Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.
Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.
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DOI：
10.1126/scitranslmed.abo4474
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发表时间：
2022-06-22
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在非酒精性脂肪性肝病(NAFLD)患者中，预测肝细胞癌(HCC)风险是一个迫切而未得到满足的需求。在来自多个全球地区的409名NAFLD患者的队列中，我们定义并验证了预测NAFLD患者长期肝细胞癌风险的肝脏转录组和血清分泌组特征。在长达15年的纵向观察中，133个基因的标志物--预后肝脏标志物[PLS]-NAFLD预测了肝细胞癌的发生。高危的PLS-NAFLD与纤维化门脉中IDO1+树突状细胞和功能障碍的CD8+T细胞以及受损的代谢调节因子如成纤维细胞生长因子19、FGF21和法尼醇X受体信号有关。FL-NAFLD在非酒精性脂肪肝患者的独立队列中得到了验证，这些患者是单纯的(15年的肝癌发病率在高风险和低风险患者中分别为22.7%和0%)或有肝细胞癌经历的患者(5年的新发肝癌复发率在高风险和低风险患者中分别为71.8%和42.9%)。PLS-NAFLD被生物信息学翻译成一个由4种蛋白组成的分泌组标记PLSec-NAFLD，这在一组患有NAFLD和肝硬变的单纯肝癌患者中得到了验证(15年的肝癌发病率在高危和低危患者中分别为37.6%和0%)。PLSec-NAFLD与我们先前定义的病因不可知的PLSec-AFP的组合产生了改善的肝细胞癌风险分层。FL-NAFLD可以通过减肥手术、亲脂性他汀类药物和IDO1抑制剂进行修饰，这表明该签名可用于药物开发，并可作为肝细胞癌化学预防临床试验的替代终点。总的来说，PLS/PLSec-NAFLD可以实现NAFLD特异性的肝癌风险预测，并促进NAFLD指导的肝癌化学预防的临床翻译。肝脏转录组和血清分泌组衍生特征可预测NAFLD患者的长期肝细胞癌风险和预防干预效果。
Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with non-alcoholic 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 such as fibroblast growth factor (FGF)19, FGF21, and farnesoid X receptor signaling. 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 4-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 endpoint 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. Hepatic transcriptome and serum secretome-derived signatures predict long-term HCC risk and preventive intervention efficacy in patients with NAFLD.
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影响因子：
16.6
作者：
Crouchet E;Bandiera S;Fujiwara N;Li S;El Saghire H;Fernández-Vaquero M;Riedl T;Sun X;Hirschfield H;Jühling F;Zhu S;Roehlen N;Ponsolles C;Heydmann L;Saviano A;Qian T;Venkatesh A;Lupberger J;Verrier ER;Sojoodi M;Oudot MA;Duong FHT;Masia R;Wei L;Thumann C;Durand SC;González-Motos V;Heide D;Hetzer J;Nakagawa S;Ono A;Song WM;Higashi T;Sanchez R;Kim RS;Bian CB;Kiani K;Croonenborghs T;Subramanian A;Chung RT;Straub BK;Schuppan D;Ankavay M;Cocquerel L;Schaeffer E;Goossens N;Koh AP;Mahajan M;Nair VD;Gunasekaran G;Schwartz ME;Bardeesy N;Shalek AK;Rozenblatt-Rosen O;Regev A;Felli E;Pessaux P;Tanabe KK;Heikenwälder M;Schuster C;Pochet N;Zeisel MB;Fuchs BC;Hoshida Y;Baumert TF
通讯作者：
Baumert TF
影响因子：
25.7
作者：
Fujiwara N;Friedman SL;Goossens N;Hoshida Y
通讯作者：
Hoshida Y
DOI：
10.1016/j.cgh.2015.10.010
发表时间：
2016-11
期刊：
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
影响因子：
--
作者：
Goossens N;Hoshida Y;Song WM;Jung M;Morel P;Nakagawa S;Zhang B;Frossard JL;Spahr L;Friedman SL;Negro F;Rubbia-Brandt L;Giostra E
通讯作者：
Giostra E
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser
影响因子：
9.8
作者：
Bair E;Tibshirani R
通讯作者：
Tibshirani R