Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.
Sema4, Stamford, Connecticut, USA.
J Hepatol. 2021 Oct;75(4):865-878. doi: 10.1016/j.jhep.2021.04.049. Epub 2021 May 13.
Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies.
We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays.
Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-β proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved.
NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature.
The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
非酒精性脂肪性肝炎（NASH）相关的肝细胞癌（HCC）在全球范围内呈上升趋势，但它的分子特征尚未得到很好的定义。我们旨在确定 NASH-HCC 与其他 HCC 病因相比具有独特的分子特征。
我们从 5 个机构收集了 80 例 NASH-HCC 和 125 例 NASH 样本。对 53 例 NASH-HCC 和 74 例 NASH 的表达谱（n）和全外显子测序（n）数据进行了比较，并与其他病因的 HCC（n=184）进行了比较。对 3 种 NASH-HCC 小鼠模型进行了 RNA-seq/表达谱分析（n=20）。在 HCC 细胞中沉默激活素 A 受体 2A（ACVR2A），并通过比色和集落形成测定评估增殖。
对 NASH-HCC 肿瘤的突变分析显示，TERT 启动子（56%）、CTNNB1（28%）、TP53（18%）和 ACVR2A（10%）是最常突变的基因。NASH-HCC 中 ACVR2A 的突变率高于其他 HCC 病因（10% vs. 3%，p<0.05）。在体外，ACVR2A 的沉默显著促进了 HCC 细胞的增殖。我们发现了一种新的突变特征（MutSig-NASH-HCC），与 NASH-HCC 显著相关（16% vs. 病毒性/酒精性 HCC 的 2%，p=0.03）。非肝硬化 NASH-HCC 的肿瘤突变负荷高于肝硬化 NASH-HCC（1.45 与 0.94 个突变/兆碱基；p<0.0017）。与其他 HCC 病因相比，NASH-HCC 富含胆汁和脂肪酸信号、氧化应激和炎症，具有更高比例的 Wnt/TGF-β 增殖亚类肿瘤（42% vs. 26%，p=0.01）和更低的 CTNNB1 亚类患病率。与其他病因相比，NASH-HCC 表现出更高的免疫抑制性肿瘤微环境的发生率。在 3 种 NASH-HCC 小鼠模型中，保留了人类 NASH-HCC 的关键特征。
NASH-HCC 具有独特的分子特征，包括更高的 ACVR2A 突变率和新发现的突变特征。
医脉通
