Novel biomarker strategies for HCC early detection in AI/AN patients

AI/AN 患者 HCC 早期检测的新型生物标志物策略

• 批准号: 10286759
• 负责人: William Mallory Grady
• 金额: $ 15.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10286759
• 关键词: AFP gene; Age; Alaska; Alaska Native; Algorithms; American Indians; Bayesian Method; Bayesian Modeling; Biological Markers; Case-Control Studies; Caucasians; Cells; Cessation of life; Characteristics; Cirrhosis; Collection; Colorectal Cancer; Cross-Sectional Studies; DNA; DNA Markers; DNA Sequence Alteration; Diagnostic; Early Diagnosis; Environmental Exposure; Epidemiology; Epigenetic Process; Ethnic group; Etiology; Face; Functional disorder; Future; Gender; Genetic; Genetic Polymorphism; Genomics; HBV Genotype; HCV Cirrhosis; Hepatitis B Virus; Image; Incidence; Indian reservation; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Methylation; Modeling; Native-Born; Patients; Pattern; Performance; Persons; Phase; Plasma; Population; Primary carcinoma of the liver cells; Proteins; Research Design; Risk; Science; Sensitivity and Specificity; Serum; Serum Proteins; Severities; Specialized Center; Testing; Time; Tumor Tissue; Woman; base; biomarker development; biomarker panel; biomarker performance; biomarker validation; blood-based biomarker; cancer health disparity; cohort; design; disparity elimination; epigenetic marker; epigenetic profiling; epigenomics; imaging facilities; improved; innovation; liquid biopsy; malignant breast neoplasm; men; molecular marker; mortality; novel; novel marker; performance tests; peripheral blood; phase 2 study; phase 3 study; prospective; racial and ethnic; screening; translational approach; tribal community; tumor; tumor DNA

ABSTRACT: PROJECT 1 – Novel Biomarker Strategies Peripheral blood-based HCC biomarker panels are an essential component of early detection strategies, especially in remote AI/AN tribal communities and Indian reservations that are very far from any imaging facilities. Additionally, blood-based biomarker screening achieves greater compliance than imaging-based screening, even when imaging is readily available. Promising serum biomarker panels have been undergoing phase 2 and 3 studies of biomarker validation in the last 5-7 years, such as the GALAD test by Fujifilm-Wako and the methylated DNA marker (MDM) panel by EXACT Sciences, which raises the possibility of a “liquid biopsy” for early detection of HCC. Unfortunately, none of these panels have ever been tested in AI/AN patients. It is likely that the performance of these biomarkers will be significantly different in AI/AN patients than what was described in predominantly Caucasian populations in whom they were developed. The overarching aim of Project 1 is to use a translational approach to develop novel biomarker strategies for early detection of HCC that are designed specifically for AI/AN through 3 interconnected specific aims: SA1: Determine if hepatocellular carcinoma (HCC) in AI/AN patients is associated with unique or enriched genomic and/or epigenomic alterations or patterns of alterations compared to other racial/ethnic groups in order to identify molecular markers, including circulating free methylated DNA (cf mDNA) markers that can be used for surveillance in AI/AN patients at risk of HCC. SA2: (Phase 2 study of biomarker development). Perform a case-control study of 100 cases with T1 or T2 HCC (n=50 AI/AN, n=50 other racial/ethnic groups) and 100 at-risk control patients without HCC with cirrhosis or HBV (n=50 AI/AN, n=50 other racial/ethnic groups) matched by liver disease etiology and cirrhosis severity, to determine and compare the performance characteristics (sensitivity, specificity, AUROC) of the following novel HCC screening biomarker panels: • Circulating methylated DNA marker (MDM) panel (EXACT sciences) • Serum protein-based biomarker panel GALAD (FujiFilm-Wako Diagnostics) If necessary, we will modify GALAD to optimize its performance for AI/AN persons and consider if its performance can be further improved by combining it with cf mDNA markers. SA3: (Phase 3 study of biomarker development). Develop and validate HCC early detection algorithms in an Alaska cohort of AI/AN patients with HCV-cirrhosis or HBV using longitudinal (serial) AFP or GALAD, or modified GALAD developed in SA2 specifically for AI/AN patients, modeled by a Parametric Empirical Bayesian (PEB) and Multivariate Fully Bayesian (mFB) approach.

摘要：项目 1 – 新型生物标志物策略 基于外周血的 HCC 生物标志物组是早期检测策略的重要组成部分， 特别是在远离任何成像设施的偏远 AI/AN 部落社区和印第安人保留地。 此外，基于血液的生物标志物筛查比基于成像的筛查具有更高的合规性， 即使成像很容易获得。 有前途的血清生物标志物组合已在以下国家进行生物标志物验证的第 2 期和第 3 期研究： 过去 5-7 年的数据，例如 Fujifilm-Wako 的 GALAD 测试以及 Fujifilm-Wako 的甲基化 DNA 标记 (MDM) 面板 EXACT Sciences 提出了通过“液体活检”早期发现 HCC 的可能性，但不幸的是，没有。 这些组中的一些已在 AI/AN 患者中进行过测试，这些生物标志物的性能很可能会改变。 AI/AN 患者中的情况与在以白种人为主的人群中所描述的情况存在显着差异 他们是由谁开发的。 项目 1 的总体目标是使用转化方法来开发新颖的生物标志物策略 专为 AI/AN 设计的 HCC 早期检测通过 3 个相互关联的具体目标： SA1：确定 AI/AN 患者的肝细胞癌 (HCC) 是否与独特或富集相关 与其他种族/族裔群体相比，基因组和/或表观基因组改变或改变模式 为了识别分子标记，包括循环游离甲基化 DNA (cf mDNA) 标记，这些标记可以 用于监测有 HCC 风险的 AI/AN 患者。 SA2：（生物标志物开发的第 2 期研究）对 100 例 T1 或 T2 病例进行病例对照研究。 HCC（n=50 AI/AN，n=50 其他种族/族裔群体）和 100 名无 HCC 且肝硬化的高危对照患者 或 HBV（n=50 AI/AN，n=50 其他种族/族裔群体）与肝病病因和肝硬化严重程度相匹配， 确定和比较以下各项的性能特征（灵敏度、特异性、AUROC） 新型 HCC 筛查生物标志物组合： • 循环甲基化 DNA 标记 (MDM) 组合（精确科学） • 基于血清蛋白的生物标志物组 GALAD (FujiFilm-Wako Diagnostics) 如有必要，我们将修改 GALAD 以优化其针对 AI/AN 人员的性能，并考虑其是否 通过与 cf mDNA 标记结合，可以进一步提高性能。 SA3：（生物标志物开发的第 3 阶段研究）。 使用纵向（连续）AFP 或 GALAD 的阿拉斯加 AI/AN 患者 HCV 肝硬化或 HBV 队列，或 修改后的 GALAD 在 SA2 中专门针对 AI/AN 患者开发，由参数经验模型建模 贝叶斯 (PEB) 和多元完全贝叶斯 (mFB) 方法。