Basic Cancer Research in Cancer Health Disparities

描述(申请人提供)：前列腺癌是美国男性中最常见的致命肿瘤，但人们对其致病机制知之甚少。这项研究建议研究性激素结合球蛋白(SHBG)的糖基化如何影响前列腺癌中的类固醇激素信号。我们将确定SHBG糖基化，包括D327N SHBG多态，对非洲和高加索美国人中类固醇激素相关前列腺癌风险和差异的影响。蛋白质糖基化是前列腺细胞与环境相互作用的关键。我们将评估SHBG的糖基化如何影响蛋白质在血浆和组织之间的分布，以及这如何影响疾病的发展。SHBG糖型的定量将通过新的LC-MS分析来实现。此外，我们还将全面总结多态对人类蛋白质组N-糖基化的影响。我们的假设是前列腺癌的风险和进展与SHBG糖基化的可变性有关。我们的目标是结合类固醇激素的测量，进行SHBG糖基化的定量质谱分析。我们将通过对具有50%非裔美国人代表性的病例对照人群进行基因分型来选择男性进行表型鉴定。此外，我们将对血清和组织均可获得的病例系列进行分型。类固醇激素将用气相色谱-质谱法测定。我们将在组织水平和循环中分析SHBG糖形式和类固醇激素。这项研究有望填补我们在前列腺癌病因和进展方面的重要空白。SHBG糖型的分析将为前列腺癌发生的生物学因素提供新的信息。这一结果有望改善前列腺癌的预防、检测和干预策略。 公共卫生相关性：这项研究很重要，因为以前还没有对前列腺癌，特别是非裔美国人男性的SHBG糖基化和类固醇激素进行比较分析。我们建议对前列腺癌的SHBG部位占有率和疾病的健康差异进行首次大规模检查。新建立的信息学资源和方法有望促进新的癌症预防和健康差异研究。

DESCRIPTION (provided by applicant): Prostate cancer is the most common lethal tumor among US males yet little is known about its causative mechanisms. This study proposes to examine how glycosylation of sex hormone binding globulin (SHBG) affects steroid hormone signaling in prostate cancer. We will define the impact of SHBG glycosylation, including the D327N SHBG polymorphism, on steroid hormone associated prostate cancer risk and disparity in African and Caucasian Americans. Protein glycosylation is critical for interaction of prostate cells with its environment. We will evaluate how glycosylation of SHBG affect the distribution of the protein between plasma and tissue and how this affects disease development. The quantification of the SHBG glycoforms will be achieved by novel LC-MS assays. In addition, we will comprehensively summarize the impact of polymorphisms on N-glycosylation in the human proteome. Our hypothesis is that prostate cancer risk and progression are related to the variability in the glycosylation of SHBG. Our objective is to perform quantitative mass spectrometric assays of SHBG glycosylation in conjunction with measurement of steroid hormones. We will select men for phenotypic characterization by genotyping of a case control population with 50% African American representation. In addition, we will genotype a case series for which both serum and tissue are available. Steroid hormones will be measured by GC-MS. We will analyze the SHBG glycoforms and steroid hormones at the tissue level and in the circulation. The study is expected to fill important gaps in our understanding of prostate cancer etiology and progression. The analysis of SHBG glycoforms will provide new information on the biological factors underlying prostate carcinogenesis. The results are expected to improve prostate cancer prevention, detection and intervention strategies. PUBLIC HEALTH RELEVANCE: This research is important because a comparative analysis of SHBG glycosylation and steroid hormones in prostate cancer, especially in African American men, has not been previously undertaken. We are proposing the first large scale examination of SHBG site occupancy in prostate cancer and health disparity of the disease. The newly established informatic resources and methods are expected to stimulate novel cancer prevention and health disparity studies.