Population-based study of DNA damage response markers of prognosis in breast canc

乳腺癌预后 DNA 损伤反应标志物的人群研究

• 批准号: 8181518
• 负责人: AMANDA G PAULOVICH
• 金额: $ 19.98万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181518
• 关键词: Acute; Address; Adjuvant Chemotherapy; Affect; Age; Antibodies; Biological Assay; Biological Markers; Breast; Breast Cancer Prognostic Factor; Cancer Prognosis; Cell Line; Cessation of life; Characteristics; Clinical; Clinical Trials; Cohort Studies; DNA Damage; DNA Repair; Data; Data Set; Decision Making; Detection; Development; Diagnosis; Diagnostic; Disease; ERBB2 gene; Epidemiologic Studies; Epithelial Cells; Estrogen Receptors; Foundations; Future; Gene Expression; Goals; Histopathology; Human; Instruction; Investigation; Ionizing radiation; Literature; Location; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mass Spectrum Analysis; Measures; Mediator of activation protein; Medical History; Messenger RNA; Molecular; Morbidity - disease rate; Multivariate Analysis; Newly Diagnosed; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Population Study; Prevention; Principal Investigator; Process; Property; Proteins; Proteomics; Recurrence; Relative (related person); Reporting; Reproduction spores; Research; Signal Transduction; Source; Specimen; TP53 gene; Testing; Tissues; Transcript; Treatment Protocols; Triage; Tumor Markers; Tumor Tissue; Washington; Woman; Work; aggressive therapy; base; candidate marker; cohort; demographics; design; feeding; flexibility; follow-up; improved; insight; interest; malignant breast neoplasm; mortality; multiple reaction monitoring; novel; novel diagnostics; outcome forecast; population based; prevent; prognostic; programs; response; response marker; text searching; therapeutic target; treatment response; tumor

The translational goal of Project 4 is to identify markers of the DNA damage response (DDR) pathway that will improve our ability to predict outcome in breast cancer and prevent the over, or under, treatinent of disease. Our foundation for evaluating candidate markers of outcome is a population-based cohort of 2337 women (approximately 1900 with available tumors) ages 45-79 diagnosed with invasive breast cancer who are being followed for recurrence and death (QUILT Study). This well-characterized cohort, which was specifically designed to assess determinants of recurrence and mortality, offers unique benefits in elucidating insights into outcomes, including: comprehensive pre- and post-diagnostic exposure data, complete treatment and medical history data, flexibility and efficiency in examining different hypotheses, information on and ability to control for many different potential confounders, and inclusion of a broad spectrum of cases. Breast cancer morbidity and mortality is substantial and there is an acute need for additional tumor markers (beyond histopathology, ER and Her2) that can predict outcome, serve as therapeutic targets, and/or guide therapy in newly diagnosed patients. Compelling evidence, largely centered on p53, indicates that the DDR pathway is a promising (but understudied) source of clinical prognostic and predictive markers for breast cancer. The lack of a clinically tractable assay to assess DDR activity has inhibited investigations to date and also, because DDR involves both p53-dependent and p53-independent responses, p53 status alone is an insufficient measure of activity or functionality of the signal transduction cascade. We will conduct a comprehensive assessment of the DDR pathway activity in human breast cancers via a multi-analyte marker panel designed to capture DDR pathway function. We will assess the association of DDR activity with breast cancer prognosis and treatment response, using the population-based cohort described above. Our specific aims are: (1) Using the QUILT Study population-based cohort and DDR markers identified from the literature and from discovery in Aim 2, test whether activation of the DNA damage response is predictive or prognostic in breast cancer; (2) Identify proteins and transcripts elevated upon activation of the DNA damage response in human mammary epithelial cells (ex vivo), and determine which of the responsive proteins are detectable in human breast cancer tissues.

项目4的翻译目标是鉴定DNA损伤反应（DDR）途径的标记物， 将提高我们预测乳腺癌预后的能力，并防止过度治疗或治疗不足。 疾病我们评估结果的候选标志物的基础是一个基于人群的队列， 年龄45 - 79岁诊断为浸润性乳腺癌的女性（约1900例有可用肿瘤）， 正在随访复发和死亡（QUILT研究）。这个特征鲜明的队列， 专门设计用于评估复发和死亡率的决定因素，在阐明 深入了解结果，包括：全面的诊断前和诊断后暴露数据，完整的 治疗和病史数据，检查不同假设的灵活性和效率， 以及控制许多不同潜在混杂因素的能力，并纳入广泛的病例。 乳腺癌的发病率和死亡率很高，迫切需要额外的肿瘤标记物 （除了组织病理学，ER和Her2），可以预测结果，作为治疗靶点，和/或指导 治疗新诊断的患者。令人信服的证据，主要集中在p53，表明DDR 通路是乳腺癌临床预后和预测标志物的一个有前途的（但研究不足）来源。 癌由于缺乏临床上易于处理的检测方法来评估DDR活性，迄今为止， 而且，由于DDR涉及p53依赖性和p53非依赖性反应，因此仅p53状态是 对信号转导级联的活性或功能的测量不足。 我们将通过一项研究，对人类乳腺癌中DDR途径的活性进行全面评估。 设计用于捕获DDR通路功能的多分析物标记物面板。我们将评估 DDR活性与乳腺癌预后和治疗反应，使用基于人群的队列 上面描述我们的具体目标是：（1）使用QUILT研究人群队列和DDR 从文献和目标2中的发现中鉴定的标记物，测试DNA的激活是否 损伤反应在乳腺癌中是预测性或预后性的;（2）鉴定升高的蛋白质和转录物 在人乳腺上皮细胞（离体）中激活DNA损伤应答后， 在人乳腺癌组织中可检测到哪些应答蛋白。