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

ABSTRACT: 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.

SUBMITTER: Fujiwara N

PROVIDER: S-EPMC9236162 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Fujiwara Naoto N Kubota Naoto N Crouchet Emilie E Koneru Bhuvaneswari B Marquez Cesia A CA Jajoriya Arun K AK Panda Gayatri G Qian Tongqi T Zhu Shijia S Goossens Nicolas N Wang Xiaochen X Liang Shuang S Zhong Zhenyu Z Lewis Sara S Taouli Bachir B Schwartz Myron E ME Fiel Maria Isabel MI Singal Amit G AG Marrero Jorge A JA Fobar Austin J AJ Parikh Neehar D ND Raman Indu I Li Quan-Zhen QZ Taguri Masataka M Ono Atsushi A Aikata Hiroshi H Nakahara Takashi T Nakagawa Hayato H Matsushita Yuki Y Tateishi Ryosuke R Koike Kazuhiko K Kobayashi Masahiro M Higashi Takaaki T Nakagawa Shigeki S Yamashita Yo-Ichi YI Beppu Toru T Baba Hideo H Kumada Hiromitsu H Chayama Kazuaki K Baumert Thomas F TF Hoshida Yujin Y

Science translational medicine 20220622 650

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 associ ...[more]

PMID: 35731891

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Project description:Non-alcoholic liver disease (NAFLD) defines liver abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis with or without cirrhosis development, occurring in the absence of significant alcohol consumption, use of teratogenic medication, or hereditary disorders. The association between NAFLD and metabolic syndrome is well documented and widely recognized. Obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia are the most common metabolic risk factors associated with NAFLD. Among the components of metabolic syndrome, current evidence strongly indicates obesity and diabetes as hepatocellular carcinoma (HCC) risk factors. There is also growing evidence that suggests an increased risk of HCC in NAFLD patients, even surpassing other etiologies in some high-income countries. Epidemiologic data demonstrate a parallel rise in prevalence of obesity, diabetes, NAFLD, and HCC. As obesity and its related diseases have steadily afflicted larger populations, HCC incidence is expected to increase in the future. Pathophysiologic mechanisms that underlie NAFLD development and subsequent progression to nonalcoholic steatohepatitis and cirrhosis (insulin resistance and hyperinsulinemia, oxidative stress, hepatic stellate cell activation, cytokine/adipocytokine signaling pathways, and genetic and environmental factors) appear to play a significant role in the development of NAFLD-related HCC. However, a comprehensive view of molecular mechanisms linking obesity, T2DM, and NAFLD-related HCC, as well as the exact sequence of molecular events, is still not understood in its entirety. Good-quality data are still necessary, and efforts should continue towards better understanding the underlying carcinogenic mechanisms of NAFLD-related HCC. In this paper, we aimed to centralize the most important links supporting these relationships, focusing on obesity, T2DM, and NAFLD-related HCC, as well as point out the major gaps in knowledge regarding the underlying molecular mechanisms behind them.

Dataset Information

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

Publications

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

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