A Biomarker Risk Prediction Model for Prostate Cancer

描述（由申请人提供）： 非裔美国人（AA）男性比白人男性患侵袭性前列腺癌（PrCa）的风险更大。因此，鉴定参与侵袭性PrCa的生物标志物，可用于鉴定AA男性的特异性和/或新型治疗，将为公共卫生提供重大进展。因此，有大量的努力，以确定潜在的生物标志物，可以独立地预测不良的临床结果，并确定新的治疗男性与积极的PrCa。值得注意的是，热休克蛋白，PrCa抗原3和丝氨酸蛋白酶抑制剂Kazal-1型，都在PrCa男性中过表达，其中膜联蛋白II被抑制。尽管这些生物标志物的生物学重要性，但尚未有研究评估这些生物标志物在患有侵袭性PrCa的AA男性中的意义。我们认为，霍华德大学医院泌尿科诊所每年评估约200例PrCa患者，是研究生物标志物作为AA男性侵袭性PrCa预测因子的重要性的理想来源。我们建议评估双向表达的蛋白质和基因签名对不同的档案组织样本AA男子已被诊断为侵略性形式的PrCa在华盛顿VA医学中心和霍华德和约翰霍普金斯大学癌症中心。主要的假设是基因和蛋白质的双向表达是侵略性的预测， 致命PrCa风险。为了验证这一假设，我们提出了两个目标。第一个目标将测试微阵列基因表达谱产生双向生物标志物签名对的假设，该双向生物标志物签名对可用于构建PrCa的风险预测模型。第二个目标将检验以下假设：用双向基因和蛋白质表达对预测不良临床结果的风险上级使用单个基因或蛋白质。候选对包括在目标1中发现的那些。我们预计，这些研究可能会提供深入了解选定的基因和蛋白质作为可靠的预测生物标志物，用于识别AA男性的侵袭性PrCa，并可能为未来的人类临床应用提供信息，用于治疗侵袭性PrCa。 公共卫生相关性： 前列腺癌（PrCa）仍然是科学和临床界面临的重大挑战，因为它仍然是西方世界男性中最常见的恶性肿瘤。因此，人们一直致力于通过与早期发现和筛查、饮食和营养以及化学预防有关的研究工作来预防癌症。然而，即使在早期发现、筛查和治疗方面有所改善，与其他族裔群体相比，非洲裔美国人的总体PrCa死亡率并未显著下降。因此，识别分子生物标志物和/或遗传特征非常重要，可以解决非洲裔美国人癌症健康差异，并可能为高危人群提供新的治疗方法。该提案旨在研究从接受经直肠超声引导前列腺活检（TRUS）的非洲裔美国人和白人男性队列中获得的侵袭性和非侵袭性前列腺癌标本中双向基因或蛋白质的表达水平。

DESCRIPTION (provided by applicant): Modified Project Summary/Abstract Section African American (AA) men are at a greater risk of developing aggressive prostate cancer (PrCa) than are Caucasian men. Therefore, identifying biomarkers involved in aggressive PrCa that can be used to identify AA men for specific and/or novel therapies would provide a major advance in public health. Consequently, there is intense effort to identify potential biomarkers that could independently predict poor clinical outcome and identify novel therapies for men with aggressive PrCa. Notably, heat shock proteins, PrCa Antigen 3, and Serine Protease Inhibitor Kazal-type 1, are all overexpressed in men with PrCa, where as Annexin II is suppressed. Despite the biological importance of these biomarkers, no studies have yet evaluated the significance of these biomarkers in AA men with aggressive PrCa. We believe that Howard's University Hospital urologic clinic which evaluates approximately 200 PrCa patients per year, is an ideal source for studying the importance of biomarkers as predictors of aggressive PrCa in AA men. We propose to evaluate the bi-directional expression of protein and gene signature pairs different in archival tissue samples from AA men who had been diagnosed with an aggressive form of PrCa at the Washington VA Medical Center and Howard and Johns Hopkins University Cancer Centers. The main hypothesis is that the bi-directional expression of genes and proteins is predictive of aggressive, lethal PrCa risk. To test this hypothesis we propose two aims. The first aim will test the hypothesis that microarray gene expression profiling produces bi-directional biomarker signature pairs that can be used to build a risk prediction model for PrCa. The second aim will test the hypothesis that the risk prediction of poor clinical outcome with bi-directional gene and protein expression pairs is superior to the use of a single gene or protein. Candidate pairs include those discovered in Aim 1. We anticipate that these studies may provide insight into selected genes and proteins as reliable predictive biomarkers for identifying aggressive PrCa in AA men, and could inform future human clinical applications for treatment of aggressive PrCa. PUBLIC HEALTH RELEVANCE: Project Narrative Prostate carcinoma (PrCa) continues to represent a significant challenge to the scientific and clinical community as it remains the most common malignancy in men of the Western World. As a result, there has been a committed focus to cancer prevention through research efforts related to early detection and screening, diet and nutrition, and chemoprevention. However, even with improvements in early detection and screening and treatment, overall PrCa mortality rates for African American men have not significantly declined when compared with those of other ethnic groups. Thus, it is extremely important to identify molecular biomarkers and/or genetic profiles that can address the cancer health disparity in African American men, and possibly inform novel therapies for high-risk populations. This proposal seeks to investigate the expression levels of bi-directional genes or proteins in aggressive and non-aggressive prostate cancer specimens obtained from a cohort of African American and Caucasian men who have undergone trans-rectal ultrasound guided prostate biopsy (TRUS).