Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores

被引：254

作者：

Bianco, Cristiana ^{[1
]}

Jamialahmadi, Oveis ^{[2
]}

Pelusi, Serena ^{[3
]}

Baselli, Guido ^{[1
]}

Dongiovanni, Paola ^{[4
]}

Zanoni, Irene ^{[1
]}

Santoro, Luigi ^{[1
]}

Maier, Silvia ^{[5
]}

Liguori, Antonio ^{[6
]}

Meroni, Marica ^{[4
]}

Borroni, Vittorio ^{[7
]}

D'Ambrosio, Roberta ^{[8
]}

Spagnuolo, Rocco ^{[2
]}

Alisi, Anna ^{[9
]}

Federico, Alessandro ^{[10
]}

Bugianesi, Elisabetta ^{[11
]}

Petta, Salvatore ^{[12
]}

Miele, Luca ^{[6
]}

Vespasiani-Gentilucci, Umberto ^{[13
]}

Anstee, Quentin M. ^{[14
,15
]}

Stickel, Felix ^{[16
]}

Hampe, Jochen ^{[17
]}

Fischer, Janett ^{[18
]}

Berg, Thomas ^{[18
]}

Fracanzani, Anna Ludovica ^{[3
,4
]}

Soardo, Giorgio ^{[5
,19
]}

Reeves, Helen ^{[14
,15
]}

Prati, Daniele ^{[1
]}

Romeo, Stefano ^{[2
,20
]}

Valenti, Luca ^{[1
]}

机构：

[1] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Transfus Med & Hematol, Translat Med, Milan, Italy

[2] Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Clin & Mol Med, Gothenburg, Sweden

[3] Univ Milan, Dept Pathophysiol & Transplantat, Milan, Italy

[4] Fdn IRCCS Ca Granda Osped Maggiore Policli, Gen Med & Metab Dis, Milan, Italy

[5] Univ Udine, Dept Med Area DAME, Clin Internal Med Liver Unit, Udine, Italy

[6] Univ Cattolica Roma, Dept Internal Med, Fdn Policlin A Gemelli, Rome, Italy

[7] ASST Valle Olona, Med Unit, Osped Gallarate, Varese, Italy

[8] Fdn IRCCS Ca Granda Osped Maggiore Policlin, CRC AM & A Migliavacca Ctr Liver Dis, Div Gastroenterol & Hepatol, Milan, Italy

[9] IRCCS Osped Bambino Gesu, Res Unit Mol Genet Complex Phenotypes, Rome, Italy

[10] Univ Campania Luigi Vanvitelli, Div Hepatogastroenterol, Deparment Precis Med, Naples, Italy

[11] Univ Torino, AO Citta Salute & Sci Torino, Div Gastrohepatol, Dept Med Sci, Turin, Italy

[12] Univ Palermo, Gastroenterol & Hepatol, PROMISE, Palermo, Italy

[13] Univ Campus Bio Medico Roma, Dept Hepatol, Rome, Italy

[14] Newcastle Univ, Translat & Clin Res Inst, Fac Med Sci, Newcastle Upon Tyne, Tyne & Wear, England

[15] Newcastle Tyne Hosp NHS Fdn Trust, Newcastle NIHR Biomed Res Ctr, Newcastle Upon Tyne, Tyne & Wear, England

[16] Univ Hosp Zurich, Dept Gastroenterol & Hepatol, Zurich, Switzerland

[17] Tech Univ Dresden, Univ Hosp Dresden, Med Dept 1, Dresden, Germany

[18] Univ Leipzig, Med Ctr, Dept Med 2, Lab Clin & Expt Hepatol,Divis Hepatol, Leipzig, Germany

[19] Italian Liver Fdn, Area Sci Pk,Basovizza Campus, Trieste, Italy

[20] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Clin Nutr Unit, Catanzaro, Italy

来源：

JOURNAL OF HEPATOLOGY | 2021年 / 74卷 / 04期

基金：

欧盟地平线“2020”; 英国医学研究理事会; 瑞典研究理事会;

关键词：

Biomarker; Cirrhosis; Genetics; Hepatic fat; Non-alcoholic fatty liver disease; DISEASE; VARIANT; PATTERNS; GENETICS; HCC;

D O I：

10.1016/j.jhep.2020.11.024

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. Methods: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). Results: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis ( p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p < 10(-7)). In the NAFLD cohort, we identified high PRS cut-offs (>-0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with similar to 90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p < 10(-5)) and without cirrhosis (p <0.05). Conclusions: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. Lay summary: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.

引用

页码：775 / 782

页数：8

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