Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development
Menée à l'aide de données génomiques portant sur des patients pédiatriques atteints d'une tumeur de Wilms et menée à l'aide d'échantillons tumoraux et d'échantillons sanguins provenant de patients pédiatriques présentant à la fois une tumeur de Wilms et un syndrome de Wiedemann-Beckwith, cette étude met en évidence, pour ce syndrome, des voies de signalisation impliquées dans la prédisposition aux tumeurs de Wilms
Background : Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have increased risk for WT. The aim of this study is to identify the molecular signaling signatures in BWS driving these tumors. Methods : We performed whole exome sequencing, methylation array analysis, and gene expression analysis on BWS-WT samples. Our data were compared to publicly available nonBWS data. We categorized WT from BWS and nonBWS patients by assessment of 11p15 methylation status and defined 5 groups– control kidney, BWS-nontumor kidney, BWS-WT, normal-11p15 nonBWS-WT, altered-11p15 nonBWS-WT. Results : BWS-WT samples showed single nucleotide variants in BCORL1, ASXL1, ATM and AXL but absence of recurrent gene mutations associated with sporadic WT. We defined a narrow methylation range stratifying nonBWS-WT samples. BWS-WT and altered-11p15 nonBWS-WT showed enrichment of common and unique molecular signatures based on global differential methylation and gene expression analysis. CTNNB1 overexpression and broad range of interactions were seen in the BWS-WT interactome study. Conclusion : While WT predisposition in BWS is well-established, as are 11p15 alterations in nonBWS-WT, this study focused on stratifying tumor genomics by 11p15 status. Further investigation of our findings may identify novel therapeutic targets in WT oncogenesis.