Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease

Naoto Fujiwara, Naoto Kubota, Emilie Crouchet, Bhuvaneswari Koneru, Cesia A. Marquez, Arun K. Jajoriya, Gayatri Panda, Tongqi Qian, Shijia Zhu, Nicolas Goossens, Xiaochen Wang, Shuang Liang, Zhenyu Zhong, Sara Lewis, Bachir Taouli, Myron E. Schwartz, Maria Isabel Fiel, Amit G. Singal, Jorge A. Marrero, Austin J. FobarNeehar D. Parikh, Indu Raman, Quan Zhen Li, Masataka Taguri, Atsushi Ono, Hiroshi Aikata, Takashi Nakahara, Hayato Nakagawa, Yuki Matsushita, Ryosuke Tateishi, Kazuhiko Koike, Masahiro Kobayashi, Takaaki Higashi, Shigeki Nakagawa, Yo Ichi Yamashita, Toru Beppu, Hideo Baba, Hiromitsu Kumada, Kazuaki Chayama, Thomas F. Baumert, Yujin Hoshida

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Original languageEnglish (US)
Article numbereabo4474
JournalScience translational medicine
Issue number650
StatePublished - Jun 22 2022

ASJC Scopus subject areas

  • Medicine(all)


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