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，我们将利用马约诊所 研究登记处，生物储存库和我们的胰腺肿瘤实践，以开发资源， 旨在改善早期胰腺导管检测的合作研究 腺癌（PDAC）及其前体。马约诊所是一个卓越的中心， 胰腺疾病的研究，其正在进行的生物标本资源包含来自超 快速识别并前瞻性入组PDAC患者（n= 3，092）;家族性高风险成员 胰腺激酶（n= 2，575）;高风险胰腺疾病患者（n= 1，599）;和健康对照 （n= 2 791）。我们将引入从受试者中纵向采集生物样本以验证生物标志物 在各种设置中的性能。将评估创新鉴定的生物标志物：使用细胞 Zaret实验室发现，当再分化时， 经历了PDAC的早期阶段，导致新的候选生物标志物，包括THBS 2; Ahlquist实验室 使用无偏整体分析鉴定了PDAC和高度异型增生的新型甲基化DNA标记物。 甲基化测序。我们的具体目标是：（1）从DNA构建正式的生物标本集， 适用于PRoBE 2期和3期生物标志物验证研究的血清或血浆。我们将利用现有的 每1-2年收集一次血液和胰液， 胰腺囊肿;我们将每2年从现有和前瞻性招募的高风险家族中采集血液 成员年龄> 50岁。(2)胰腺癌早期检测的血清或血浆生物标志物 根据2期和3期研究中的证据和PCDC共识。我们将进行第三阶段 使用PLCO样品验证THBS 2和CA 19 -9适用于初级保健环境。我们将执行 THBS 2和CA 19 -9的2期验证，适用于高风险受试者的胰腺病学临床环境， 区分PDAC与慢性胰腺炎、囊性肿瘤或神经内分泌肿瘤。我们将执行 一组甲基化DNA标志物（包括ADCY 1、CD 1D、BMP 3、CLEC 11 A， TWIST 1，埃尔莫）来区分健康受试者与PDAC患者。(3)进行II期研究， 验证生物标志物用于早期检测胰腺癌或高度异型增生患者， 胰腺囊肿我们将检测DNA甲基化标志物（包括ZNF 781，PRKCB，CD 1D， BMP 3、CLEC 11 A、HOXA、埃尔莫），其在IPMN中区分低度异型增生和高度异型增生。 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、新型生物标志物开发的经验和生物标本，以及 与PDAC中的早期检测和生物标志物验证相关的生物统计学专业知识。