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（由申请人提供）：作为手术活检的先决条件，目前用于前列腺癌筛查和风险评估的技术基于对个体血清生物标志物或循环恶性细胞中个体基因表达的测量。这些技术具有许多局限性，包括诊断缺乏特异性和准确性，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大量不必要的手术活检。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，可以通过外周血中循环的白细胞基因表达的改变水平来检测到免疫反应。对循环白细胞中许多单个基因的 mRNA 转录本的定量表明了基因表达水平与肿瘤存在之间的关联。此外，研究表明，个别蛋白质的血清水平与白细胞差异基因表达存在一定程度的相关性，可提供有关肿瘤分期的一些信息。我们已经启动了一项测量白细胞基因表达的试点研究，并产生了与之前报告一致的初步数据。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情况。根据具体目标一，我们将收集和处理前列腺癌患者和健康对照受试者的血液。然后，我们将采用微阵列技术同时测量来自前列腺癌患者和对照受试者血液的白细胞中转录的多达 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组特有的基因表达模式。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保守的基因表达水平模式，这与对照受试者的外周血白细胞中的表达模式不同。在具体目标二下，我们将测试进一步的假设，即具有不同组织学级别的前列腺肿瘤的癌症患者将产生反映肿瘤的生物学阶段和侵袭性的不同表达特征，因此可用于区分不同病理级别的肿瘤阶段。我们相信，我们建议开发的诊断技术可能最终构成临床检测的基础，该临床检测将在患者不适最小化的情况下，能够识别患有前列腺癌的男性，并提供重要的特定阶段信息。