Mayo Clinic Prospective Resource for Biomarker Validation and Early Detection of Pancreatic Cancer

梅奥诊所生物标志物验证和胰腺癌早期检测的前瞻性资源

• 批准号: 9352900
• 负责人: GLORIA M. PETERSEN
• 金额: $ 23.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352900
• 关键词: Age; BMP3 gene; Biological Markers; Biometry; Blood; Blood specimen; CA-19-9 Antigen; Cancer Detection; Cells; Centers of Research Excellence; Clinic; Clinical; Collection; Colorectal; Consensus; Cystic Neoplasm; DNA; DNA Markers; DNA Methylation; Data; Detection; Development; Diagnosis; Dysplasia; Early Diagnosis; Enrollment; Epidemiology; Evaluation; Family member; Funding; Gastroenterology; Goals; Home environment; Human; Individual; Intervention; Lesion; Liquid substance; Lung; Malignant neoplasm of pancreas; Methods; Neuroendocrine Tumors; Nitrogen; Non-Malignant; Ovarian; Pancreas; Pancreatic Cyst; Pancreatic Diseases; Pancreatic Ductal Adenocarcinoma; Patients; Performance; Phase; Plasma; Process; Prostate; Recruitment Activity; Registries; Research; Research Infrastructure; Resources; Sampling; Secretin; Serum; Specificity; Specimen; Staging; THBS2 gene; TNFRSF5 gene; TWIST1 gene; Testing; Time; Tissues; Validation; Work; biobank; biomarker development; biomarker panel; blood-based biomarker; candidate marker; chronic pancreatitis; cohort; disorder control; early detection biomarkers; experience; genetic pedigree; high risk; improved; kindred; member; methylation biomarker; methylome; multidisciplinary; novel; novel marker; pancreatic juice; pancreatic neoplasm; patient registry; phase 2 study; phase 3 study; primary care setting; prospective; protein kinase C beta; screening; statistics; validation studies

To achieve the goals of the Pancreatic Cancer Detection Consortium (PCDC), we will leverage Mayo Clinic research registries, biorepositories, and our pancreatic neoplasia practice to develop a resource for collaborative research aimed at improved detection of early stage pancreatic ductal adenocarcinoma (PDAC) and its precursors. Mayo Clinic is an established center of excellence for research in pancreatic conditions, and its ongoing biospecimen resources contain blood samples from ultra- rapidly identified and prospectively enrolled PDAC patients (n=3,092); high risk members in familial pancreatic kindreds (n=2,575); patients with high risk pancreatic conditions (n=1,599); and healthy controls (n=2,791). We will introduce longitudinal biospecimen collection from subjects to validate biomarker performance in various settings. Innovatively identified biomarkers will be evaluated: using cell reprogramming of late stage human PDAC generated cells, the Zaret lab found that, when re-differentiated, underwent early stages of PDAC leading to new candidate biomarkers, including THBS2; the Ahlquist lab identified novel methylated DNA markers for PDAC and high grade dysplasia using unbiased whole methylome sequencing. Our Specific Aims are to: (1) Construct formal biospecimen sets from DNA, serum, or plasma suitable for PRoBE Phase 2 and 3 biomarker validation studies. We will use existing resources and also prospectively collect blood and pancreatic juice every 1-2 years from patients with pancreatic cysts; we will collect blood every 2 years from existing and prospectively recruited high risk family members >age 50. (2) Validate serum or plasma biomarkers for early detection of pancreatic cancer as directed by the evidence and PCDC consensus in Phase 2 and 3 studies. We will perform a Phase 3 validation of THBS2 and CA19-9 suitable for the primary care setting using PLCO samples. We will perform a Phase 2 validation of THBS2 and CA19-9 suitable for a pancreatology clinic setting of high risk subjects to discriminate PDAC from chronic pancreatitis, cystic neoplasms, or neuroendocrine tumors. We will perform a Phase 2 validation of a panel of methylated DNA markers (including ADCY1, CD1D, BMP3, CLEC11A, TWIST1, ELMO) to discriminate healthy subjects from PDAC patients. (3) Perform a Phase 2 study to validate biomarkers for early detection of pancreatic cancer or high grade dysplasia in patients with pancreatic cysts. We will examine the DNA methylation markers (including ZNF781, PRKCB, CD1D, BMP3, CLEC11A, HOXA, ELMO) that discriminate low grade dysplasia from high grade dysplasia in IPMN. We will validate a panel of these biomarkers in prospectively collected plasma and pancreatic juice of pancreatic cyst patients. Our resources and experience are extensive, from a depth of biobanking experience and biospecimens to epidemiology, gastroenterology, novel biomarker development, and biostatistics expertise relevant to early detection and biomarker validation in PDAC.

为了实现胰腺癌检测联盟(PCDC)的目标，我们将利用梅奥诊所 研究登记、生物信息库和我们的胰腺肿瘤实践，以开发资源 旨在改善早期胰管检测的合作研究 腺癌(PDAC)及其前体。梅奥诊所是一家公认的卓越中心 对胰腺状况的研究，其正在进行的生物样本资源包含来自超 快速识别和预期登记的PDAC患者(n=3,092)；家族性高危成员 胰腺家族(n=2,575)；高危胰腺疾病患者(n=1,599)；健康对照组 (n=2,791)。我们将引入从受试者身上纵向收集生物样品来验证生物标记物 在各种环境下的性能。创新识别的生物标记物将被评估：使用细胞 对晚期人类PDAC产生的细胞进行重新编程后，Zaret实验室发现，当重新分化时， 经历了PDAC的早期阶段，导致了新的候选生物标记物，包括THBS2；Ahlquist实验室 无偏全筛选PDAC和高度异型增生的甲基化DNA标记 甲基组测序。我们的具体目标是：(1)从DNA中构建正式的生物样品集， 适合进行2期和3期生物标记物验证研究的血清或血浆。我们将使用现有的 资源，并前瞻性地每1-2年收集一次血液和胰液 胰腺囊肿；我们将每两年从现有的和预期招募的高危家庭中采集血液。 成员&>年龄50岁。(2)验证血清或血浆生物标志物对胰腺癌早期诊断的价值 根据证据和PCDC在第二和第三阶段研究中的共识。我们将执行阶段3 使用PLCO样本验证适合初级保健环境的THBS2和CA19-9。我们将表演 THBS2和CA19-9的第二阶段验证适用于胰腺科高危对象的临床环境 区分PDAC与慢性胰腺炎、囊性肿瘤或神经内分泌肿瘤。我们将表演 一组甲基化DNA标记(包括ADCY1、CD1D、BMP3、CLEC11A、 Twist1，Elmo)来区分健康受试者和PDAC患者。(3)执行第二阶段研究，以 验证生物标志物在早期发现胰腺癌或高度不典型增生患者中的作用 胰腺囊肿。我们将检测DNA甲基化标记(包括ZNF781、PRKCB、CD1D、 BMP3、CLEC11A、HOXA、ELMO)鉴别IPMN中低级别异型增生与高度异型增生。 我们将在前瞻性收集的血浆和胰液中验证一组这些生物标志物 胰腺囊肿症患者。我们的资源和经验是广泛的，从生物库的深度 流行病学、胃肠病学、新生物标记物开发的经验和生物样本 与PDAC早期检测和生物标记物验证相关的生物统计学专业知识。