BACKGROUND AND AIMS Hepatoblastoma (HB) is a rare disease. Nevertheless, it is the predominant pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. Here we sought to increase knowledge of HB pathobiology in an effort to move towards precision medicine. To this end, we used high-throughput technologies to identify new biomarkers and therapeutic targets for HB patients with poor prognosis METHODS: We performed a comprehensive genomic, transcriptomic and epigenomic characterization of 159 clinically-annotated samples from 113 HB patients RESULTS: We discovered an unprecedented widespread epigenetic footprint of HB that includes hyperediting of the tumor suppressor BLCAP concomitant with a genome-wide dysregulation of RNA editing and the overexpression of mainly non-coding genes of the oncogenic 14q32 DLK1-DIO3 locus. By unsupervised analysis, we identified two epigenomic clusters (Epi-CA, Epi-CB) with distinct degree of DNA hypomethylation and CpG island hypermethylation that are associated with the C1/C2/C2B transcriptomic subtypes. Based on these findings, we defined the first Molecular Risk Stratification of HB (MRS-HB), which encompasses three main prognostic categories and improves the current clinical risk stratification approach. The MRS-3 category (28%), defined by strong 14q32 locus expression and Epi-CB methylation features, was characterized by CTNNB1 and NFE2L2 mutations, a progenitor-like phenotype and clinical aggressiveness. Finally, we identified choline kinase alpha as a promising therapeutic target for intermediate and high-risk HBs since its inhibition in HB cell lines and patient-derived xenografts strongly abrogated tumor growth CONCLUSIONS: Our findings expand our knowledge about the molecular features of HB and may contribute to improve current clinical stratification approaches and treatments to increase the survival of patients with HB.

中文翻译：

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表观遗传足迹使肝母细胞瘤的分子风险分层具有临床意义

背景和目的肝母细胞瘤（HB）是一种罕见的疾病。然而，它是主要的儿科肝癌，对侵袭性肿瘤患者的治疗选择有限。在这里，我们试图增加对 HB 病理生物学的了解，以努力迈向精准医学。为此，我们使用高通量技术为预后不良的 HB 患者确定新的生物标志物和治疗靶点方法：我们对来自 113 名 HB 患者的 159 个临床注释样本进行了全面的基因组、转录组和表观基因组表征 我们发现了前所未有的广泛的 HB 表观遗传足迹，包括肿瘤抑制基因 BLCAP 的超编辑，伴随着全基因组 RNA 编辑的失调和致癌 14q32 DLK1-DIO3 基因座的主要非编码基因的过度表达。通过无监督分析，我们确定了两个表观基因组簇（Epi-CA、Epi-CB），它们具有与 C1/C2/C2B 转录组亚型相关的不同程度的 DNA 低甲基化和 CpG 岛高甲基化。基于这些发现，我们定义了第一个 HB 分子风险分层 (MRS-HB)，它包含三个主要的预后类别，并改进了当前的临床风险分层方法。MRS-3 类别 (28%)，由强 14q32 基因座表达和 Epi-CB 甲基化特征定义，以 CTNNB1 和 NFE2L2 突变为特征，祖细胞样表型和临床侵袭性。最后，我们将胆碱激酶 α 确定为中高风险 HBs 的有希望的治疗靶点，因为它在 HB 细胞系和患者来源的异种移植物中的抑制作用强烈地消除了肿瘤生长。有助于改进当前的临床分层方法和治疗，以提高 HB 患者的生存率。