Blood biomarkers in the TGF-β pathway identify latent liver cancer risk

A new research paper was published in Genes & Cancer on February 5, 2023, titled, “Mechanism-Based Blood Proteomic Markers of the TGF-β Pathway Stratify Hepatocellular Cancer Risk in Cirrhotic Patients.”

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, but is often diagnosed at an advanced incurable stage. However, despite the urgent need for blood-based biomarkers for early detection, few studies capture the ongoing biology to identify biomarkers that stratify risk.

In this new study, researchers Xiyan Xiang, Krishanu Bhowmick, Kirti Shetty, Kazufumi Ohshiro, Xiaochun Yang, Linda L. Wong, Herbert Yu, Patricia S. Latham, Sanjaya K. Satapathy, Christina Brennan, Richard J. Dima, Nyasha Chambwe, Gulru Sharifova, Fellanza Ca Sahara John, James M. Crawford, Hai Huang, Srinivasan Dasarathy, Adrian R. Krainer, Aiwu R. He, Richard L. Amdur, and Lopa Mishrafrom The Feinstein Institutes for Medical Research, Cold Spring Harbor Laboratory, University of Maryland, University of Hawaii, University of Hawaii Cancer Center, The George Washington University, North Shore University Hospital, Northwell Health, Hofstra Northwell School of Medicine, Cleveland Clinic, and at the Georgetown Lombardi Comprehensive Cancer Center, are addressing 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.

“Changes in the TGF-β signaling pathway could reflect a continuum of fibrosis to cirrhosis to cancer in the liver. Thus, we hypothesize that TGF-β pathway-enriched biomarkers may serve as biomarkers in HCC progression and stratify patients at risk.Furthermore, we hypothesized that the comprehensive program of human animal model studies would yield novel TGF-β-based mechanistic biomarkers that could be valuable in generating additional biomarkers that could stratify HCC risk.”

Using machine learning methods with blood levels of 108 protein markers in the TGF-β family, the team found a pattern that differentiates HCC from non-HCC in a group of 216 patients with cirrhosis, referred to as TGF-β-based protein markers. for the early detection of HCC (TPEARLE) comprising 31 markers. Notably, 20 of the cirrhosis-only patients showed a HCC-like pattern, suggesting that they may be a group with undetected HCC or at high risk for HCC development.

In addition, the researchers found two other biologically relevant markers, myostatin and pyruvate kinase M2 (PKM2), which were significantly associated with HCC. They tested these for HCC risk stratification in multivariate models adjusted for demographic and clinical variables, as well as lot and site. These markers reflect ongoing biology in the liver.

“They potentially indicate the presence of HCC early in its progression and before it manifests as a detectable lesion, thus providing a set of markers that may be able to stratify risk for HCC.”