Construction of gene expression signatures with RAGE

使用 RAGE 构建基因表达特征

• 批准号: 6585975
• 负责人: Michael C MacLeod
• 金额: $ 15.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-16 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6585975
• 关键词: biotechnology; breast neoplasm /cancer diagnosis; capillary electrophoresis; cooperative study; female; gene expression; genetic mapping; genetic markers; genetic screening; high throughput technology; human tissue; lymph nodes; neoplasm /cancer classification /staging; neoplasm /cancer relapse /recurrence; prognosis

Breast cancer affects one in eight women in the United States. Current treatment regimes tend to extend post-surgical adjuvant chemotherapy to lymph node negative patients with ever smaller original tumors, even though the majority of such patients do not appear to benefit from such treatment. The establishment of molecular signatures that define subgroups of these patients with different likelihoods of tumor recurrence would be useful allowing therapy to be tailored of the prognosis of the patient. We will also a novel global gene expression analysis procedure called RAGE to establish gene expression profiles for early node- negative breast tumors. A retrospective group of T1N0M0 and T2N0M0 breast tumors, 20 that have recurred within 5 years and 20 that have not, will be studied in Phase 1. The RAGE method will be adapted to a high throughput separation and analysis technology, multiple capillary electrophoresis, and throughput will be increased through various means to about 10,000 measurements per week. Expression levels of a set of approximately 3000 genes will be measured in each of the 40 retrospective tumors. These data will be combined with analogous data collected in Project 1 using SAGE on a subset of these tumors. The combined RAGE and SAGE data obtained in Phase I will be used to identify a set of approximately 700 candidate signature genes that show significant variance in expression between recurrent and non-recurrent tumors or that are expected to be important in breast tumorigenesis. The RAGE technique will then be used in Phase II to study expression of these candidate genes in a prospective set of 250 T1N0M0 and T2N0M0 breast tumors. Additional genes will be added to this set as new candidate genes are identified by further SAGE studies (Project 1) and as advances in our understanding of the biology of breast cancer are made. Ultimately, we expect to determine expression levels for about 1000 genes in the prospective tumor set. Novel genes whose expression may contribute to molecular signatures will be identified and cloned. Personnel in this Project will work closely with statisticians, information scientists and programmers in Project 3 and in the Data Management Core to analyze this dataset for molecular signatures characteristic of subsets of the tumor population.

在美国，乳腺癌影响着八分之一的女性。目前的治疗方案倾向于将术后辅助化疗扩展到原始肿瘤越来越小的淋巴结阴性患者，尽管大多数此类患者似乎没有从这种治疗中受益。建立分子标记来定义具有不同肿瘤复发可能性的这些患者的亚组将是有用的，从而可以根据患者的预后量身定做治疗。我们还将使用一种新的全局基因表达分析程序RAGE来建立早期结节阴性乳腺肿瘤的基因表达谱。第一阶段将对T1N0M0和T2N0M0乳腺肿瘤进行回顾性研究，其中20例在5年内复发，20例未复发。RAGE方法将适应高通量分离分析技术，多毛细管电泳法，并通过各种手段将吞吐量提高到每周约10,000次。一组大约3000个基因的表达水平将在40个回溯性肿瘤中进行测量。这些数据将与在项目1中使用SAGE在这些肿瘤的子集上收集的类似数据相结合。在第一阶段获得的RAGE和SAGE组合数据将用于识别一组大约700个候选签名基因，这些基因在复发和非复发肿瘤之间的表达存在显著差异，或者预计在乳腺肿瘤发生中具有重要作用。RAGE技术随后将在第二阶段用于研究这些候选基因在250个T1N0M0和T2N0M0乳腺肿瘤中的表达。随着进一步的SAGE研究(项目1)以及我们对乳腺癌生物学的理解取得进展，新的候选基因将被添加到这个集合中。最终，我们希望确定未来肿瘤集中约1000个基因的表达水平。其表达可能有助于分子签名的新基因将被识别和克隆。该项目的人员将与项目3和数据管理核心中的统计学家、信息科学家和程序员密切合作，分析该数据集，以确定肿瘤群体亚群的分子特征。