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

摘要：项目1--新的生物标记策略 基于外周血液的肝细胞癌生物标记物面板是早期检测策略的重要组成部分， 特别是在偏远的AI/AN部落社区和印第安人保留地，这些社区离任何成像设施都很远。 此外，基于血液的生物标记物筛查比基于成像的筛查实现了更高的遵从性， 即使成像是现成的。 有希望的血清生物标记物小组一直在进行生物标记物验证的第二和第三阶段研究 过去5-7年，例如Fujifilm-Wako的Galad测试和DNAM甲基化标记(MDM)小组 Exact Science，这增加了早期发现肝细胞癌的“液体活检”的可能性。不幸的是，一个也没有 这些面板中有一组曾在AI/AN患者中进行过测试。很可能这些生物标记物的表现将 在AI/AN患者中与在以高加索人为主的人群中描述的显著不同 他们是被培养出来的。 项目1的总体目标是使用翻译方法来开发新的生物标志物策略 通过3个相互关联的具体目标，早期发现专为AI/AN设计的肝细胞癌： SA1：确定AI/AN患者的肝细胞癌(HCC)是否与独特或丰富相关 与其他种族/民族相比，基因组和/或表观基因组改变或改变模式 以识别分子标记，包括循环游离甲基化DNA(Cf MDNA)标记，这些标记可以 用于监测有肝癌风险的AI/AN患者。 SA2：(生物标志物开发的第二阶段研究)。对100例T1或T2患者进行病例对照研究 肝细胞癌(n=50个AI/AN，n=50个其他种族/民族)和100名无肝细胞癌合并肝硬变的高危对照患者 或与肝病病因和肝硬变严重程度相匹配的乙肝病毒(n=50 AI/AN，n=50其他种族/民族)， 确定和比较以下各项的性能特征(敏感度、特异度、AUROC 新型肝细胞癌筛查生物标志物面板： ·循环甲基化DNA标记(MDM)小组(精密科学) ·基于血清蛋白的生物标记物面板Galad(Fujifilm-Wako Diagnostics) 如有必要，我们将修改Galad以优化其对人工智能/人工智能人员的性能，并考虑其 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)。开发和验证肝细胞癌早期检测算法 使用纵向(序列)AFP或Galad的丙型肝炎肝硬化或乙肝患者的阿拉斯加队列AI/AN患者，或 在SA2中专门为AI/AN患者开发的改进的Galad，由参数经验建模 贝叶斯(PEB)和多元完全贝叶斯(MFB)方法。

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.