Inserm UMR-1162, Génomique fonctionnelle des Tumeurs solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium.
Int J Cancer. 2019 Feb 1;144(3):533-544. doi: 10.1002/ijc.31910. Epub 2018 Nov 9.
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.
少数单核苷酸多态性（SNPs）与肝细胞癌（HCC）有重复的相关性。我们的目的是检测 9 个 SNPs 与 HCC 发生之间的关联。GWAS 中与 HCC（DEPDC5、GRIK1、KIF1B、STAT4、MICA、DLC1、DDX18）或肝损伤（PNPLA3-rs738409、TM6SF2-rs58542926）相关的基因中的 SNPs 在包括 1020 例 HCC、2021 例慢性肝病和 2484 例健康个体的发现队列中进行了基因分型，并在酒精性肝病（ALD，n=249）和丙型肝炎（n=268）的前瞻性队列中进行了复制。在发现队列中，PNPLA3 和 TM6SF2 SNPs 与 HCC 相关（OR=1.67[95%CI：1.16-2.40]，p=0.005；OR=1.45[95%CI：1.08-1.94]，p=0.01），经过纤维化、年龄、性别和病因调整后。相比之下，STAT4-rs7574865 仅在乙型肝炎病毒感染患者中与 HCC 相关（p=0.03），其他测试的 SNP 与 HCC 风险无关。PNPLA3 和 TM6SF2 变体在 ALD 患者中与 HCC 独立相关（OR=3.91[95%CI：2.52-6.06]，p=1.14E-09；OR=1.79[95%CI：1.25-2.56]，p=0.001），但与其他病因无关。PNPLA3 SNP 也与非纤维化肝脏上发生的 HCC 显著相关（OR=2.19[95%CI：1.22-3.92]，p=0.007）。在 ALD 的前瞻性队列中，PNPLA3 和 TM6SF2 与 HCC 风险的关联得到了证实。包括 PNPLA3 和 TM6SF2 次要等位基因的遗传评分显示，ALD 患者的 HCC 风险呈逐渐显著增加。总之，PNPLA3-rs738409 和 TM6SF2-rs58542926 是 ALD 患者 HCC 发展的遗传风险变异，呈剂量依赖性。PNPLA3 与非纤维化肝脏上 HCC 的关联表明其在肝癌发生中具有直接作用。
