Vitamin D and Prostate Cancer: Biomarkers and Genetic Variation

描述(由申请人提供)：本提案的总体目标是阐明维生素D影响前列腺癌风险的机制。来自实验研究的有力证据表明，维生素D参与了与癌症相关的关键过程，包括基因转录、细胞分化、T细胞介导的免疫、细胞周期控制、增殖和凋亡。先前关于血清[25(OH)D]和前列腺癌风险的研究结果并不一致。这些研究的局限性包括样本量小，对照(对照组)临床前癌症的潜在污染，以及无法调查在前列腺组织水平上循环中的[25(OH)]浓度与维生素D相关过程的程度。在遗传证据方面，维生素D相关基因的多态性研究很少。以前的研究主要集中在维生素D受体(VDR)的少数几个多态性上，而VDR是维生素D效应的关键媒介；然而，最近的测序数据表明，需要25个标签多态性来捕捉这个大基因的遗传变异。其他相关候选基因，包括与维生素D激活[27-羟基酶(CYP27A1)、1-1-羟基酶(CYP27B1)]、共激活(NCOA1-3，SMAD3)、失活[24-羟基酶(CYP24A1)]、转运蛋白[组特异性成分(GC)编码的维生素D结合蛋白]以及维生素D信号转导[维甲酸X受体(RXRA、RXRB、RXRG)]等与前列腺癌风险相关的研究还不够充分。我们建议在前列腺癌预防试验(PCPT)中进行嵌套式病例对照研究(1800例病例和1800例对照)。作为主要目标，我们将研究维生素D途径中的循环[25(OH)D]和遗传变异，包括它们之间的相互作用与前列腺癌风险的关系。重要的是，我们还将检查病例和对照组前列腺组织中VDR和RXR的表达，以及循环[25(OH)D]是否预测前列腺中维生素D的表达。我们还将调查非那雄胺(PCPT中使用的活性药物)对前列腺癌风险的干预效果是否在血清维生素D水平低和血清维生素D水平高的男性以及维生素D途径基因有或没有多态性的男性中有所不同。第二个目标将探索与前列腺癌有关的维生素D和雄激素途径的相互作用，以及维生素D生物标记物或基因是否影响来自病例和对照的前列腺活检标本的增殖或凋亡测量。所有PCPT参与者都接受了前列腺活检，并进行了中央病理复查，以确定病例或对照状态。我们将研究全前列腺癌和高级别(Gleason&Gt；7)前列腺癌患者的血清[25(OH)D]浓度。我们将使用标签SNPs来检测以下与总前列腺癌和高级别前列腺癌相关的维生素D途径基因的变异性：VDR、CYP27A1、CYP27B1、CYP24A1、GC、RXRA、RXRB、RXRG、NCOA1-3、SMAD3。该项目将提供前列腺癌病因学的重要数据和相关的翻译潜力，特别是关于谁可能从使用非那雄胺预防前列腺癌中受益最大的数据。 公共卫生相关性：前列腺癌是男性中最常见的癌症，也是美国男性癌症死亡的第二大原因。由于男性在做出治疗决定时面临着高度的压力和焦虑，以及用于治疗的高昂的医疗费用，预防前列腺癌是一个重要的目标。这项研究将调查维生素D(身份和遗传变异的生物标志物)在前列腺癌风险中的作用。我们的最终目标是获得用于前列腺癌预防和治疗的翻译计划的信息。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to elucidate mechanisms by which vitamin D influences prostate cancer risk. Strong evidence from experimental studies indicates that vitamin D is involved in key carcinogenesis- related processes including gene transcription, cellular differentiation, T-cell mediated immunity, cell cycle control, proliferation and apoptosis. Results from previous studies of serum [25(OH)D] and prostate cancer risk have been inconsistent. Limitations from these studies include small sample sizes, potential contamination of the comparison (control) group with preclinical cancers and the inability to investigate the extent to which circulating concentrations of [25(OH)] with vitamin D-related processes at the level of prostate tissue. With regard to genetic evidence, few polymorphisms in vitamin D related genes have been investigated. Previous studies mainly focused on a few polymorphisms in the vitamin D receptor (VDR), a critical mediator of vitamin D effects; however, recent resequencing data showed that 25 tagging polymorphisms are needed to capture the genetic variation in this large gene. Other relevant candidate genes, including those important for vitamin D activation [27-hydroxylase (CYP27A1), 1-1-hydroxylase (CYP27B1)], co-activation (NCOA1-3, SMAD3), deactivation [24-hydroxylase (CYP24A1)], transport [vitamin D binding protein encoded by group- specific component (GC)], and vitamin D signaling [retinoid X receptors (RXRA, RXRB, RXRG)] have not been sufficiently studied in relation to prostate cancer risk. We propose a nested case-control study (1800 cases and 1800 controls) to be conducted in the Prostate Cancer Prevention Trial (PCPT). As primary aims, we will investigate both circulating [25(OH)D] and genetic variability in the vitamin D pathway, including their interaction, in relation to prostate cancer risk. Importantly, we will also examine expression of VDR and RXR in prostate tissue from cases and controls and whether circulating [25(OH)D] predicts vitamin D expression in the prostate. We will also investigate whether the intervention-effect of finasteride (the active drug used in PCPT) on prostate cancer risk differs in men with low vs. high serum vitamin D or in men with or without polymorphisms in vitamin D pathway genes. Secondary aims will explore interactions of the vitamin D and androgen pathways in relation to prostate cancer and whether vitamin D biomarkers or genes influence measures of proliferation or apoptosis in prostate biopsy specimens from both cases and controls. All PCPT participants underwent a prostate biopsy with central pathology review to determine case or control status. We will investigate serum concentrations of [25(OH)D] with total and high-grade (Gleason > 7) prostate cancer. We will use tagSNPs to examine the variability in the following vitamin D pathway genes in relation to total and high-grade prostate cancer: VDR, CYP27A1, CYP27B1, CYP24A1, GC, RXRA, RXRB, RXRG, NCOA1-3, SMAD3. This project will provide important data on prostate cancer etiology with relevant translational potential, particularly regarding who might benefit most from use of finasteride for prostate cancer prevention. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most commonly diagnosed cancer among men and the second leading cause of male cancer deaths in the United States. Due to the high degree of stress and anxiety men face when making treatment decisions and the exorbitant health care expenditures for treatment, prevention of prostate cancer is an important objective. This study will investigate the role of vitamin D (both biomarkers of status and genetic variation) in relation to prostate cancer risk. Our ultimate goal is to gain information for use in translational programs of prostate cancer prevention and treatment.