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 - 新颖的生物标志物策略 基于外围血液的HCC生物标志物面板是早期检测策略的重要组成部分， 尤其是在偏远的AI/一个部落社区和印度保留地，远离任何成像设施。 此外，基于血液的生物标志物筛查比基于成像的筛选更大的合规性， 即使很容易获得成像。 有希望的血清生物标志物板已经进行了第2阶段和3阶段的生物标志物验证研究 过去的5 - 7年，例如Fujifilm-Wako的Galad测试和甲基化的DNA标记（MDM）面板 精确的科学，这增加了“液体活检”的可能性，以便早期检测HCC。不幸的是，没有 这些面板中曾经在AI/A/A AN患者中进行了测试。这些生物标志物的性能可能会 AI/A A/A的患者的显着差异与主要是高加索人群中所描述的 他们被发展的人。 项目1的总体目的是使用翻译的方法来制定新颖的生物标志物策略 针对AI/AN至3个相互联系的特定目的专门设计的HCC的早期检测： SA1：确定AI/A AN患者中的肝细胞癌（HCC）是否与独特或富集有关 与其他种族/族裔群体相比 为了识别分子标记，包括可以是循环的游离甲基化DNA（CF MDNA）标记 用于AI/A A/A的患者的监视。 SA2 ：（生物标志物开发的第2阶段研究）。对100例T1或T2病例进行病例对照研究 HCC（n = 50 AI/AN，n =其他种族/种族群体）和100名没有肝硬化HCC的高危患者 或HBV（n = 50 AI/AN，n =其他种族/种族群体）与肝病病因和肝硬化严重程度相匹配 确定和比较以下的性能特征（灵敏度，特异性，AUROC） 新型HCC筛选生物标志物面板： •循环甲基化的DNA标记（MDM）面板（精确科学） •基于血清蛋白质的生物标志物面板（Fujifilm-Wako诊断） 如有必要，我们将修改Galad，以优化AI/AN人的性能，并考虑是否 通过将其与CF MDNA标记相结合，可以进一步提高性能。 SA3 ：（生物标志物开发的第三阶段研究）。开发和验证HCC早期检测算法 AI/AI/A的AI/A A A AI/A A A A AI患者使用纵向（串行）AFP或GALAD或GALAD或HBV患者 在SA2中开发了专门针对AI/A的患者开发的修饰galad，由参数经验建模 贝叶斯（PEB）和多元完全贝叶斯（MFB）方法。