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

IF 5.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Liver International Pub Date : 2025-09-08 DOI:10.1111/liv.70325

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

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Abstract

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.

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基于TGF-β通路的血清蛋白质组学分析肝细胞癌的风险

肝细胞癌（HCC）是癌症相关死亡的第三大原因，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，对肝硬化（CP）患者的HCC风险进行分层，以进行早期诊断。方法对A队列（477例CP，其中肝癌125例）的588种血清蛋白（Somascan）进行分析。在纵向前瞻性队列B （312 CP，其中18例在5年随访期间发生HCC）中进行了TGF-β通路相关蛋白特征的聚类分析。接下来，对匹配亚组（n = 328，队列C）的横断面数据进行logistic回归分析，建立多变量预测模型。在整个队列A （n = 477）中对模型性能进行了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5倍（9.68% vs. 1.91%）。与肝硬化相比，通过ELISA验证HCC患者血清MSTN、TGFBR2和AFP水平升高（n = 200，优势比= 1.4-2.9,p < 0.05）。在队列C中，与肝硬化相比，HCC中有88种蛋白显著改变（p < 0.05）。6蛋白组（TGFBR2、MSTN、AFP、COL18A1、GLUL、TP63）与4个临床因素（年龄、性别、BMI、胆红素）在匹配队列C中显示出较强的表现（AUC 0.87，敏感性0.88，特异性0.72）。10倍交叉验证显示，队列A的平均AUC为0.86，对肥胖/MASLD/ ald相关患者具有较强的预测能力（AUC: 0.862-0.921）。基于机制的研究小组有效地对肝硬化患者的HCC风险进行了分层，强调了II/III期验证的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.