@article{86f1db6050d6475dae06d39b509e6a75,
title = "Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition",
abstract = "Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.",
keywords = "cancer chemoprevention, gene signature, hepatocellular carcinoma, prognostic prediction, transcriptome",
author = "Shigeki Nakagawa and Lan Wei and Song, {Won Min} and Takaaki Higashi and Sarani Ghoshal and Kim, {Rosa S.} and Bian, {C. Billie} and Suguru Yamada and Xiaochen Sun and Anu Venkatesh and Nicolas Goossens and Gretchen Bain and Lauwers, {Gregory Y.} and Koh, {Anna P.} and Mohamed El-Abtah and Ahmad, {Noor B.} and Hiroki Hoshida and Erstad, {Derek J.} and Ganesh Gunasekaran and Youngmin Lee and Yu, {Ming Lung} and Chuang, {Wan Long} and Dai, {Chia Yen} and Masahiro Kobayashi and Hiromitsu Kumada and Toru Beppu and Hideo Baba and Milind Mahajan and Nair, {Venugopalan D.} and Michael Lanuti and Augusto Villanueva and Angelo Sangiovanni and Massimo Iavarone and Massimo Colombo and Llovet, {Josep M.} and Aravind Subramanian and Tager, {Andrew M.} and Friedman, {Scott L.} and Baumert, {Thomas F.} and Schwarz, {Myron E.} and Chung, {Raymond T.} and Tanabe, {Kenneth K.} and Bin Zhang and Fuchs, {Bryan C.} and Yujin Hoshida",
note = "Funding Information: The nCounter assay was performed at Mount Sinai qPCR Shared Resource Facility. Bioinformatics analysis was performed by using the High Power Computing facility at Mount Sinai Genomics Core and Department of Scientific Computing. De-identified clinical liver tissues for organotypic ex vivo culture were obtained via Mount Sinai Biorepository. S.N. was supported by Uehara Memorial Foundation. N.G. was supported by FLAGS foundation, Nuovo-Soldati Cancer Research Foundation, and an advanced training grant from Geneva University Hospital. M.Y., W.-L.C., and C.-Y.D. were supported partially by Kaohsiung Medical University “Aim for the Top Universities Grant, grant No. KMU-TP103E06 & No. KMU-TP103E07 & No. KMU-TP103E08,” and by a grant from Kaohsiung Medical University Hospital (KMUH102-2T01). T.F.B. was supported by ARC, Paris, Institut Hospitalo-Universitaire, Strasbourg (IHUARC IHU201301187), Laboratory of Excellence HEPSYS (ANR-10-LABX-0028), and European Union (ERC-2014-AdG-671231-HEPCIR). R.T.C. was supported by NIH/NIDDK (DK078772, DK098079). B.C.F. was supported by NIH/NCI (CA140861), NIH/NIDDK (DK104956), and grant from American Institute for Cancer Research. Y.H. was supported by NIH/NIDDK (DK099558), Irma T. Hirschl Trust, Dr. Harold and Golden Lamport Research Award, European Union (ERC-2014-AdG-671231-HEPCIR), and U.S. Department of Defense (W81XWH-16-1-0363). The HCC risk gene signature Elements assay probes are available upon request to the lead contact (Y.H.) or at www.hoshida-lab.org. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = dec,
day = "12",
doi = "10.1016/j.ccell.2016.11.004",
language = "English",
volume = "30",
pages = "879--890",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}