Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, aflatoxin B1 and HBV infection. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV) and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 24% of the tumors, we identified genetic alterations potentially targetable by FDA-approved drugs. In conclusion, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.EGA study EGAS00001001002

基因组分析有望改善肝细胞癌（hepatocellular carcinoma, HCC）患者的肿瘤表征，进而优化其个体化治疗方案。对243例肝脏肿瘤开展的外显子组测序分析，揭示了与特定危险因素相关的突变特征，这些危险因素主要包括烟酒联合暴露、黄曲霉毒素B1以及乙型肝炎病毒（HBV）感染。本研究共鉴定出161个潜在驱动基因，它们与11条频发异常通路相关。通过突变关联分析，研究人员将相关基因划分为3组，各组均与特定危险因素相关，核心基因分别为CTNNB1（关联酒精暴露）、TP53（关联HBV感染）与AXIN1。结合肿瘤分期进展的分析显示，端粒酶逆转录酶（TERT）启动子突变为肿瘤发生的早期事件；而在侵袭性肿瘤中，成纤维细胞生长因子/细胞周期蛋白D1（FGF/CCND1）扩增、TP53与CDKN2A变异则多见于疾病进展的晚期阶段。在24%的肿瘤样本中，研究人员鉴定出了可被美国食品药品监督管理局（FDA）批准的靶向药物干预的遗传变异。综上，本研究明确了与危险因素特异性相关的突变特征，并绘制了肝细胞癌中异常基因与通路的全景图谱，该成果将为靶向治疗相关临床试验的设计提供重要参考。欧洲基因组学档案（EGA）研究编号：EGAS00001001002