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Front. Genet. | doi: 10.3389/fgene.2018.00668

Whole-Genome Sequencing Identifies a Novel Variation of WAS Gene Coordinating with Heterozygous Germline Mutation of APC to Enhance Hepatoblastoma Oncogenesis

 Li Zhang1,  Yaqiong Jin2, Kai Zheng2, 3, Huanmin Wang2,  Shen Yang2, Wei Han2, Yongbo Yu2, Yeran Yang2, Di Geng2, Chenkai Lv1, Hui Yang2, Yongli Guo2, Xin Ni2 and  Tieliu Shi1*
  • 1School of Life Sciences, East China Normal University, China
  • 2Capital Medical University, China
  • 3Wuhan Children's Hospital, China

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) may result in HB carcinogenesis by activating Wnt signaling. The WAS variant (c.G3T, p.M1-P5del) may 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 acitivity of natural killer and dendritic cells. In summary, the obtained results imply that an APC mutant together with an X-linked WAS mutant, may lead to HB tumorigenesis by activating Wnt and PLK1 signaling, inhibiting TCR signaling, and reducing the antitumor activity of natural killer and dendritic cells.

Keywords: Hepatoblastoma, Whole-genome sequencing, Wiskott–Aldrich syndrome (WAS), Adenomatous polyposis coli (APC), Cancer predisposition gene

Received: 03 Jul 2018; Accepted: 04 Dec 2018.

Edited by:

Nora L. Nock, Case Western Reserve University, United States

Reviewed by:

Kevin Gerrish, National Institute of Environmental Health Sciences (NIEHS), United States
Annamaria Colacci, Agency for Prevention, Environment and Energy (Arpae) - Emilia Romagna, Italy  

Copyright: © 2018 Zhang, Jin, Zheng, Wang, Yang, Han, Yu, Yang, Geng, Lv, Yang, Guo, Ni and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Tieliu Shi, School of Life Sciences, East China Normal University, Shanghai, China,