Homo sapiens Exome. Homo sapiens

Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the β-catenin gene that leads to constitutive activation of Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of 6 paired HB tumors and their corresponding lymphocytes. This identified 24 somatic non-synonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations in HB. These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis.

肝母细胞瘤（Hepatoblastoma, HB）是儿童最常见的原发性肝脏肿瘤。编码β-连环蛋白的基因发生突变可导致Wnt通路组成型激活，此类突变在多数HB肿瘤中均已被检出。为鉴定HB中的新型突变，我们对6对配对的HB肿瘤组织及其对应的淋巴细胞开展了全外显子组测序（whole-exome sequencing）。该测序在21个基因中鉴定出24个体细胞非同义突变，其中多数为新型突变，包括3处靶向Wnt通路中CTNNB1（G512V）与CAPRIN2（R968H/S969C）基因的新型突变，以及此前被证实参与泛素连接酶复合物的相关基因（SPOP、KLHL22、TRPC4AP与RNF169）。功能实验证实，CTNNB1（G512V）与CAPRIN2（R968H/S969C）这两处突变均为HB中的功能获得性突变。本研究拓展了HB的遗传变异谱，并凸显了Wnt通路与泛素通路失调在HB肿瘤发生中的关键作用。