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

基本信息

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
项目类别：
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

项目摘要

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财团（PCDC）的目标，我们将利用梅奥诊所研究登记册，生物震荡和我们的胰腺肿瘤实践，以开发用于合作研究旨在改善对早期胰管的检测腺癌（PDAC）及其前体。梅奥诊所是一个既定的卓越中心胰腺条件的研究及其正在进行的生物镜资源包含来自超级的血液样本迅速鉴定并前瞻性地招募的PDAC患者（n = 3,092）；家族中的高风险成员胰腺亲戚（n = 2,575）;具有高风险胰腺疾病的患者（n = 1,599）；和健康对照（n = 2,791）。我们将介绍从受试者的纵向生物循环收集以验证生物标志物在各种设置中的性能。将评估创新的生物标志物：使用单元格重新编程了晚期人类PDAC产生的细胞，Zaret Lab发现，重新分化时，经过PDAC的早期阶段，导致了包括THBS2在内的新候选生物标志物； Ahlquist实验室使用公正的整体确定了PDAC和高级发育不良的新型甲基化DNA标记甲基质测序。我们的具体目的是：（1）从DNA中构建正式的生物镜集，血清或适用于探针2和3生物标志物验证研究的血浆。我们将使用现有的资源，还每1 - 2年从患者中每1 - 2年收集血液和胰汁胰腺囊肿；我们将每2年从现有和前瞻性招募的高风险家庭中收集血液成员> 50岁。（2）验证血清或血浆生物标志物早日检测按照证据和第2阶段和第3阶段的PCDC共识为指示。我们将执行3阶段使用PLCO样品的THB2和CA19-9验证适用于初级保健设置。我们将表演 THBS2和CA19-9的2阶段验证适用于高风险受试者的胰岛诊所设置与慢性胰腺炎，囊性肿瘤或神经内分泌肿瘤区分PDAC。我们将表演 2期2验证甲基化DNA标记的面板（包括ADCY1，CD1D，BMP3，CLEC11A， Twist1，Elmo），以区分PDAC患者的健康受试者。（3）进行2期研究验证生物标志物，以早日检测胰腺癌或高级发育不良患者胰腺囊肿。我们将检查DNA甲基化标记（包括Znf781，PrkCB，CD1D， Bmp3，Clec11a，Hoxa，Elmo），将低级发育不良与IPMN中的高级发育不良区分开。我们将在前瞻性收集的血浆和胰汁中验证这些生物标志物的一组胰腺囊肿患者。我们的资源和经验是广泛的，从生物群的深度流行病学，胃肠病学，新生物标志物发展和生物测量的经验和生物测量与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。