Zhang Li, Jin Yaqiong, Zheng Kai, Wang Huanmin, Yang Shen, Lv Chenkai, Han Wei, Yu Yongbo, Yang Yeran, Geng Di, Yang Hui, Shi Tieliu, Guo Yongli, Ni Xin
Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Front Genet. 2018 Dec 19;9:668. doi: 10.3389/fgene.2018.00668. eCollection 2018.
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.
肝母细胞瘤（HB）是儿童主要的原发性肝脏恶性肿瘤，起源于原始肝干细胞。本研究旨在揭示导致HB发生的基因变异。招募了一个家庭，包括健康的父母以及两名患HB的兄弟。对所有家庭成员的生殖系DNA进行全基因组测序（WGS），发现了两个位于APC基因和X连锁WAS基因内的母系变异，这两个变异由两名兄弟携带。APC的突变（rs137854573，c.C1606T，p.R536X）可通过激活Wnt信号通路导致HB发生癌变。WAS变异（c.G3T，p.M1 - P5del）可通过激活PLK1信号通路和使TCR信号通路失活来促进HB细胞增殖并抑制基于T细胞的免疫。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，所得结果表明，APC突变体与X连锁WAS突变体一起，可通过激活Wnt和PLK1信号通路、抑制TCR信号通路以及降低自然杀伤细胞和树突状细胞的抗肿瘤活性，导致HB肿瘤发生。
