Naoto Fujiwara1,2, Masahiro Kobayashi3, Austin J Fobar4, Ayaka Hoshida1, Cesia A Marquez1, Bhuvaneswari Koneru1, Gayatri Panda1, Masataka Taguri5, Tongqi Qian1, Indu Raman6, Quan-Zhen Li6, Hiroki Hoshida1, Hitomi Sezaki3, Hiromitsu Kumada3, Ryosuke Tateishi2, Takeshi Yokoo7, Adam C Yopp8, Raymond T Chung9, Bryan C Fuchs10,11, Thomas F Baumert12, Jorge A Marrero1, Neehar D Parikh4, Shijia Zhu1, Amit G Singal1, Yujin Hoshida1. 1. Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S. 2. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. 3. Department of Hepatology, Toranomon Hospital, Tokyo, 105-8470, Japan. 4. Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, 48109, U.S. 5. Department of Data Science, School of Data Science, Yokohama City University, Kanagawa, 236-0027, Japan. 6. Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S. 7. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S. 8. Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S. 9. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, U.S. 10. Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, U.S. 11. Ferring Pharmaceuticals, San Diego, CA, 92121, U.S. 12. Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and IHU, Pole Hépato-digestif, Strasbourg University Hospitals, Strasbourg, 67200, France.
Abstract
BACKGROUND: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need. METHODS: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection. FINDINGS: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively). CONCLUSIONS: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.
BACKGROUND: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need. METHODS: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection. FINDINGS: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively). CONCLUSIONS: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.
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