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

Li Zhang; Yaqiong Jin; Kai Zheng; Huanmin Wang; Shen Yang; Chenkai Lv; Wei Han; Yongbo Yu; Yeran Yang; Di Geng; Hui Yang; Tieliu Shi; Yongli Guo; Xin Ni

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

Front Genet. 2018 Dec 19:9:668. doi: 10.3389/fgene.2018.00668. eCollection 2018.

Authors

Li Zhang¹, Yaqiong Jin^{2

3}, Kai Zheng⁴, Huanmin Wang⁵, Shen Yang⁵, Chenkai Lv¹, Wei Han⁵, Yongbo Yu^{2

3}, Yeran Yang^{2

3}, Di Geng³, Hui Yang^{2

3}, Tieliu Shi¹, Yongli Guo^{2

3}, Xin Ni^{2

3

6}

Affiliations

¹ Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
² 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.
³ Biobank for Clinical Data and Samples in Pediatrics, Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
⁴ Department of General Surgery, Wuhan Children's Hospital, Wuhan, China.
⁵ Department of Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
⁶ Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

Abstract

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.

Keywords: Wiskott–Aldrich syndrome (WAS); adenomatous polyposis coli (APC); cancer predisposition gene; hepatoblastoma; whole-genome sequencing.