基于转化生长因子-β信号通路的血清蛋白质组学特征可对肝细胞癌风险进行分层。

Serum Proteomic Profile Based on the TGF-β Pathway Stratifies Risk of Hepatocellular Carcinoma.

作者信息

Xiang Xiyan, Shetty Kirti, Yu Herbert, Mishra Bibhuti, Wong Linda L, Zhou Xianghong Jasmine, Satapathy Sanjaya K, Crawford James M, Latham Patricia S, Han Steven-Huy, Mathew Brandon, Dagher Nabil N, Lau Lawrence, Cacaj Fellanza, Vegesna Anil K, Dasarathy Srinivasan, He Aiwu R, Huang Hai, Amdur Richard L, Mishra Lopa

机构信息

Division of Gastroenterology and Hepatology, Department of Medicine, The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Northwell Health, Manhasset, New York, USA.

Division of Gastroenterology and Hepatology, Department of Medicine, The University of Maryland, School of Medicine, Baltimore, Maryland, USA.

出版信息

Liver Int. 2025 Oct;45(10):e70325. doi: 10.1111/liv.70325.

BACKGROUND

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths, primarily due to late-stage diagnosis. In this multicenter study, our goal is to identify functional biomarkers that stratify the risk of HCC in patients with cirrhosis (CP) for early diagnosis.

METHODS

Five thousand and eight serum proteins (Somascan) were analysed in Cohort A (477 CP, including 125 HCC). Clustering analysis of the TGF-β pathway-associated protein signature was performed in a longitudinal, prospective Cohort B (312 CP, in which 18 cases developed HCC over a 5-year follow-up period). Next, a multivariable prediction model was built using logistic regression analysis of cross-sectional data from a matched subgroup (n = 328, Cohort C). Model performance was 10-fold cross-validated across the entire Cohort A (n = 477).

RESULTS

Longitudinal follow-up analysis revealed that patients with elevated TGF-β-related protein signature displayed a five-fold increased risk of developing HCC (9.68% vs. 1.91%). Compared to cirrhosis, serum MSTN, TGFBR2, and AFP levels raised in HCC were validated by ELISA (n = 200, odds ratio = 1.4-2.9, p < 0.05). In Cohort C, 88 proteins were significantly altered in HCC compared to cirrhosis (p < 0.05). The six-protein panel (TGFBR2, MSTN, AFP, COL18A1, GLUL, TP63) displayed a strong performance in the matched cohort C (AUC 0.87, sensitivity 0.88, specificity 0.72), alongside four clinical factors (Age, Sex, BMI, Bilirubin). A 10-fold cross-validation demonstrated a mean AUC of 0.86 in cohort A, with strong predictive power in obese/MASLD/ALD-related patients (AUCs: 0.862-0.921).

CONCLUSIONS

The mechanism-based panel effectively stratifies HCC risk in cirrhotic patients, underscoring the need for Phase II/III validation.

背景

肝细胞癌（HCC）是癌症相关死亡的第三大主要原因，主要是由于晚期诊断。在这项多中心研究中，我们的目标是确定功能性生物标志物，以对肝硬化（CP）患者的HCC风险进行分层，从而实现早期诊断。

方法

在队列A（477例CP患者，包括125例HCC患者）中分析了5008种血清蛋白（Somascan）。在纵向、前瞻性队列B（312例CP患者，其中18例在5年随访期内发展为HCC）中对与转化生长因子-β（TGF-β）途径相关的蛋白特征进行聚类分析。接下来，使用来自匹配亚组（n = 328，队列C）的横断面数据进行逻辑回归分析，建立多变量预测模型。在整个队列A（n = 477）中对模型性能进行10倍交叉验证。

结果

纵向随访分析显示，TGF-β相关蛋白特征升高的患者发生HCC的风险增加了五倍（9.68%对1.91%）。与肝硬化相比，通过酶联免疫吸附测定（ELISA）验证了HCC患者血清中肌肉生长抑制素（MSTN）、转化生长因子β受体2（TGFBR2）和甲胎蛋白（AFP）水平升高（n = 200，比值比 = 1.4 - 2.9，p < 0.05）。在队列C中，与肝硬化相比，88种蛋白在HCC中发生了显著改变（p < 0.05）。六种蛋白组合（TGFBR2、MSTN、AFP、胶原蛋白18α1（COL18A1）、谷氨酰胺合成酶（GLUL）、肿瘤蛋白p63（TP63））在匹配队列C中表现出强大性能（曲线下面积（AUC）为0.87，敏感性为0.88，特异性为0.72），同时还有四个临床因素（年龄、性别、体重指数、胆红素）。10倍交叉验证显示队列A中的平均AUC为0.86，在肥胖/代谢相关脂肪性肝病/酒精性肝病相关患者中具有强大的预测能力（AUC：0.862 - 0.921）。