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参与了癌症发生的关键过程，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。以往关于血清[25(OH)D]与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，比较（对照）组与临床前癌症的潜在污染，以及无法调查前列腺组织水平上[25(OH)]循环浓度与维生素d相关过程的程度。在遗传证据方面，维生素D相关基因的多态性很少被研究。先前的研究主要集中在维生素D受体（VDR）的一些多态性上，VDR是维生素D作用的关键介质；然而，最近的重测序数据显示，需要25个标记多态性才能捕获该大基因的遗传变异。其他相关的候选基因，包括对维生素D激活[27-羟化酶（CYP27A1）、1-1-羟化酶（CYP27B1）]、共激活（NCOA1-3、SMAD3）、失活[24-羟化酶（CYP24A1）]、转运[组特异性成分（GC）编码的维生素D结合蛋白]和维生素D信号传导[类视黄醛X受体（RXRA、RXRB、RXRG）]的重要基因，与前列腺癌风险的关系尚未得到充分研究。我们建议在前列腺癌预防试验（PCPT）中进行巢式病例对照研究（1800例和1800例对照）。作为主要目的，我们将研究维生素D途径中的循环[25(OH)D]和遗传变异，包括它们与前列腺癌风险的相互作用。重要的是，我们还将检测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。我们还将研究非那雄胺（PCPT中使用的活性药物）对低血清维生素D和高血清维生素D或有或没有维生素D通路基因多态性的男性前列腺癌风险的干预作用是否不同。次要目的是探索与前列腺癌相关的维生素D和雄激素途径的相互作用，以及维生素D生物标志物或基因是否影响病例和对照组前列腺活检标本中增殖或凋亡的测量。所有PCPT参与者都进行了前列腺活检，并进行了中心病理检查，以确定病例或对照状态。我们将研究血清[25(OH)D]在全前列腺癌和高级别（Gleason >7）前列腺癌患者中的浓度。我们将使用标签snp来检测以下维生素D途径基因在全前列腺癌和高级别前列腺癌中的可变性：VDR、CYP27A1、CYP27B1、CYP24A1、GC、RXRA、RXRB、RXRG、NCOA1-3、SMAD3。该项目将提供具有相关转化潜力的前列腺癌病因学的重要数据，特别是关于谁可能从使用非那雄胺预防前列腺癌中获益最多。

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.