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

Xiyan Xiang, 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.
Kirti Shetty, Division of Gastroenterology and Hepatology, Department of Medicine, The University of Maryland, School of Medicine, Baltimore, Maryland, USA.
Herbert Yu, Department of Epidemiology, The University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
Bibhuti Mishra, 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.
Linda L. Wong, Department of Surgery, University of Hawaii, Honolulu, Hawaii, USA.
Xianghong Jasmine Zhou, Department of Pathology and Laboratory Medicine, Ronald Reagan Medical Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
Sanjaya K. Satapathy, Division of Hepatology, Northwell Health, and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
James M. Crawford, Department of Pathology and Laboratory Medicine, Northwell, New Hyde Park, New York, USA.
Patricia S. Latham, Department of Pathology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.
Steven-Huy Han, Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California, USA.
Brandon Mathew, 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.
Nabil N. Dagher, Center for Liver Disease and Transplantation, Northwell Transplant Institute, Northwell, Manhasset, New York, USA.
Lawrence Lau, Department of Surgery, North Shore University Hospital, Northwell Health, Manhasset, New York, USA.
Fellanza Cacaj, 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.
Anil K. Vegesna, 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.
Srinivasan Dasarathy, Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio, USA.
Aiwu R. He, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
Hai Huang, Division of Hepatology, Northwell Health, and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
Richard L. Amdur, Quantitative Intelligence Unit, the Institutes for Health Systems Science & Bioelectronic Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, USA.
Lopa Mishra, 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.

Document Type

Journal Article

Publication Date

10-1-2025

Journal

Liver international : official journal of the International Association for the Study of the Liver

Volume

45

Issue

10

DOI

10.1111/liv.70325

Keywords

cirrhosis; early diagnosis; liver cancer; proteomics; surveillance

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.

Department

Pathology

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