Abstract 7061: Biomarkers in TGF-β and corresponding Immune pathway stratify HCC-risk in cirrhotic patients
Authors: Xiyan Xiang, Richard L. Amdur, Kirti Shetty, Herbert Yu, Linda L. Wong, Nyasha Chambwe, Sanjaya K. Satapathy, James M. Crawford, Lopa Mishra
Journal: Cancer Research (2025)

Abstract Purpose: Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths worldwide, which is mostly diagnosed at advanced and incurable stages. The suboptimal performance of current screening approaches including serum alpha-fetoprotein testing and ultrasound, highlights the urgent need for novel biomarkers to enable risk stratification and early detection of HCC. Based on our previous mechanistic insights with data from human genomic studies available in The Cancer Genome Atlas (TCGA) and from animal models (Cell Rep. 2024.43(9):114676 and Sci Transl Med. 2021.13(624): eabk2267), we have identified functional protein markers associated with HCC such as TGFBR2, MSTN, and PKM2. In this study, we present a model based on the TGF-β and associated immune pathways for the HCC stratification in cirrhotic patients that incorporates biologically relevant proteins to capture ongoing pathophysiological changes that drive hepatocarcinogenesis. Experimental Procedures: A proteomic analysis of 7, 000 proteins (SomaScan) utilizing serum samples (55 uL/each) from 311 individuals with cirrhosis, 18 of whom developed HCC by imaging criteria during the median 5-year follow-up. Using a multivariable logistic regression method, we conducted an unsupervised clustering analysis of TGF-β and the corresponding immune pathway and combined with well-described serum biomarkers to create a risk prediction model. We followed this with ELISA validation of the most promising biomarkers. Results: In our prospective cirrhosis cohort (n=311), 18 HCC cases (5.8%) developed over a median follow-up of 5 years. Using unsupervised hierarchical clustering, we analyzed TGF-β pathway (n=28) and inflammatory/immune response proteins (n=36), grouping patients into two subgroups based on serum protein expression. Among HCC cases, 77.8% showed higher SMAD3 and 66.7% showed higher TGFBR2 expression. Cirrhotic patients with elevated expression of serum HMGB1/IL34/CCL3L1/IL37/SMAD3/TGFBR2 had a six-fold higher HCC risk (10.64% vs. 1.76%). A TGF-β model combining TGFBR2, GPC3, ANGPTL8, and GZMK outperformed the AFP model, with AUCs of 0.88 vs. 0.60 and better sensitivity (0.61 vs. 0.11) at 0.90 specificity. ELISA validation confirmed that MSTN, TGFBR2, and HMGB2 levels were significantly elevated in HCC (p&amp;lt;0.05). Conclusions and Next Steps: This study successfully demonstrates the high performance of our TGF-β and corresponding immune pathway biologically related biomarkers for HCC risk stratification in cirrhotic patients. The next steps will be large-scale validations of this biomarker panel in cirrhotic patients across all racial and ethnic subgroups in Phase II/III studies. Citation Format: Xiyan Xiang, Richard L. Amdur, Kirti Shetty, Herbert Yu, Linda L. Wong, Nyasha Chambwe, Sanjaya K. Satapathy, James M. Crawford, Lopa Mishra. Biomarkers in TGF-β and corresponding Immune pathway stratify HCC-risk in cirrhotic patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7061.