Breast Cancer Diagnosis: Blood-Cell Multigene Signatures

描述(由申请人提供)：目前筛查乳腺癌的技术包括乳房体格检查和乳房X光摄影，作为活检对潜在肿瘤进行诊断评估的先决条件。这些技术有许多局限性，包括缺乏诊断的特异性和准确性，以及缺乏癌症分期和预后信息。这最终会产生大量的假阳性诊断，并因此产生不必要的大量手术活检。这一建议背后的理由基于两个数据来源：1)当前的科学文献，其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(如前列腺癌)的人表现出免疫反应，可以在外周血液循环中白细胞基因表达改变的水平上检测到这种反应。对白细胞中一些单独基因的mRNA转录本的定量检测表明，在乳腺癌和前列腺癌患者中，基因表达水平与肿瘤的存在之间存在关联。2)调查前列腺癌患者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令人震惊；对外周白细胞基因表达数据的监督聚类分析，使用来自11名前列腺癌患者和7名匹配的对照组受试者的数千个基因的转录水平测量，得出了所有受试者归入正确组的结果。这些观察构成了这项拟议研究的假设和实验设计的基础。在特定目标一下，我们将采集和处理55例乳腺癌患者和25例健康对照的血液。然后，我们将使用微阵列技术同时测量从乳腺癌患者和对照受试者的血液中提取的白细胞中转录的多达14,000个基因的表达水平，并使用数据分析算法来确定每个受试组特有的基因表达模式。利用这项技术，我们建议研究我们的中心假设：乳腺癌患者外周血白细胞中的基因表达水平显示出一种保守的模式，这与对照组外周血白细胞中的表达模式不同。在特定的目标二下，我们将检验进一步的假设，即具有不同组织学分级的乳腺癌患者将产生反映肿瘤的生物学阶段和侵袭性的不同的表达特征，从而可以用于区分不同病理阶段的肿瘤。我们相信，我们建议开发的诊断技术最终可能形成临床测试的基础，该测试将在最大限度地减少患者不适的情况下，具有识别患有乳腺癌的女性的能力，并提供重要的阶段特定信息。

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.