(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes

(PQ3) 膀胱癌结果的免疫表观遗传生物标志物

基本信息

批准号：
10225457
负责人：
Brock Clarke Christensen
金额：
$ 47.25万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225457
关键词：
Address Aftercare Age Archives B-Lymphocytes Bacillus Calmette-Guerin Therapy Biology Bladder Neoplasm Blood Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Patient Cells Cessation of life Classification Clinical Communities DNA DNA Methylation Data Diagnosis Disease Disease Management Environment Epigenetic Process Event Frequencies Goals Healthcare Systems Immune Immune response Immunologic Markers Immunologic Monitoring Immunomodulators Immunosuppression Immunotherapeutic agent Inflammation Leukocytes Libraries Lymphocyte Malignant Neoplasms Malignant neoplasm of urinary bladder Measures Methods Methylation Molecular Monitoring for Recurrence Morbidity - disease rate Muscle Myeloid Cells Myeloid-derived suppressor cells Myelopoiesis Natural Killer Cells New Hampshire Newly Diagnosed Outcome Patient-Focused Outcomes Patients Peripheral Population Study Predictive Value Procedures Prognosis Recurrence Resources Risk Risk Factors Role Sampling Screening procedure Smoking History Stratification Testing Time Treatment outcome Tumor stage United States Work age group anticancer research base cancer diagnosis cancer recurrence cell type clinical application clinical decision-making cost efficient disorder risk epigenetic marker flexibility follow-up granulocyte improved methylation biomarker monocyte neutrophil novel novel strategies peripheral blood population based predictive marker prognostic prognostic value prospective response risk stratification screening success time use tool tumor tumor DNA

项目摘要

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.

抽象的估计有765,000人患有膀胱癌居住在美国，风险疾病复发和进展可能很高。频繁的，侵入性的尿道筛查程序监测患者和医疗保健系统的复发和进展负担。更好了解膀胱癌患者中与肿瘤相关的免疫反应可能提供更多关于侵入性随访程序必要频率并减少患者的临床决定的知情临床决策发病率。我们建议利用现有的基于人群的膀胱癌研究，其中包括一个范围患者年龄组的随访数年，包括患者治疗和结果数据，以及匹配的肿瘤样品。我们的协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志物允许使用档案DNA研究免疫谱。在这里我们将使用我们经过验证的框架扩展了我们的白细胞表观遗传生物标志物的曲目，包括骨髓抑制细胞（MDSC），并测试和验证MDSC和其他白细胞亚型的关系（包括中性粒细胞与淋巴细胞比：NLR）和具有膀胱癌预后的细胞类型激活态；复发，进展和生存。我们将使用时间到事实分析，并旨在了解免疫特征的独立贡献，诊断年龄，肿瘤阶段和等级，吸烟史以及治疗（包括BCG免疫疗法），并具有膀胱癌预后。另外，我们建议测量来自匹配受试者的膀胱肿瘤的体细胞改变谱并评估血液免疫的关系具有肿瘤甲基化和生存的签名，以了解肿瘤轮廓与患者之间的串扰免疫反应。最后，在探索目的中，我们将前瞻性地研究预处理和后膀胱癌患者的治疗免疫特征。在这个合适的时机免疫调节治疗剂我们现有的基于人群的研究资源提供了一种成本效益的环境通过迎接新颖而灵活免疫监测工具包，可以使用有关肿瘤相关免疫的数据为临床决策提供信息回答。