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

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.

Compound Heterozygous Variants in Pediatric Cancers: A Systematic Review

“…The sequencing methods used were highly variable across the studies ( Table 3 and Supplementary Data 1:T1). Of the studies in this review, 10 indicated that they used one or more forms of NGS sequencing (whole-exome, whole-genome, RNA-seq) and thus were able to sample CH variants broadly (Valentine et al, 2014;Spinella et al, 2015;Zhang et al, 2015Zhang et al, , 2018Diets et al, 2018;Diness et al, 2018;Gröbner et al, 2018;Waszak et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019). Thirteen studies indicated that they used non-NGS methods (Sanger, Direct sequencing, SNP-array, Multiplex ligation-dependent probe amplification) and were therefore limited in the number of genes and CH variants analyzed (Quesnel et al, 1999;De Rosa et al, 2000;Østergaard et al, 2005;Okkels et al, 2006;Scott et al, 2007;Herkert et al, 2011;Leenen et al, 2011;Chmara et al, 2013;Bakry et al, 2014;Piane et al, 2016;Svojgr et al, 2016;Moriyama et al, 2017;Sharapova et al, 2018).…”

“…One study used evidence from RNA-seq data that the alternate alleles were on different chromosomes (Zhang et al, 2015). All other studies that performed phasing used sequence data from the patient and his/her parent(s) (i.e., Mendelian inheritance; Quesnel et al, 1999;De Rosa et al, 2000;Okkels et al, 2006;Scott et al, 2007;Peters et al, 2009;Majumdar et al, 2010;Herkert et al, 2011;Leenen et al, 2011;Chmara et al, 2013;Bakry et al, 2014;Valentine et al, 2014;Spinella et al, 2015;Piane et al, 2016;Svojgr et al, 2016;Diets et al, 2018;Diness et al, 2018;Salih et al, 2018;Sharapova et al, 2018;Zhang et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019).…”

“…Eight studies used predictive algorithms as the sole means of pathogenicity assessment (Herkert et al, 2011;Bakry et al, 2014;Spinella et al, 2015;Piane et al, 2016;Diets et al, 2018;Gröbner et al, 2018;Sharapova et al, 2018;Waszak et al, 2018). Four studies used guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) (Zhang et al, 2015(Zhang et al, , 2018Maciaszek et al, 2019;Schieffer et al, 2019). Two studies used literature searches to look for known effects of the identified variants (Scott et al, 2007;Leenen et al, 2011).…”

“…The remaining 18 genes may provide clues about alternative mechanisms of cancer predisposition. For example, one study identified 6 ALL and 13 AML patients with a CH variant in KMT2C (Valentine et al, 2014), and one study identified two hepatoblastoma patients with a CH variant in MUC4 (Zhang et al, 2018). DNA alterations in KMT2C and MUC4 have been observed in the somatic tissue of medulloblastoma and head and neck squamous cell carcinoma patients, respectively (Tate et al, 2019).…”

The Emerging Roles of Cancer Stem Cells and Wnt/Beta-Catenin Signaling in Hepatoblastoma

“…Recurrent mutations in CTNNB1 and increased expression of the transcription factor NFE2L2 have been reported in HB [14]. Mutations in other components of the beta-catenin degradation complex, including those affecting APC and Axin have also been reported [19,64,65]. Beta-catenin-mediated expression of hepatic stem/progenitor markers and interplay of Wnt/beta-catenin and Myc signaling have been observed in aggressive HB [13].…”