Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
Med. 2021 Jul 9;2(7):836-850.e10. doi: 10.1016/j.medj.2021.03.017. Epub 2021 Apr 21.
Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need.
A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection.
An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively).
The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.
在晚期肝纤维化中，准确预测长期肝细胞癌（HCC）风险对于具有成本效益的 HCC 筛查至关重要；然而，这仍然是一个未满足的需求。
从先前验证的肝转录组特征中通过生物信息学衍生出一种基于血清蛋白的预测性肝脏分泌组特征（PLSec），并在 79 名晚期肝纤维化患者中进行了优化。我们在混合病因的 331 名肝硬化患者中独立验证了 PLSec 在 HCC 风险中的作用（验证集 1 [V1]），并随后开发了一个包含临床预后变量的评分。该评分随后在两个独立队列中进行了验证：验证集 2（V2）：164 名因丙型肝炎病毒（HCV）感染而接受直接作用抗病毒治疗后治愈的晚期纤维化患者；验证集 3（V3）：146 名晚期纤维化且成功治疗 HCC 并治愈 HCV 感染的患者。
一种基于 8 种蛋白的血液 PLSec 重现了基于转录组的肝脏 HCC 风险状态。在 V1 中，PLSec 与 HCC 风险显著相关（调整后的危险比[aHR]，2.35；95%置信区间[CI]，1.30-4.23）。在 V1 中定义了一个包含血清甲胎蛋白（PLSec-AFP）的综合评分，并在 V2（调整后的优势比，3.80[95%CI，1.66-8.66]）和 V3（aHR，3.08[95%CI，1.78-5.31]；C 指数，0.74）中进行了验证。PLSec-AFP 优于 AFP 单独检测（V2 中 Brier 评分分别为 0.165 比 0.186；V3 中分别为 0.196 比 0.206）。
基于血液的 PLSec-AFP 可以准确分层晚期纤维化患者的长期 HCC 风险，从而指导基于风险的个体化 HCC 筛查。
