TY - JOUR
T1 - A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis
AU - Translational Liver Cancer (TLC) Consortium and Precision Liver Cancer Prevention Consortium
AU - Fujiwara, Naoto
AU - Kobayashi, Masahiro
AU - Fobar, Austin J.
AU - Hoshida, Ayaka
AU - Marquez, Cesia A.
AU - Koneru, Bhuvaneswari
AU - Panda, Gayatri
AU - Taguri, Masataka
AU - Qian, Tongqi
AU - Raman, Indu
AU - Li, Quan Zhen
AU - Hoshida, Hiroki
AU - Sezaki, Hitomi
AU - Kumada, Hiromitsu
AU - Tateishi, Ryosuke
AU - Yokoo, Takeshi
AU - Yopp, Adam C.
AU - Chung, Raymond T.
AU - Fuchs, Bryan C.
AU - Baumert, Thomas F.
AU - Marrero, Jorge A.
AU - Parikh, Neehar D.
AU - Zhu, Shijia
AU - Singal, Amit G.
AU - Hoshida, Yujin
N1 - Funding Information:
Y.H. serves as an advisory board member for Helio Health, is a founding shareholder in Alentis Therapeutics, and received research funding from Morphic Therapeutics. T.F.B. serves as an advisor and is a founding shareholder in Alentis Therapeutics. R.T. received lecture fees from Bayer, Chugai, Eisai, Takeda, and Wako/Fujifilm. N.D.P. has served as a consultant to Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome. A.G.S. has served on the advisory boards of Genentech, Eisai, Bayer, Exelixis, and Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest.
Funding Information:
N.F. and Y.H. designed the research, analyzed the data, and wrote the manuscript. M.K. A.J.F. H.S. H.K. and R.T. provided the clinical data and input on the study design. C.A.M. B.K. G.P. T.Y. A.C.Y. and B.C.F. contributed to the experimental design. M.T. T.Q. and S.Z. performed and reviewed the data analyses. A.H. I.R. and Q.-Z.L. conducted the experiments. H.H. developed the web application for the analyses. R.T.C. T.F.B. J.A.M. N.D.P. and A.G.S. contributed to the critical revision of the manuscript for important intellectual content. Y.H. serves as an advisory board member for Helio Health, is a founding shareholder in Alentis Therapeutics, and received research funding from Morphic Therapeutics. T.F.B. serves as an advisor and is a founding shareholder in Alentis Therapeutics. R.T. received lecture fees from Bayer, Chugai, Eisai, Takeda, and Wako/Fujifilm. N.D.P. has served as a consultant to Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome. A.G.S. has served on the advisory boards of Genentech, Eisai, Bayer, Exelixis, and Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7/9
Y1 - 2021/7/9
N2 - 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 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 2 independent cohorts: V2, 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy, and 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 α-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 versus 0.186 in V2 and 0.196 versus 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. Funding: Uehara Memorial Foundation, US NIH (DK099558, CA233794, CA226052, CA222900, CA230694, CA230669, and CA237659), European Commission (ERC-2014-AdG-671231), Cancer Prevention and Research Institute of Texas (RR180016), LABEX HepSYS (ANR-10-LABX-0028_HEPSYS), ARC Foundation (IHU201901299), IUF, Inserm Plan Cancer (HCCMICTAR), and MGH Research Scholars Program.
AB - 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 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 2 independent cohorts: V2, 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy, and 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 α-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 versus 0.186 in V2 and 0.196 versus 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. Funding: Uehara Memorial Foundation, US NIH (DK099558, CA233794, CA226052, CA222900, CA230694, CA230669, and CA237659), European Commission (ERC-2014-AdG-671231), Cancer Prevention and Research Institute of Texas (RR180016), LABEX HepSYS (ANR-10-LABX-0028_HEPSYS), ARC Foundation (IHU201901299), IUF, Inserm Plan Cancer (HCCMICTAR), and MGH Research Scholars Program.
KW - Translation to patients
KW - biomarker
KW - cirrhosis
KW - liver cancer
KW - risk stratification
KW - secretome
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U2 - 10.1016/j.medj.2021.03.017
DO - 10.1016/j.medj.2021.03.017
M3 - Article
C2 - 34318286
AN - SCOPUS:85105340046
SN - 2666-6359
VL - 2
SP - 836-850.e10
JO - Med
JF - Med
IS - 7
ER -