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

Xiyan Xiang, 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.
Krishanu Bhowmick, 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.
Kirti Shetty, Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA.
Kazufumi Ohshiro, 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.
Xiaochun Yang, 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.
Linda L. Wong, Department of Surgery, University of Hawaii, Honolulu, HI 96813, USA.
Herbert Yu, Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Patricia S. Latham, Department of Pathology, The George Washington University, Washington, DC 20037, USA.
Sanjaya K. Satapathy, Department of Medicine, Sandra Atlas Bass Center for Liver Diseases and Transplantation, North Shore University Hospital/Northwell Health, Manhasset, NY 11030, USA.
Christina Brennan, Office of Clinical Research, Northwell Health, Lake Success, NY 11042, USA.
Richard J. Dima, Office of Clinical Research, Northwell Health, Lake Success, NY 11042, USA.
Nyasha Chambwe, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Gulru Sharifova, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
Fellanza Cacaj, 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.
Sahara John, 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.
James M. Crawford, Hofstra Northwell School of Medicine, Hempstead, NY 11549, USA.
Hai Huang, The Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
Srinivasan Dasarathy, Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44106, USA.
Adrian R. Krainer, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Aiwu R. He, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA.
Richard L. Amdur, 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.
Lopa Mishra, 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.

Document Type

Journal Article

Publication Date

1-1-2024

Journal

Genes & cancer

Volume

15

DOI

10.18632/genesandcancer.234

Keywords

TGF-β; biomarker; hepatocellular carcinoma; myostatin; pyruvate kinase M2

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.

Department

Pathology

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