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Beckwith‐Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are predisposed to developing hepatoblastoma (HB). To better understand the mechanism of HB oncogenesis in this cancer predisposition background, we performed the first multi‐dimensional study of HB samples collected from patients diagnosed with BWS. This multi‐omic investigation of seven BWS HB and five matched nontumor BWS liver samples from 7 unique patients included examination of whole exome sequences, messenger RNA/microRNA expression, and methylation levels to elucidate the genomic, transcriptomic, and epigenomic landscape of BWS‐associated HB. We compared the transcriptional profiles of the BWS samples, both HB and nontumor, to that of control livers. Genes differentially expressed across BWS tissues were identified as BWS HB predisposition factors; this gene group included cell cycle regulators, chromatin organizers, and WNT, mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT members. We also compared transcriptional changes associated with non‐syndromic HB carrying BWS‐like 11p15 alterations compared to those without, as well as to BWS HB. Through this analysis, we identified factors specific to 11p15‐altered HB oncogenesis, termed the BWS oncogenesis network. We propose that 11p15 alterations drive HB oncogenesis by initially dysregulating cell‐cycle regulators and chromatin organizers, including  histone deacetylase 1  ( HDAC1 ),  ATP‐dependent helicase X, and F‐Box and WD repeat domain containing 7 . Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4,  WNT16, forkhead box O3 (FOXO3) , and  MAPK10  are differentially expressed in 11p15‐altered HB in both the BWS and non‐syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.

Molecular networks of hepatoblastoma predisposition and oncogenesis in Beckwith‐Wiedemann syndrome