The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China; Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao, China.
The Third Department of Hepatic Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
J Hepatol. 2019 May;70(5):904-917. doi: 10.1016/j.jhep.2019.01.007. Epub 2019 Jan 14.
BACKGROUND & AIMS: Genetic variability in the hepatitis B virus X gene (HBx) is frequently observed and is associated with hepatocellular carcinoma (HCC) progression. However, a genotype classification based on the full-length HBx sequence and the impact of genotypes on hepatitis B virus (HBV)-related HCC prognosis remain unclear. We therefore aimed to perform this genotype classification and assess its clinical impact.
We classified the genotypes of the full-length HBx gene through sequencing and a cluster analysis of HBx DNA from a cohort of patients with HBV-related HCC, which served as the primary cohort (n = 284). Two independent HBV-related HCC cohorts, a validation cohort (n = 171) and a serum cohort (n = 168), were used to verify the results. Protein microarray assay analysis was performed to explore the underlying mechanism.
In the primary cohort, the HBx DNA was classified into 3 genotypes: HBx-EHBH1, HBx-EHBH2, and HBx-EHBH3. HBx-EHBH2 (HBx-E2) indicated better recurrence-free survival and overall survival for patients with HCC. HBx-E2 was significantly correlated with the absence of liver cirrhosis, a small tumor size, a solitary tumor, complete encapsulation and Barcelona Clinic Liver Cancer (BCLC) stage A-0 tumors. Additionally, HBx-E2 served as a significant prognostic factor for patients with BCLC stage B HCC after hepatectomy. Mechanistically, HBx-E2 is unable to promote proliferation in HCC cells and normal hepatocytes. It also fails to activate the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3)/STAT5 pathway.
Our study identifies a novel HBx genotype that is unable to promote the proliferation of HCC cells and suggests a potential marker to preoperatively predict the prognosis of patients with BCLC stage B, HBV-associated, HCC.
We classified a novel genotype of the full-length hepatitis B virus X gene (HBx), HBx-E2. This genotype was identified in tumor and nontumor tissues from patients with hepatitis B virus-related hepatocellular carcinoma. HBx-E2 could preoperatively predict the prognosis of patients with intermediate stage hepatocellular carcinoma, after resection.
乙型肝炎病毒 X 基因（HBx）的遗传变异很常见，并且与肝细胞癌（HCC）的进展有关。然而，基于全长 HBx 序列的基因型分类以及基因型对乙型肝炎病毒（HBV）相关 HCC 预后的影响尚不清楚。因此，我们旨在进行这种基因型分类并评估其临床影响。
我们通过测序对全长 HBx 基因进行基因型分类，并对来自 HBV 相关 HCC 患者的 HBx DNA 进行聚类分析，这是一个主要队列（n=284）。两个独立的 HBV 相关 HCC 队列，验证队列（n=171）和血清队列（n=168），用于验证结果。通过蛋白质微阵列分析进行了探索潜在机制的研究。
在主要队列中，HBx DNA 分为 3 种基因型：HBx-EHBH1、HBx-EHBH2 和 HBx-EHBH3。HBx-EHBH2（HBx-E2）表明 HCC 患者的无复发生存率和总生存率更好。HBx-E2 与无肝硬化、肿瘤较小、单发肿瘤、完全包膜和巴塞罗那临床肝癌（BCLC）分期 A-0 肿瘤显著相关。此外，HBx-E2 是肝癌切除术后 BCLC 分期 B HCC 患者的重要预后因素。从机制上讲，HBx-E2 不能促进 HCC 细胞和正常肝细胞的增殖。它也不能激活 Janus 激酶 1（JAK1）/信号转导和转录激活因子 3（STAT3）/STAT5 通路。
我们的研究确定了一种新型的 HBx 基因型，它不能促进 HCC 细胞的增殖，并提出了一种潜在的标志物，可在术前预测 BCLC 分期 B、HBV 相关 HCC 患者的预后。
我们对全长乙型肝炎病毒 X 基因（HBx）的一种新型基因型，HBx-E2 进行了分类。这种基因型在乙型肝炎病毒相关肝细胞癌患者的肿瘤和非肿瘤组织中均有发现。HBx-E2 可以在术前预测切除术后中期肝细胞癌患者的预后。
