(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes

摘要 据估计，美国有76.5万人被诊断患有膀胱癌和膀胱癌 疾病复发和进展的可能性可能很高。频繁的、侵入性的经尿道筛查程序 监测复发和进展给患者和医疗保健系统带来负担。更好的 了解膀胱癌患者的肿瘤相关免疫反应可以提供更多 知情的临床决定必要的侵入性随访程序的频率和减少患者 发病率。我们建议利用现有的一项基于人群的膀胱癌研究，该研究包括一系列 有几年的随访，包括患者的治疗和结果数据，以及 匹配的肿瘤样本。我们的合作小组已经开发并广泛验证了表观遗传学 白细胞亚型的生物标记物，允许使用档案DNA来研究免疫图谱。在这里，我们将使用 我们已证实的框架，将我们的白细胞表观遗传生物标记物库扩展到包括髓系来源 抑制细胞(MDSC)，并测试和验证MDSC与其他白细胞亚型(包括 中性粒细胞/淋巴细胞比率(NLR)和细胞类型激活状态与膀胱癌预后的关系； 复发、进展和生存。我们将使用事件发生时间分析，旨在了解 免疫档案、确诊年龄、肿瘤分期和分级、吸烟史和 治疗(包括卡介苗免疫疗法)，与膀胱癌的结果。此外，我们建议衡量 配对人群膀胱癌的体细胞变化特征及其与血液免疫的关系 肿瘤甲基化和存活率的特征，以了解肿瘤特征和患者之间的串扰 免疫反应。最后，为了探索性的目的，我们将前瞻性地调查治疗前和治疗后的情况。 膀胱癌患者的治疗免疫信号。在这个出现的时机 免疫调节疗法我们现有的基于人群的研究资源提供了一个具有成本效益的环境 通过引入新的和灵活的方法来改进新诊断患者的风险预测 免疫监测工具包，可使用肿瘤相关免疫数据为临床决策提供信息 回应。

ABSTRACT There are an estimated 765,000 people with a diagnosis of bladder cancer living in the United States and risk of disease recurrence and progression can be high. Frequent, invasive transurethral screening procedures to monitor for recurrence and progression burden both patients and the health care system. A better understanding of the tumor-associated immune responses in bladder cancer patients could provide for more informed clinical decisions on the necessary frequency of invasive follow up procedures and reduce patient morbidity. We propose to leverage an existing population-based study of bladder cancer that includes a range of patient age groups, has several years of follow up, includes patient treatment and outcome data, as well as matched tumor samples. Our collaborative group has developed and extensively validated epigenetic biomarkers of leukocyte subtypes allowing the use of archival DNA to study immune profiles. Here we will use our proven framework to expand our repertoire of leukocyte epigenetic biomarkers to include myeloid derived suppressor cells (MDSC), and test and validate the relation of MDSC and other leukocyte subtypes (including the neutrophil to lymphocyte ratio: NLR), and cell type activation states with bladder cancer outcomes; recurrence, progression, and survival. We will use time-to-event analysis and aim to understand the independent contributions of immune profiles, age at diagnosis, tumor stage and grade, smoking history, and treatment (including BCG immunotherapy), with bladder cancer outcomes. In addition, we propose to measure somatic alteration profiles of bladder tumors from matched subjects and assess the relation of blood immune signatures with tumor methylation and survival to understand the crosstalk between tumor profiles and patient immune responses. Finally, in an exploratory aim we will prospectively investigate both pre-treatment and post- treatment immune signatures in bladder cancer patients. At this opportune time of emerging immunomodulatory therapeutics our existing population-based study resource provides a cost-efficient setting to advance towards improved risk projection in newly diagnosed patients by ushering in a novel and flexible immune monitoring toolkit that can inform clinical decision-making using data on tumor-associated immune responses.