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

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的AI/AN部落社区和印第安保留地。 此外，基于血液的生物标志物筛查比基于成像的筛查实现了更大的依从性， 即使在成像容易获得时也是如此。 有前途的血清生物标志物组已经在进行生物标志物验证的2期和3期研究， 最近5-7年，如Fujifilm-Wako的GALAD测试和Fujifilm-Wako的甲基化DNA标记（MDM）面板， EXACT Sciences，这提高了“液体活检”用于早期检测HCC的可能性。不幸的是， 在AI/AN患者中进行过测试。这些生物标志物的性能很可能将 在AI/AN患者中与在主要白人人群中描述的显著不同， 他们是谁开发的。 项目1的总体目标是使用转化方法开发新的生物标志物策略， 通过3个相互关联的特定目标，专门为AI/AN设计的HCC早期检测： SA 1：确定AI/AN患者中的肝细胞癌（HCC）是否与独特或富集相关 与其他人种/种族群体相比， 为了鉴定分子标记物，包括循环游离甲基化DNA（cf mDNA）标记物， 用于有HCC风险的AI/AN患者的监测。 SA 2：（生物标志物开发的II期研究）。对100例T1或T2病例进行病例对照研究 HCC（n=50例AI/AN，n=50例其他人种/种族）和100例无HCC伴肝硬化的风险对照患者 或HBV（n=50个AI/AN，n=50个其他人种/种族组），根据肝病病因和肝硬化严重程度匹配， 确定并比较以下性能特征（灵敏度、特异性、AUROC） 新的HCC筛选生物标志物组： ·循环甲基化DNA标志物（MDM）组（EXACT sciences） ·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，以优化其对AI/AN人员的性能，并考虑其 通过将其与cf mDNA标记物结合，可以进一步提高性能。 SA 3：（生物标志物开发的III期研究）。开发并验证HCC早期检测算法， 使用纵向（系列）AFP或GALAD的患有HCV-肝硬化或HBV的AI/AN患者的阿拉斯加队列，或 在SA 2中专门为AI/AN患者开发的改良GALAD，通过参数经验模型建模 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.