INSERM, INRA, Univ Rennes, CHU Rennes, Nutrition Metabolisms and Cancer (NuMeCan), CRB-Santé, Biosit, Biogenouest, UBL, Rennes, France.
Diamantina Institute and Translational Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Hepatology. 2017 Nov;66(5):1502-1518. doi: 10.1002/hep.29254. Epub 2017 Sep 26.
Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (<2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% β-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133-HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type β-catenin) and perivenous-type (mutant β-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was down-regulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients.
Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection. (Hepatology 2017;66:1502-1518).
肝细胞癌 (HCC) 表现出多种分子表型，这对临床管理提出了重大挑战。通过早期监测计划检测到的 HCC 是潜在可治愈疗法（局部消融、切除或移植）的候选者。从长远来看，移植提供的复发率最低。治疗分配基于肿瘤数量、大小、血管侵犯、表现状态、功能性肝储备以及对早期（<2 年）复发的预测，这反映了肿瘤的内在侵袭性。分化良好、潜在侵袭性低的肿瘤形成非增殖性 HCC 的异质分子类，其特征是大约 50%的β-连环蛋白突变率。为了定义非增殖性 HCC 的临床、病理和分子特征以及结果，我们构建了一个包含 1133 个 HCC 转录组元数据的数据集，并在一个公开的 210 个 HCC RNA 测序集中验证了研究结果。我们表明，非增殖性 HCC 保留了沿门静脉轴分布代谢功能的分区程序。更准确地说，我们确定了两种分化良好、非增殖的亚型，即门脉周围型（野生型β-连环蛋白）和门脉周围型（突变型β-连环蛋白），它们表达负相关的基因网络。新的门脉周围型亚型占所有 HCC 的 29%；表达肝细胞核因子 4A 驱动的基因网络，该网络在小鼠肝细胞核因子 4A 敲除小鼠中被下调；巴塞罗那临床肝癌、意大利肝癌计划和肿瘤-淋巴结-转移分期系统均为早期肿瘤；无大血管侵犯；并且显示出最低的转移特异性基因表达水平和 TP53 突变率。此外，我们鉴定了一个由八个基因组成的门脉周围型 HCC 特征，该特征在两个独立的 247 名和 210 名患者队列的多变量分析中与 2 年无复发生存率最高独立相关。
分化良好的 HCC 显示出相互排斥的门脉周围或门脉周围分区程序。在所有 HCC 中，门脉周围型肿瘤在根治性切除后早期复发的内在潜力最低。（《肝脏病学》2017；66：1502-1518）。
