Whole-Genome Sequencing Identifies a Novel Variation of WAS Gene Coordinating With Heterozygous Germline Mutation of APC to Enhance Hepatoblastoma Oncogenesis
Whole-Genome Sequencing Identifies a Novel Variation of WAS Gene Coordinating With Heterozygous Germline Mutation of APC to Enhance Hepatoblastoma Oncogenesis
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DOI：
10.3389/fgene.2018.00668
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发表时间：
2018-12
影响因子：
3.7
通讯作者：
Li Zhang;Yaqiong Jin;Kai Zheng;Huanmin Wang;Shen Yang;Chenkai Lv;Wei Han;Yongbo Yu;Yeran Yang;D. Geng;Hui Yang;Tieliu Shi;Yongli Guo;X. Ni
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文献类型：
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作者：
Li Zhang;Yaqiong Jin;Kai Zheng;Huanmin Wang;Shen Yang;Chenkai Lv;Wei Han;Yongbo Yu;Yeran Yang;D. Geng;Hui Yang;Tieliu Shi;Yongli Guo;X. Ni
肝母细胞瘤（Hepatoblastoma，HB）是儿童原发性肝脏恶性肿瘤中的一种，起源于原始肝干细胞.这项研究旨在揭示HB肿瘤发生的遗传变异。招募了一个家庭，其中包括健康的父母和两个受HB影响的兄弟。对所有家族成员的生殖系DNA进行全基因组测序（WGS），鉴定出两个位于APC基因和X连锁WAS基因内的母系变异体，这两个变异体由两兄弟所携带。APC基因突变（rs 137854573，c.C1606T，p.R536X）可能通过激活Wnt信号通路而导致HB的癌变。WAS突变体（c.G3T，p.M1-P5 del）可通过激活PLK 1信号通路和灭活TCR信号通路促进HB细胞增殖并抑制T细胞免疫。进一步分析表明，WAS缺陷可能影响自然杀伤细胞和树突状细胞的抗肿瘤活性。总之，所获得的结果意味着APC突变体与X连锁的WAS突变体一起可以通过激活Wnt和PLK 1信号传导、抑制TCR信号传导以及降低自然杀伤细胞和树突状细胞的抗肿瘤活性而导致HB肿瘤发生。
Hepatoblastoma (HB), a leading primary hepatic malignancy in children, originates from primitive hepatic stem cells. This study aimed to uncover the genetic variants that are responsible for HB oncogenesis. One family, which includes the healthy parents, and two brothers affected by HB, was recruited. Whole-genome sequencing (WGS) of germline DNA from all the family members identified two maternal variants, located within APC gene and X-linked WAS gene, which were harbored by the two brothers. The mutation of APC (rs137854573, c.C1606T, p.R536X) could result in HB carcinogenesis by activating Wnt signaling. The WAS variant (c.G3T, p.M1-P5del) could promote HB cell proliferation and inhibit T-cell-based immunity by activating PLK1 signaling and inactivating TCR signaling. Further analysis reflected that WAS deficiency might affect the antitumor activity of natural killer and dendritic cells. In summary, the obtained results imply that an APC mutant together with an X-linked WAS mutant, could lead to HB tumorigenesis by activating Wnt and PLK1 signaling, inhibiting TCR signaling, and reducing the antitumor activity of natural killer and dendritic cells.