Prostate Tumor Diagnosis:Blood Cell Multigene Signatures

前列腺肿瘤诊断：血细胞多基因特征

• 批准号: 6755031
• 负责人: CATHERINE L CLELLAND
• 金额: $ 16.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-04 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755031
• 关键词: biotechnology; blood chemistry; clinical research; diagnosis design /evaluation; diagnostic tests; gene expression; genetic markers; human subject; leukocytes; male; mathematical model; messenger RNA; microarray technology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer immunodiagnosis; neoplastic growth; neoplastic process; patient oriented research; prognosis; prostate neoplasms

DESCRIPTION (provided by applicant): Current techniques for the screening and risk assessment of prostate cancer, as a prerequisite to surgical biopsy, are based upon measurements of either individual serum biomarkers, or of expression of individual genes in circulating malignant cells. These techniques possess a number of limitations, including lack of specificity and accuracy in diagnosis, and a lack of detailed prognostic information. The resultant high numbers of false positive diagnoses lead to numerous unnecessary surgical biopsies. There is evidence that individuals with prostate cancer and other forms of malignant disease exhibit immune responses that can be detected at the level of altered gene expression in leukocytes circulating in peripheral blood. Quantitation of the mRNA transcripts in circulating leukocytes of a number of individual genes has demonstrated an association between gene expression level and the presence of a tumor. Furthermore, it has been shown that serum levels of individual proteins, which exhibit a degree of correlation with differential gene expression in leukocytes, provide some information on tumor stage. We have initiated a pilot study to measure gene expression in leukocytes and have produced initial data that concurs with previous reports. We have further documented the use of algorithms to classify prostate cancer patients and healthy controls. Under Specific Aim One, we will collect and process blood from prostate cancer patients and healthy control subjects. We will then employ microarray technology to measure simultaneously the expression levels of up to 14,000 genes transcribed in leukocytes derived from the blood of prostate cancer patients and control subjects, and employ data analysis algorithms to determine patterns of gene expression specific for each subject group. With this technology we propose to investigate our central hypothesis: that individuals suffering from prostate cancer exhibit a conserved pattern of gene expression levels in their peripheral blood leukocytes, which is distinct from the pattern of expression in peripheral blood leukocytes from control subjects. Under Specific Aim Two, we will test the further hypothesis that cancer patients with prostate tumors at different histological grades will yield distinct expression signatures that reflect the biological stage and aggressiveness of the tumor, and that can thus be employed to differentiate among tumors at different pathological stages. We believe that the diagnostic technique we propose to develop may ultimately form the basis of a clinical assay that will, with a minimum of patient discomfort, have the capacity to identify men with prostate cancer, and also provide important stage-specific information.

描述（申请人提供）：作为手术活检的先决条件，用于筛查和风险评估的当前技术基于对单个血清生物标志物的测量，或在循环恶性细胞中表达单个基因的表达。这些技术具有许多局限性，包括缺乏诊断的特异性和准确性，以及缺乏详细的预后信息。由此产生的大量假阳性诊断导致了许多不必要的手术活检。有证据表明，患有前列腺癌和其他形式的恶性疾病的个体表现出免疫反应，可以在周围血液中循环的白细胞中基因表达改变的水平上检测到。在许多单个基因的循环白细胞中的mRNA转录物的定量表明基因表达水平与肿瘤的存在之间存在关联。此外，已经表明，各个蛋白质的血清水平与白细胞中差异基因表达相关的程度提供了有关肿瘤阶段的一些信息。我们已经启动了一项试点研究，以测量白细胞中的基因表达，并产生了与以前的报道一致的初始数据。我们进一步记录了使用算法对前列腺癌患者和健康对照进行分类的使用。在特定目标下，我们将从前列腺癌患者和健康对照组中收集和处理血液。然后，我们将采用微阵列技术来同时测量从前列腺癌患者的血液中衍生出的白细胞中最多14,000个基因的表达水平，并采用数据分析算法来确定每个受试者的基因表达模式。通过这项技术，我们建议研究我们的中心假设：患有前列腺癌的个体在其外周血白细胞中表现出了基因表达水平的保守模式，这与来自控制受试者的外周血白细胞中表达模式不同。在特定目标二下，我们将进一步测试以下假设：不同组织学等级的前列腺肿瘤的癌症患者将产生不同的表达特征，反映了肿瘤的生物学阶段和攻击性，因此可以用来分化不同病理学的肿瘤。阶段。我们认为，我们建议开发的诊断技术最终可能构成临床测定法的基础，该测定最少的患者不适感有能力识别患有前列腺癌的男性，并提供重要的阶段特定信息。