Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis
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https://doi.org/10.18632/genesandcancer.234
Xiyan Xiang1,*, Krishanu Bhowmick1,*, Kirti Shetty2, Kazufumi Ohshiro1, Xiaochun Yang1, Linda L. Wong3, Herbert Yu4, Patricia S. Latham5, Sanjaya K. Satapathy6, Christina Brennan7,8, Richard J. Dima7, Nyasha Chambwe9, Gulru Sharifova10, Fellanza Cacaj1, Sahara John1, James M. Crawford11, Hai Huang8, Srinivasan Dasarathy12, Adrian R. Krainer13, Aiwu R. He14, Richard L. Amdur1,15 and Lopa Mishra1,13,16
1 The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
2 Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA
3 Department of Surgery, University of Hawaii, Honolulu, HI 96813, USA
4 Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
5 Department of Pathology, The George Washington University, Washington, DC 20037, USA
6 Department of Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, North Shore University Hospital/Northwell Health, Manhasset, NY 11030, USA
7 Office of Clinical Research, Northwell Health, Lake Success, NY 11042, USA
8 The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
9 Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
10 Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
11 Hofstra Northwell School of Medicine, Hempstead, NY 11549, USA
12 Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44106, USA
13 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
14 Georgetown Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA
15 Quantitative Intelligence, The Institutes for Health Systems Science, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
16 Department of Surgery, The George Washington University, Washington, DC 20037, USA
* These authors contributed equally to this work
Correspondence:
Lopa Mishra, email:[email protected], [email protected]
Richard L. Amdur, email:[email protected]
Keywords: TGF-β; hepatocellular carcinoma; myostatin; pyruvate kinase M2; biomarker
Received: November 04, 2023 Accepted: December 05, 2023 Published: February 05, 2024
Abstract
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.
