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

项目4的翻译目标是确定DNA损伤反应(DDR)途径的标记 将提高我们预测乳腺癌预后的能力，并防止过度或不足的治疗 疾病。我们评估候选结果标志的基础是2337个基于总体的队列 45-79岁被诊断为浸润性乳腺癌的女性(约1900名有可用肿瘤) 因复发和死亡而接受随访(被子研究)。这个特征很好的队列，这是 专为评估复发和死亡的决定因素而设计，在阐明 对结果的洞察，包括：全面的诊断前和诊断后暴露数据，完整 治疗和病史数据，检查不同假设的灵活性和效率，关于 以及控制许多不同的潜在混杂因素的能力，并包括广泛的病例。 乳腺癌的发病率和死亡率很高，迫切需要更多的肿瘤标志物。 (超越组织病理学，ER和Her2)可以预测结果，作为治疗靶点，和/或指导 对新诊断的患者进行治疗。令人信服的证据，主要集中在p53，表明DDR PATH是一种有希望的(但未被研究的)乳腺癌临床预后和预测标记物来源 癌症。到目前为止，缺乏一种临床上易于处理的方法来评估DDR活性，这阻碍了研究的进行。 此外，由于DDR既涉及P53依赖的反应，也涉及P53非依赖的反应，因此仅P53状态就是 对信号转导级联反应活性或功能的不充分衡量。 我们将通过一项研究对乳腺癌中DDR通路的活性进行全面评估。 设计用于捕获DDR途径功能的多分析物标记面板。我们将评估两国之间的联系 应用人群队列研究DDR活性与乳腺癌预后和治疗反应的关系 如上所述。我们的具体目标是：(1)利用被子研究基于人群的队列和DDR 从文献和在Aim 2中发现的标记中确定，测试DNA是否激活 乳腺癌的损伤反应是预测性的或预后的；(2)鉴定蛋白质和转录本升高 在激活人乳腺上皮细胞DNA损伤反应时(体外)，并确定 在人类乳腺癌组织中可以检测到哪种反应蛋白。

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.