Surgery and cisplatin‐based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%‐80% of patients. However, some important challenges remain in diagnosing high‐risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16‐gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four‐gene signature: hydroxysteroid 17‐beta dehydrogenase 6, integrin alpha 6, topoisomerase 2‐alpha, and vimentin, with topoisomerase 2‐alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT‐PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration–approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway–associated double‐strand DNA repair, and significantly impedes HB growth in vivo. Conclusion: The highly proliferating C2A subtype is characterized by topoisomerase 2‐alpha gene up‐regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89‐102).

中文翻译：

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对增殖性肝母细胞瘤的诊断和治疗选择的新见解

目前，手术和基于顺铂的肝母细胞瘤 (HB) 治疗可保证 70%-80% 的患者存活。然而，在诊断高风险肿瘤和确定提供新治疗途径的相关靶向通路方面仍然存在一些重要挑战。以前，已经描述了 HB 肿瘤的两个分子亚类，C1 和 C2，其中 C2 是预后最差、肿瘤分期更晚期和总生存率最差的亚组。提出了一种相关的 16 基因特征来区分两个肿瘤亚组，但尚未转移到临床常规中。为了解决这些问题，我们对 25 个肿瘤进行了 RNA 测序，并匹配了患者的正常肝脏样本。转录分析将 HB 分为三个不同的亚组，分别命名为 C1、C2A 和 C2B，可通过简明的四基因特征识别：羟基类固醇 17-β 脱氢酶 6、整联蛋白 α 6、拓扑异构酶 2-α 和波形蛋白，其中拓扑异构酶 2-α 是增殖性 C2A 肿瘤的特征。这些基因的差异表达通过扩大队列的定量 RT-PCR 和免疫组织化学得到证实。我们还揭示了 C2A 亚组中参与范可尼贫血 (FA) 途径的基因的显着过度表达。然后我们研究了几种描述的 FA 抑制剂在体外和体内阻断 HB 细胞生长的能力。我们证明硼替佐米是一种食品和药物管理局批准的蛋白酶体抑制剂，在体外强烈损害 HB 细胞系的增殖和存活，阻断 FA 途径相关的双链 DNA 修复，并显着阻碍体内 HB 生长。结论：高度增殖的 C2A 亚型的特征是拓扑异构酶 2-α 基因上调和 FA 通路激活，HB 治疗武器库可能包括硼替佐米，用于治疗最具侵袭性的肿瘤患者。（肝病学 2018 年；68：89-102）。