A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis

被引：60

作者：

Fujiwara, Naoto ^{[1
,2
]}

Kobayashi, Masahiro ^{[3
]}

Fobar, Austin J. ^{[4
]}

Hoshida, Ayaka ^{[1
]}

Marquez, Cesia A. ^{[1
]}

Koneru, Bhuvaneswari ^{[1
]}

Panda, Gayatri ^{[1
]}

Taguri, Masataka ^{[5
]}

Qian, Tongqi ^{[1
]}

Raman, Indu ^{[6
]}

Li, Quan-Zhen ^{[6
]}

Hoshida, Hiroki ^{[1
]}

Sezaki, Hitomi ^{[3
]}

Kumada, Hiromitsu ^{[3
]}

Tateishi, Ryosuke ^{[2
]}

Yokoo, Takeshi ^{[7
]}

Yopp, Adam C. ^{[8
]}

Chung, Raymond T. ^{[9
]}

Fuchs, Bryan C. ^{[10
,11
]}

Baumert, Thomas F. ^{[12
,13
]}

Marrero, Jorge A. ^{[1
]}

Parikh, Neehar D. ^{[4
]}

Zhu, Shijia ^{[1
]}

Singal, Amit G. ^{[1
]}

Hoshida, Yujin ^{[1
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Div Digest & Liver Dis, Dept Internal Med, Dallas, TX 75390 USA

[2] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan

[3] Toranomon Gen Hosp, Dept Hepatol, Tokyo 1058470, Japan

[4] Univ Michigan, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA

[5] Yokohama City Univ, Dept Data Sci, Sch Data Sci, Yokohama, Kanagawa 2360027, Japan

[6] Univ Texas Southwestern Med Ctr Dallas, Microarray Core Facil, Dept Immunol, Bioctr, Dallas, TX 75390 USA

[7] Univ Texas Southwestern Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA

[8] Univ Texas Southwestern Med Ctr Dallas, Div Surg Oncol, Dept Surg, Dallas, TX 75390 USA

[9] Harvard Med Sch, Gastrointestinal Unit, Massachusetts Gen Hosp, Boston, MA 02114 USA

[10] Harvard Med Sch, Div Surg Oncol, Massachusetts Gen Hosp, Boston, MA 02114 USA

[11] Ferring Pharmaceut, San Diego, CA 92121 USA

[12] Univ Strasbourg, INSERM, Inst Rech Malad Virales & Hepat, U1110, F-67200 Strasbourg, France

[13] Strasbourg Univ Hosp, Pole Hepatodigestif, IHU, F-67200 Strasbourg, France

来源：

MED | 2021年 / 2卷 / 07期

关键词：

GENE-EXPRESSION SIGNATURE; SERUM-LEVELS; DISEASE; TRANSCRIPTOME; CANCER; SURVEILLANCE; ASSOCIATION; PREDICTION; SURVIVAL; MODEL;

D O I：

10.1016/j.medj.2021.03.017

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 a-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.

引用

页码：836 / +

页数：26

共 91 条

[1] DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric Surgery [J].

Ahrens, Markus ;

Ammerpohl, Ole ;

von Schoenfels, Witigo ;

Kolarova, Julia ;

Bens, Susanne ;

Itzel, Timo ;

Teufel, Andreas ;

Herrmann, Alexander ;

Brosch, Mario ;

Hinrichsen, Holger ;

Erhart, Wiebke ;

Egberts, Jan ;

Sipos, Bence ;

Schreiber, Stefan ;

Haesler, Robert ;

Stickel, Felix ;

Becker, Thomas ;

Krawczak, Michael ;

Roecken, Christoph ;

Siebert, Reiner ;

Schafmayer, Clemens ;

Hampe, Jochen .

CELL METABOLISM, 2013, 18 (02) :296-302

[2] Identifying Genes for Establishing a Multigenic Test for Hepatocellular Carcinoma Surveillance in Hepatitis C Virus-Positive Cirrhotic Patients [J].

Archer, Kellie J. ;

Mas, Valeria R. ;

David, Krystle ;

Maluf, Daniel G. ;

Bornstein, Karen ;

Fisher, Robert A. .

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2009, 18 (11) :2929-2932

[3] Altered Hepatic Gene Expression in Nonalcoholic Fatty Liver Disease Is Associated With Lower Hepatic n-3 and n-6 Polyunsaturated Fatty Acids [J].

Arendt, Bianca M. ;

Comelli, Elena M. ;

Ma, David W. L. ;

Lou, Wendy ;

Teterina, Anastasia ;

Kim, TaeHyung ;

Fung, Scott K. ;

Wong, David K. H. ;

McGilvray, Ian ;

Fischer, Sandra E. ;

Allard, Johane P. .

HEPATOLOGY, 2015, 61 (05) :1565-1578

[4] SignalP 5.0 improves signal peptide predictions using deep neural networks [J].

