Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis

• Published in: Genes & cancer 2024-02, Vol.15, p.1-14
• Main Authors: Xiang, Xiyan, Bhowmick, Krishanu, Shetty, Kirti, Ohshiro, Kazufumi, Yang, Xiaochun, Wong, Linda L, Yu, Herbert, Latham, Patricia S, Satapathy, Sanjaya K, Brennan, Christina, Dima, Richard J, Chambwe, Nyasha, Sharifova, Gulru, Cacaj, Fellanza, John, Sahara, Crawford, James M, Huang, Hai, Dasarathy, Srinivasan, Krainer, Adrian R, He, Aiwu R, Amdur, Richard L, Mishra, Lopa
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1947-6019; 1947-6027; 1947-6027
• DOI: 10.18632/genesandcancer.234

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-β pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies. Using machine learning methods with blood levels of 108 proteomic markers in the TGF-β family, we found a pattern that differentiates HCC from non-HCC in a cohort of 216 patients with cirrhosis, which we refer to as TGF-β based Protein Markers for Early Detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the patients with cirrhosis alone presented an HCC-like pattern, suggesting that they may be a group with as yet undetected HCC or at high risk for developing HCC. In addition, we found two other biologically relevant markers, Myostatin and Pyruvate Kinase M2 (PKM2), which were significantly associated with HCC. We tested these for risk stratification of HCC in multivariable models adjusted for demographic and clinical variables, as well as batch and site. These markers reflect ongoing biology in the liver. They potentially indicate the presence of HCC early in its evolution and before it is manifest as a detectable lesion, thereby providing a set of markers that may be able to stratify risk for HCC.