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

Authors

• 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.

APA Citation

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.; and Mishra, Lopa, "Serum Proteomic Profile Based on the TGF-β Pathway Stratifies Risk of Hepatocellular Carcinoma" (2025). GW Authored Works. Paper 8336.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8336

Department

Pathology