PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

被引：87

作者：

Yang, Jie ^{[1
]}

Trepo, Eric ^{[1
,2
]}

Nahon, Pierre ^{[1
,3
,4
]}

Cao, Qian ^{[5
]}

Moreno, Christophe ^{[2
]}

Letouze, Eric ^{[1
]}

Imbeaud, Sandrine ^{[1
]}

Gustot, Thierry ^{[2
]}

Deviere, Jacques ^{[2
]}

Debette, Stephanie ^{[6
,7
]}

Amouyel, Philippe ^{[8
]}

Bioulac-Sage, Paulette ^{[9
,10
]}

Calderaro, Julien ^{[11
,12
]}

Ganne-Carrie, Nathalie ^{[1
,3
,4
]}

Laurent, Alexis ^{[13
,14
]}

Blanc, Jean Frederic ^{[15
]}

Guyot, Erwan ^{[16
]}

Sutton, Angela

Ziol, Marianne ^{[1
,4
]}

Zucman-Rossi, Jessica ^{[1
]}

Nault, Jean-Charles ^{[1
,4
]}

机构：

[1] Univ Paris 13, Univ Paris Diderot, Univ Paris Descartes,Labex Immunooncol, INSERM,Genom Fonct Tumeurs Solides,UMR 1162, Paris, France

[2] Univ Libre Bruxelles, Clin Univ Bruxelles Hop Erasme, Dept Gastroenterol Hepatopancreatol & Digest Onco, Brussels, Belgium

[3] Hop Univ Paris Seine St Denis, Hop Jean Verdier, AP HP, Liver Unit, Bondy, France

[4] Univ Paris 13, Sorbonne Paris Cite, Communaute Univ & Etab, Unite Format & Rech Sante Med & Biol Humaine, Paris, France

[5] Wuhan Univ, Zhongnan Hosp, Dept Infect Dis, Wuhan, Hubei, Peoples R China

[6] Univ Bordeaux, INSERM, Bordeaux Populat Hlth Res Ctr, Bordeaux, France

[7] CHU Bordeaux, Dept Neurol, Bordeaux, France

[8] Univ Lille, INSERM, CHU Lille, Inst Pasteur Lille, Lille, France

[9] Univ Bordeaux, Bordeaux Res Translat Oncol, UMR1053, Bordeaux, France

[10] CHU Bordeaux, Hop Pellegrin, Serv Pathol, Bordeaux, France

[11] Hop Henri Mondor, Serv Anatomopathol, Creteil, France

[12] Univ Paris Est Creteil, INSERM, Inst Mondor Rech Biomed, U955,Team 18, Paris, France

[13] Hop Henri Mondor, Serv Chirurg Digest, Creteil, France

[14] Univ Paris Est Creteil, Inst Mondor Rech Biomed, Paris, France

[15] CHU Bordeaux, Hop Haut Leveque, Ctr Medicochirurg Magellan, Serv Hepatogastroenterol & Oncol Digest, Bordeaux, France

[16] Hop Univ Paris Seine St Denis, Hop Jean Verdier, AP HP, Lab Biochim, Bondy, France

来源：

INTERNATIONAL JOURNAL OF CANCER | 2019年 / 144卷 / 03期

关键词：

single nucleotide polymorphisms; STAT4; cirrhosis; predisposition; liver cancer; GENOME-WIDE ASSOCIATION; GREATER-THAN-G; CONFERS SUSCEPTIBILITY; RS738409; I148M; LOCUS; REPLICATION; PROGRESSION; INCREASE; GENE;

D O I：

10.1002/ijc.31910

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3-rs738409, TM6SF2-rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16-2.40], p = 0.005; OR = 1.45 [CI95%:1.08-1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4-rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52-6.06], p = 1.14E-09; OR = 1.79 [CI95%:1.25-2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22-3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3-rs738409 and TM6SF2-rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.

引用

页码：533 / 544

页数：12

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