是雄激素受体的配体结合结构域内存在突变的结果。我们对分析基因组水平的候选基因的遗传变异感兴趣，这可能使个体易于增加前列腺癌的风险。我们已经完成了对内静脉素自然产生的基因的分析（COL18A1，无统计差异），该基因直接参与胆固醇合成睾丸激素的合成（CYP17）（CYP17，结果，结果表明，多态性表明与雄激素独立癌症的患者中的总体生存有关，与毒素疾病的毒性分解（毒性）与毒素的毒性分解（COMETAST）的总体生存相关（观察到的），药物代谢（CYP3A4和5，所研究的遗传变异不太可能对癌症患者的表型CYP3A活性具有重要的功能意义），并且具有细胞运输和结合的基因（UGT1A9）（UGT1A9，功能变体在多头派中很少见，并且可能在iriNICEC中具有临床上的象征性。由SLCO1B3编码的有机阴离子转运蛋白OATP1B3参与类固醇激素的运输。但是，其在睾丸激素摄取和前列腺癌的进展中的作用尚不清楚。通过测序在NCI-60肿瘤细胞中评估SLCO1B3基因型，而在用野生型（WT），334G和699A SLCO1B3变体转染的COS-7细胞中分析睾丸激素的转运。通过荧光显微镜检查了前列腺组织中OATP1B3的表达，并在患者中检查了SLCO1B3单倍型与存活之间的关系。我们最近的研究表明，与正常或良性增生组织相比，前列腺癌过表达OATP1B3，而普通的SLCO1B3 GG/AA单倍型与前列腺癌患者的睾丸激素转运受损和改善的存活率有关。 我们假设增加睾丸激素转运的T等位基因将与ADT到雄激素独立性的较短间隔有关。我们研究了这种SLCO1B3多态性与从ADT到雄激素独立性的时间之间的关联，ADT到前列腺特异性抗原（PSA）Nadir和PSA Nadir与68例高加索人的晚期前列腺癌患者的雄激素独立性，这些患者患有ADT患有ADT患有转移性疾病（D2）或不接受的ADT的患者。当分别检查时，单个阶段的患者在D0（p = 0.11）和D2（p = 0.18）组中的T等位基因具有较短的雄激素独立性。将这些组组合并按阶段进行分层，产生了与T等位基因的雄激素独立性的统计学意义（p = 0.048）。 因此，在转运蛋白中增加睾丸激素进口的多态性与使用ADT治疗的前列腺癌患者的雄激素独立性较短有关。由于ABCG2在前列腺中的表达，以及饮食中癌和类固醇在前列腺癌的发育和进展中所谓的作用，我们确定C421A单核苷酸多态性（SNP）在ATP结合的磁带cassette Transporter abcg2中是否会增加前列腺癌的风险或影响前列腺癌的风险。我们还评估了该SNP对致癌杂环胺2-氨基-1-甲基-6-苯基咪唑唑[4,5-B]吡啶（PHIP）（pHIP）的影响，ABCG2的已知底物和testosterone in Vitro。尽管基于该人群的ABCG2遗传变异，前列腺癌的患病率没有显着差异，但与C421A SNP的异性或纯合子相比，野生型ABCG2的个体的生存率明显更长（7.4岁，PS 5.3岁，P = 0.044）。在用Q141K ABCG2转染的HEK293细胞中，PHIP的细胞内积累比野生型细胞高80％，证实该SNP降低了PHIP的运输。相比之下，睾丸激素均未通过野生型或变异转染的细胞运输，在随后的运输分析中也没有像ABCG2抑制剂一样起作用。 pHIP暴露的增加可能会降低生存率，但是ABCG2 C421A多态性似乎并没有增加前列腺癌的风险。 此外，对其他基因（SRD5A1和2，LOX，CYP19，ER）的分析，这些基因表明它们可能扮演重要角色，并且在完成的各个阶段都表明它们可能扮演重要角色。最近在筛查前列腺癌患者的DNA对涉及代谢和药物传输涉及的基因的基因芯片的DNA后，最近已经确定了其他包含感兴趣基因的多态性基因。这些重要的基因将被添加到前列腺癌分子指纹的持续目标中。该项目的某些总体目标是：（a）更好地了解重要的雄激素调节基因多态性和前列腺癌风险之间的关联，以及（b）评估这些多态性和血清激素浓度对使用丁那雄胺作为化学抗化剂对前列腺癌的影响。最近完成的前列腺癌预防试验（PCPT）在七年治疗期间使用类固醇5α-还原酶抑制剂丁酰胺研究了预防前列腺癌。通过长期的合作，我们可以进入参加这项研究的18,800名男性的组织样本。我们目前正在关注与前列腺癌风险相关的与激素相关的因素，这可能有助于解释PCPT的发现（即腺癌的总体发生降低，但在Finasteride治疗组中高级疾病的患病率提高）。我们假设在基因内具有积极影响雄激素水平的男性患有前列腺癌和高级疾病的风险要高于野生型等位基因的风险。此外，长期接触非那雄胺可能会选择躯体改变并增加血清睾丸激素水平和潜在有害的睾丸激素分解产物。评估AR，SRD5A2和HSD3B2基因中的多态性变化是否与PCPT中活检检测的前列腺癌的风险有关。我们通过激光捕获显微解剖和直接的核苷酸测序识别体细胞Alterati [汇总以7800个字符截断]

项目成果

Molecular and phenotypic heterogeneity of metastatic prostate cancer.

转移性前列腺癌的分子和表型异质性。

• DOI: 10.4161/cbt.4.2.1571
• 发表时间: 2005
• 期刊: Cancer biology & therapy
• 影响因子: 3.6
• 作者: Chau,CindyH;Figg,WilliamD
• 通讯作者: Figg,WilliamD

Genetic variations in the vitamin D receptor, androgen receptor and enzymes that regulate androgen metabolism.

• DOI: 10.1097/01.ju.0000108402.60404.48
• 发表时间: 2004-02
• 期刊: The Journal of urology
• 作者: D. Price;M. Franks;W. Figg