Armenteros, Jose Juan Almagro ;

Tsirigos, Konstantinos D. ;

Sonderby, Casper Kaae ;

Petersen, Thomas Nordahl ;

Winther, Ole ;

Brunak, Soren ;

von Heijne, Gunnar ;

Nielsen, Henrik .

NATURE BIOTECHNOLOGY, 2019, 37 (04) :420-+

[5] An Assessment of Benefits and Harms of Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis [J].

Atiq, Omair ;

Tiro, Jasmin ;

Yopp, Adam C. ;

Muffler, Adam ;

Marrero, Jorge A. ;

Parikh, Neehar D. ;

Murphy, Caitlin ;

McCallister, Katharine ;

Singal, Amit G. .

HEPATOLOGY, 2017, 65 (04) :1196-1205

[6] Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals [J].

Baumert, Thomas F. ;

Juehling, Frank ;

Ono, Atsushi ;

Hoshida, Yujin .

BMC MEDICINE, 2017, 15

[7]

Bray F, 2018, CA-CANCER J CLIN, V68, P394, DOI [10.3322/caac.21492, 10.3322/caac.21609]

[8] Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study [J].

Carrat, Fabrice ;

Fontaine, Helene ;

Dorival, Celine ;

Simony, Melanie ;

Diallo, Alpha ;

Hezode, Christophe ;

De Ledinghen, Victor ;

Larrey, Dominique ;

Haour, Georges ;

Bronowicki, Jean-Pierre ;

Zoulim, Fabien ;

Asselah, Tarik ;

Marcellin, Patrick ;

Thabut, Dominique ;

Leroy, Vincent ;

Tran, Albert ;

Habersetzer, Francois ;

Samuel, Didier ;

Guyader, Dominique ;

Chazouilleres, Olivier ;

Mathurin, Philippe ;

Metivier, Sophie ;

Alric, Laurent ;

Riachi, Ghassan ;

Gournay, Jerome ;

Abergel, Armand ;

Cales, Paul ;

Ganne, Nathalie ;

Loustaud-Ratti, Veronique ;

D'Alteroche, Louis ;

Causse, Xavier ;

Geist, Claire ;

Minello, Anne ;

Rosa, Isabelle ;

Gelu-Simeon, Moana ;

Portal, Isabelle ;

Raffi, Francois ;

Bourliere, Marc ;

Pol, Stanislas ;

Bonnet, Delphine ;

Payssan-Sicart, Virginie ;

Pomes, Chloe ;

Bailly, Francois ;

Beaudoin, Marjolaine ;

Giboz, Dominique ;

Hartig-Lavie, Kerstin ;

Maynard, Marianne ;

Billaud, Eric ;

Boutoille, David ;

Cavellec, Morane .

LANCET, 2019, 393 (10179) :1453-1464

[9] Post-transplantation outcome in non-alcoholic steatohepatitis cirrhosis: Comparison with alcoholic cirrhosis [J].

Castello, Beatriz ;

Aguilera, Victoria ;

Teresa Blazquez, M. ;

Rubin, Angel ;

Garcia, Maria ;

Vinaixa, Carmen ;

Benlloch, Salvador ;

SanJuan, Fernando ;

Montalva, Eva ;

Lopez, Rafael ;

Berenguer, Marina .

ANNALS OF HEPATOLOGY, 2019, 18 (06) :855-861

[10] Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma [J].

Chaisaingmongkol, Jittiporn ;

Budhu, Anuradha ;

Dang, Hien ;

Rabibhadana, Siritida ;

Pupacdi, Benjarath ;

Kwon, So Mee ;

Forgues, Marshonna ;

Pomyen, Yotsawat ;

Bhudhisawasdi, Vajarabhongsa ;

Lertprasertsuke, Nirush ;

Chotirosniramit, Anon ;

Pairojkul, Chawalit ;

Auewarakul, Chirayu U. ;

Sricharunrat, Thaniya ;

Phornphutkul, Kannika ;

Sangrajrang, Suleeporn ;

Cam, Maggie ;

He, Ping ;

Hewitt, Stephen M. ;

Ylaya, Kris ;

Wu, Xiaolin ;

Andersen, Jesper B. ;

Thorgeirsson, Snorri S. ;

Waterfall, Joshua J. ;

Zhu, Yuelin J. ;

Walling, Jennifer ;

Stevenson, Holly S. ;

Edelman, Daniel ;

Meltzer, Paul S. ;

Loffredo, Christopher A. ;

Hama, Natsuko ;

Shibata, Tatsuhiro ;

Wiltrout, Robert H. ;

Harris, Curtis C. ;

Mahidol, Chulabhorn ;

Ruchirawat, Mathuros ;

Wang, Xin W. .

CANCER CELL, 2017, 32 (01) :57-+

← 1 2 3 4 5 6 7 8 9 10 →