Genetic Epidemiology of Prostate Cancer Aggressiveness

描述（由申请人提供）：越来越多的证据表明，与先天免疫和炎症有关的基因可能影响前列腺癌的风险，以及疾病的进展。在这个项目的初始资助期，我们已经成功地进行了一些补充研究，以调查这些候选基因中的一些。我们的初步结果表明，前列腺癌可能受到先天免疫反应和炎症途径相关基因（即RNASEL、OAS1、TNF-a和LTA）变异的影响。我们建议在这些发现的基础上，全面评估参与该途径的候选基因对前列腺癌发生和进展的影响。具体而言，我们首先旨在评估前列腺癌与以下23个候选基因的单核苷酸多态性和单倍型之间的关系：巨噬细胞清道夫受体1，toll样受体1,2,4,5,6和10，核糖核酸酶L，2‘,5’寡腺苷酸合成酶1和2，白细胞介素8,1 β和1RN，巨噬细胞迁移抑制因子，肿瘤坏死因子α，淋巴蛋白α，巨噬细胞抑制因子-1，环氧化酶-2，以及核因子kappa- β通路中的五个基因。本研究将使用在本基金初始资助期内招募的现有人群（N= 1454； 727例，727例匹配对照）。病例是诊断为临床相关疾病的男性（即Gleason评分为bb0）。7，肿瘤-淋巴结-转移（TNM）期> T2c，或前列腺特异性抗原(PSA) >10)，使这一人群非常适合研究前列腺癌的风险和疾病进展。因此，我们的第二个目标是收集病例病程的前瞻性信息（例如，治疗后PSA水平），然后评估这些候选基因与前列腺癌进展之间的关系。在这两个目标中研究相同的基因将使我们能够区分它们是否与前列腺癌的风险和/或进展有关。我们的最终目标是通过一个新的层次模型来研究这些候选基因在前列腺癌发生和发展中的联合和相互作用，从而综合这些候选基因的信息。确定与先天免疫和炎症途径相关的候选基因对前列腺癌发生和进展的影响可能对公众健康产生重大影响。特别是，这项研究的知识可能为疾病的潜在机制提供重要的见解，为未患病的男性提供有价值的筛查工具，并帮助指导诊断为前列腺癌的男性的治疗计划。

DESCRIPTION (provided by applicant): There is growing evidence that genes involved with innate immunity and inflammation may impact the risk of prostate cancer, as well as progression of the disease. During the initial funding period of this project we have successfully undertaken a number of complementary studies to investigate some of these candidate genes. Our preliminary results suggest that prostate cancer may be affected by variants in genes involved in the innate immune response and inflammation pathway (i.e., in RNASEL, OAS1, TNF-a, and LTA). We propose building on these findings by comprehensively evaluating the impact of candidate genes involved in this pathway on prostate cancer development and progression. Specifically, we first aim to evaluate the association between prostate cancer and single nucleotide polymorphisms and haplotypes in the following 23 candidate genes: Macrophage Scavenger Receptor 1, Toll-like Receptors 1, 2, 4, 5, 6, and 10, Ribonuclease L.,2',5'Oligoadenylate Sythetase 1 and 2, Interleukin 8, 1 Beta, and 1RN, Macrophage Migration Inhibitory Factor, Tumor Necrosis Factor Alpha, Lymphotoxin Alpha, Macrophage-lnhibitory-Cytokine-1, Cyclooxygenase-2, and five genes in the Nuclear Factor kappa- Beta Pathway. This study will use an existing population recruited during the initial funding period of this grant (N=1,454; 727 cases, 727 matched controls). Cases are men diagnosed with more clinically relevant disease (i.e., Gleason score >. 7, tumor-node-metastasis (TNM) stage > T2c, or prostate-specific antigen (PSA) >10), making this population ideally suited for studying both risk of prostate cancer and disease progression. Therefore, our second aim-is to collect prospective information on the course of the case's disease (e.g., post-treatment PSA levels), and then evaluate the relationship between these candidate genes and prostate cancer progression. Studying the same genes in these two aims will allow us to distinguish whether they are involved in prostate cancer risk and/or progression. Our final aim is to synthesize information on the candidate genes studied here by investigating their joint and interactive effects on prostate cancer development and progression with a novel hierarchical model. Determining the impact of candidate genes involved with the innate immunity and inflammation pathway on prostate cancer development and progression may have a significant impact on the public's health. In particular, the knowledge from this study may give important insights into the underlying mechanism of disease, provide a valuable screening tool for non-diseased men, and help guide treatment plans among men diagnosed with prostate cancer.