Breast Cancer Diagnosis: Blood-Cell Multigene Signatures

乳腺癌诊断：血细胞多基因特征

• 批准号: 6762370
• 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: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762370
• 关键词: breast neoplasms; clinical research; computer data analysis; diagnosis design /evaluation; diagnosis quality /standard; gene expression; genetic screening; genetic transcription; human subject; leukocytes; mathematics; microarray technology; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; patient oriented research; polymerase chain reaction; women' s health

DESCRIPTION (provided by applicant): Current techniques for the screening of breast cancer, as a prerequisite to biopsy for diagnostic evaluation of a potential tumor, include physical breast examination and mammography. These techniques possess a number of limitations, including lack of specificity and accuracy in the diagnosis and, also a lack of cancer stage and prognostic information. This ultimately yields high numbers of false positive diagnoses, and consequently unnecessarily large numbers of surgical biopsies. The rationale behind this proposal is based on two sources of data: 1) Current scientific literature, in which there is growing evidence that individuals with breast cancer and other forms of malignant disease such as prostate cancer, 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 leukocytes of a number of individual genes has demonstrated associations between gene expression levels and the presence of a tumor in patients with breast and prostate cancer. 2) Preliminary results from a microarray study investigating gene expression changes in men with prostate cancer. Initial results from this study have been striking; supervised cluster analysis of peripheral leukocyte gene expression data, using transcript level measurements of thousands of genes from eleven prostate cancer patients and seven matched control subjects, resulted in a classification of all the subjects into their correct group. These observations form the basis of the hypothesis and experimental design of this proposed study. Under Specific Aim One, we will collect and process blood from 55 breast cancer patients and 25 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 breast 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 breast 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 breast 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 women with breast cancer, and also provide important stage-specific information.

描述（由申请人提供）：目前用于乳腺癌筛查的技术（作为对潜在肿瘤进行诊断评估的活组织检查的先决条件）包括物理乳房检查和乳房X线照相术。这些技术具有许多局限性，包括诊断缺乏特异性和准确性，以及缺乏癌症分期和预后信息。这最终会产生大量假阳性诊断，从而导致不必要的大量手术活检。该提议背后的基本原理基于两个数据来源：1) 当前的科学文献中，越来越多的证据表明，患有乳腺癌和其他形式的恶性疾病（例如前列腺癌）的个体表现出可以在皮肤上检测到的免疫反应。外周血中循环的白细胞基因表达水平改变。对白细胞中许多单个基因的 mRNA 转录本的定量表明，基因表达水平与乳腺癌和前列腺癌患者中肿瘤的存在之间存在关联。 2) 一项调查前列腺癌男性基因表达变化的微阵列研究的初步结果。这项研究的初步结果是惊人的。使用来自 11 名前列腺癌患者和 7 名匹配对照受试者的数千个基因的转录水平测量，对外周白细胞基因表达数据进行监督聚类分析，将所有受试者分类到正确的组中。这些观察结果构成了本研究的假设和实验设计的基础。根据具体目标一，我们将收集并处理 55 名乳腺癌患者和 25 名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乳腺癌患者和对照受试者血液中白细胞转录的多达 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：患有乳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，即患有不同组织学分级的乳腺肿瘤的癌症患者将产生不同的表达特征，反映肿瘤的生物学阶段和侵袭性，因此可用于区分不同病理分级的肿瘤。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，能够识别患有乳腺癌的女性，并提供重要的特定阶段信息。