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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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 (<i>n</i> = 328, Cohort C). Model performance was 10-fold cross-validated across the entire Cohort A (<i>n</i> = 477).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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 (<i>n</i> = 200, odds ratio = 1.4–2.9, <i>p</i> < 0.05). In Cohort C, 88 proteins were significantly altered in HCC compared to cirrhosis (<i>p</i> < 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).</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>The mechanism-based panel effectively stratifies HCC risk in cirrhotic patients, underscoring the need for Phase II/III validation.</p>\n </section>\n </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 10","pages":""},"PeriodicalIF":5.2000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70325","citationCount":"0","resultStr":"{\"title\":\"Serum Proteomic Profile Based on the TGF-β Pathway Stratifies Risk of Hepatocellular Carcinoma\",\"authors\":\"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\",\"doi\":\"10.1111/liv.70325\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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 (<i>n</i> = 328, Cohort C). Model performance was 10-fold cross-validated across the entire Cohort A (<i>n</i> = 477).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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 (<i>n</i> = 200, odds ratio = 1.4–2.9, <i>p</i> < 0.05). In Cohort C, 88 proteins were significantly altered in HCC compared to cirrhosis (<i>p</i> < 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).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>The mechanism-based panel effectively stratifies HCC risk in cirrhotic patients, underscoring the need for Phase II/III validation.</p>\\n </section>\\n </div>\",\"PeriodicalId\":18101,\"journal\":{\"name\":\"Liver International\",\"volume\":\"45 10\",\"pages\":\"\"},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70325\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Liver International\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/liv.70325\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Liver International","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/liv.70325","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Serum Proteomic Profile Based on the TGF-β Pathway Stratifies Risk of Hepatocellular Carcinoma
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.
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.
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