Non-invasive etiology-adjusted precision liver cancer risk prediction

Hepatocellular carcinoma (HCC) is the major histological type of liver cancer, caused by viral (HBV, HCV) and metabolic (alcohol, metabolic dysfunction-associated steatotic liver disease [MASLD]) etiologies. The high mortality rate is attributable to failed early cancer detection, which is increasingly challenging for the current “one-size-fits-all” HCC screening owing to the rapidly changing etiological landscape and growing etiologically heterogeneous at-risk patient populations. Our prior simulation study showed that individual risk-based HCC screening is cost-effective. However, new tools to precisely evaluate the risk according to confounding factors, particularly etiology, are urgently needed. We previously developed etiology-agnostic HCC risk biomarkers, hepatic transcriptome-based Prognostic Liver Signature (PLS) and serum proteome-based Prognostic Liver Secretome signature (PLSec), which were successfully validated in phase 3 biomarker studies. Subsequently, we developed etiology-specific “plug-in” biomarkers for patients with cured HCV and MASLD, which substantially improve the etiology-agnostic HCC risk prediction. PLS/PLSec family biomarkers are therapeutically modifiable, and used as endpoints in clinical trials and studies of HCC chemopreventive agents. These results warrant further expansion of this approach to other major etiologies, HBV and ALD, and non- cirrhotic MASLD for comprehensive etiology-adjusted HCC risk prediction. Cholangiocarcinoma (CCA) risk factors remain largely unknown, as evidenced by the absence of clinically recognizable risk conditions in approximately half of the CCA patients, highlighting an urgent unmet need for CCA risk biomarkers. To address these unmet needs, our objectives are to develop a strategy for HCC risk assessment in cirrhosis and non- cirrhosis patients with the major viral and metabolic etiologies, and develop resources for CCA risk biomarker discovery. Aim 1. Develop and validate etiology-specific HCC risk biomarkers in cirrhotic and non-cirrhotic chronic liver disease patients: we will develop and validate tissue/serum-based “plug-in” HCC risk biomarkers and their integration with the etiology-agnostic PLSec as etiology-adjusted HCC risk assessment tools in cirrhosis and non-cirrhosis patients with HBV, ALD, and MASLD. Tissue/serum samples for CCA risk biomarker development will also be collected. Aim 2. Determine cost-effectiveness of etiology-adjusted HCC screening: by utilizing our established Markov models, we will determine the clinical utility of etiology-adjusted risk- stratified HCC screening, and identify optimal individualized screening strategies. We expect to establish a new strategy of comprehensive etiology-adjusted HCC risk prediction and resources for CCA risk biomarker discovery, which will collectively lead to a transformative improvement in the prognosis of this deadly cancer type. Project Number: 1R01CA292930-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Yujin Hoshida | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $2,876,456 | Activity Code: R01 | Study Section: Molecular Cancer Diagnosis and Classification Study Section[MCDC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11165723