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：
9768973
负责人：
GLORIA M. PETERSEN
金额：
$ 86.88万
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/9768973
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 Diagnostic Dysplasia Early Diagnosis Enrollment Epidemiology Evaluation Familial pancreatic cancer Family member Freezing Funding Gastroenterology Goals Home environment Human Individual Infrastructure 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 Phase Plasma Process Prostate Registries Research Resources Sampling Secretin Serum Specificity Specimen Standardization THBS2 gene TWIST1 gene Testing Time Tissues Validation Work biobank biomarker development biomarker panel biomarker performance biomarker validation blood-based biomarker candidate marker chronic pancreatitis cohort disorder control early detection biomarkers experience genetic pedigree high risk improved innovation 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 recruit screening 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联盟 (PCCDC) 的目标，我们将利用 Mayo Clinic 研究登记处、生物样本库和我们的胰腺肿瘤实践，旨在开发资源旨在改进早期胰腺导管的检测的合作研究腺癌（PDAC）及其前体癌。梅奥诊所是一家成熟的卓越中心胰腺疾病的研究及其正在进行的生物样本资源包含来自超快速识别并前瞻性招募 PDAC 患者 (n=3,092)；家庭中的高危成员胰腺亲属（n=2,575）；患有高危胰腺疾病的患者（n=1,599）；和健康控制（n=2,791）。我们将引入受试者的纵向生物样本采集来验证生物标志物各种设置下的性能。将评估创新鉴定的生物标志物：使用细胞 Zaret 实验室对晚期人类 PDAC 生成的细胞进行重新编程，发现当重新分化时，经历了 PDAC 的早期阶段，产生了新的候选生物标志物，包括 THBS2；阿尔奎斯特实验室使用无偏整体鉴定了 PDAC 和高度不典型增生的新型甲基化 DNA 标记甲基化组测序。我们的具体目标是： (1) 从 DNA 构建正式的生物样本集，适用于 PRoBE 第 2 期和第 3 期生物标志物验证研究的血清或血浆。我们将利用现有的资源，并前瞻性地每 1-2 年从患有此病的患者身上收集一次血液和胰液胰腺囊肿；我们将每两年从现有和未来招募的高风险家庭采集一次血液会员年龄 > 50 岁。 (2) 验证血清或血浆生物标志物以早期检测胰腺癌按照第 2 期和第 3 期研究的证据和 PCDC 共识的指导。我们将执行第 3 阶段使用 PLCO 样本验证 THBS2 和 CA19-9 适用于初级保健环境。我们将表演 a THBS2 和 CA19-9 的 2 期验证适用于高风险受试者的胰腺科诊所环境将 PDAC 与慢性胰腺炎、囊性肿瘤或神经内分泌肿瘤区分开来。我们将表演 a 一组甲基化 DNA 标记物（包括 ADCY1、CD1D、BMP3、CLEC11A、 TWIST1、ELMO）来区分健康受试者和 PDAC 患者。 (3) 进行第 2 阶段研究验证用于早期检测胰腺癌或重度不典型增生患者的生物标志物胰腺囊肿。我们将检查DNA甲基化标记（包括ZNF781、PRKCB、CD1D、 BMP3、CLEC11A、HOXA、ELMO）可区分 IPMN 中的低度不典型增生和高度不典型增生。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。我们的资源和经验丰富，深入生物样本库流行病学、胃肠病学、新型生物标志物开发等方面的经验和生物样本与 PDAC 早期检测和生物标志物验证相关的生物统计学专业知识。