Use of Circulating MicroRNAs for Early Detection and Risk Assessment for Pancreatic Cancer

使用循环 MicroRNA 进行胰腺癌的早期检测和风险评估

基本信息

批准号：
10541824
负责人：
VERONICA WENDY SETIAWAN
金额：
$ 44.03万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541824
关键词：
African Age Algorithms Area Under Curve Asian Biological Markers Blood Blood donor Blood specimen CA-19-9 Antigen Cancer Detection Cancer Etiology Cell Lineage Cessation of life Code Cohort Studies Colorectal Cancer Communities Data Development Diagnosis Diagnostic Disease Early Diagnosis Ethnic Population European ancestry Gene Expression Hispanic Human Incidence Individual Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Measures MicroRNAs Monitor Native Hawaiian Nested Case-Control Study Participant Patients Performance Pilot Projects Plasma Play Primary Prevention Prospective, cohort study Proteins Publications Race Regulator Genes Reporting Research Research Design Resources Risk Assessment Risk Factors Role Sampling Screening for cancer Secondary Prevention Survival Rate TIMP1 gene Technology Time Untranslated RNA Whole Blood Women&apos s Health biomarker identification biomarker performance cancer diagnosis cancer risk carcinogenesis case control chronic pancreatitis circulating microRNA clinical diagnosis clinical practice cohort diagnostic biomarker diagnostic value early detection biomarkers high risk population indexing innovation male health microRNA biomarkers mortality multi-ethnic nano-string pancreatic cancer patients posttranscriptional racial population risk prediction tumor progression

项目摘要

Detecting pancreatic cancer at an early, asymptomatic stage is a top priority for reducing incidence and mortality of this most fatal disease. MicroRNAs (miRNAs) regulate gene expression and play a critical role in carcinogenesis and cancer progression. In 2014, two blood miRNA-based diagnostic indices capable of distinguishing pancreatic cancer patients from healthy controls and chronic pancreatitis patients (AUC: 0.83 to 0.75) were reported. The utility of these indices for pancreatic cancer early detection, however, has not been evaluated. Recently, we completed a pilot study in which we measured 800 miRNAs in pre-diagnostic plasma samples from 185 pancreatic cancer cases and individually-matched controls selected from the Prostate, Lung, Colorectal and Ovary Cancer Screening Trial (PLCO). We applied the algorithms of the two reported diagnostic indices and found that one index is reasonably effective in discriminating pancreatic cancer patients from controls within 2 years (AUC= 0.73) but not from 2- <5 years (AUC=0.68) before cancer diagnosis. The AUC increased to 0.83 for both <2 years and 2- <5 years prior to cancer diagnosis when 4 miRNAs selected from our own pilot study were applied as the classifier; and for <2 years, further increased to 0.92 when CA19-9 and known risk factors were added to the classifier. To validate these highly promising findings and to evaluate the time window during which the discriminative/predictive miRNAs are most informative for cancer early detection and/or risk assessment, we propose a comprehensive and confirmatory study using additional PLCO resources as well as resources from four prospective cohort studies: the Southern Community Cohort Study (SCCS), the Multiethnic Cohort Study (MEC), the Shanghai Women's Health Study (SWHS), and the Shanghai Men's Health Study (SMHS). Specific aims for the study are: (1) To evaluate all miRNAs showing a significant association with pancreatic cancer risk in our pilot study and from publications in an independent set of 341 case-control pairs using plasma collected within 5 years prior to cancer diagnosis. (2) To evaluate the association of miRNAs replicated in Aim 1 in an independent set of 924 case-control pairs with plasma samples collected >5 years prior to cancer diagnosis by time windows (e.g., 5-9 years and 10+ years). (3) To develop indices for early detection (based on miRNAs showing a stronger association in the time window closer to diagnosis) and risk assessment (based on miRNAs showing a long-term association, e.g., 5+ years prior to cancer diagnosis) using the PLCO data and validate them using samples from the SCCS, SWHS, SMHS and MEC. (4) To assess the added value of monitoring secular changes in levels of replicated miRNAs for cancer early detection using repeated pre-diagnosis plasma samples from the PLCO cases and controls. Performance of miRNA-based indices will be compared to those based on CA19-9 and TIMP1 and known risk factors. Built upon strong pilot data and unique pre-existing resources from cohorts that include multiple ethnic populations, this innovative study has significant potential to generate highly impactful and translatable results.

在早期发现胰腺癌是降低发生率和这种最致命疾病的死亡率。 microRNA（miRNA）调节基因表达并在致癌和癌症进展。 2014年，两个基于血液的基于miRNA的诊断指数区分胰腺癌患者和健康对照和慢性胰腺炎患者（AUC：0.83至报告了0.75）。但是，这些指数用于胰腺癌早期检测的实用性并非评估。最近，我们完成了一项试点研究，其中测量了诊断前血浆中的800个miRNA 来自185例胰腺癌病例的样品和从前列腺肺中选择的单独匹配的对照结直肠癌和卵巢癌筛查试验（PLCO）。我们应用了两个报道的诊断的算法索引，发现一个指数在区分胰腺癌患者中相当有效对照在2年内（AUC = 0.73），但不能在癌症诊断前的2- <5年（AUC = 0.68）。 AUC 当选择4个miRNA时，在癌症诊断前<2年和2- <5年都增加到0.83 从我们自己的试点研究中，它被用作分类器； <2年，当 CA19-9和已知危险因素已添加到分类器中。验证这些高度有希望的发现，并评估歧视性/预测性miRNA在癌症中最有用的时间窗口尽早检测和/或风险评估，我们提出了一项全面的确认性研究 PLCO资源以及四项潜在队列研究的资源：南方社区队列研究（SCC），多民族队列研究（MEC），上海妇女健康研究（SWHS）和上海男性健康研究（SMHS）。该研究的具体目的是：（1）评估所有miRNA 在我们的试点研究中，与胰腺癌风险的重要相关性以及独立集中的出版物使用在癌症诊断前5年内收集的血浆中的341个病例对照对。（2）评估在AIM 1中复制的miRNA的关联，在独立的924个病例对照对与等离子体按时间窗口诊断前5年收集的样品（例如5 - 9年和10年以上）。（3）到开发早期检测的指标（基于miRNA，在时间窗口中显示出更强的关联更接近诊断）和风险评估（基于显示长期关联的miRNA，例如5年以上在癌症诊断之前）使用PLCO数据，并使用SCC，SWHS的样品对其进行验证 SMHS和MEC。（4）评估监测复制miRNA水平的世俗变化的附加值对于癌症，使用PLCO病例和对照的重复诊断前血浆样品进行早期检测。基于miRNA的指数的性能将与基于CA19-9和TIMP1的索引和已知风险进行比较因素。建立在强大的飞行员数据和来自人群中的独特先前存在的资源之上，其中包括多个种族人群，这项创新的研究具有产生高度影响力和可翻译结果的巨大潜力。