Abstract 6045: Methylation differences in cancer signaling pathways drive Beckwith-Wiedemann Syndrome Wilms Tumor oncogenesis

Abstract

Wilms Tumor (WT), or nephroblastoma, is the most common pediatric renal cancer. This cancer is thought to arise from the expansion of embryonal nephrogenic rest cell population. The most common (epi)genetic alterations in WT occur on chromosome 11p15, accounting for about 75% of WT. These same changes on chromosome 11p15 also cause one of the most common WT predisposition syndromes, Beckwith-Wiedemann Syndrome (BWS). BWS is a pediatric overgrowth disorder affecting numerous tissues including the kidney and up to 28% of patients with BWS develop cancer. As patients with BWS have the same 11p15 epigenetic and structural changes that arise sporadically in non-syndromic WT, BWS WT provides a unique opportunity to investigate the specific molecular effect and mechanism by which 11p15 causes oncogenesis. Using clinical data and patient samples from the International BWS Registry and Biorepository, we used whole exome sequencing (WES) and methylation array technologies to examine the genomic and epigenomic landscape of BWS non-tumor kidney (NT) and WT tumors compared to control kidney samples. We found several large-scale recurrent copy number alterations (CNAs) in the BWS WT cohort across cancer-associated chr1p36, WT-associated chr16q, and novel chr15q. Two BWS WT presented with an above average number of genomic alterations compared to previous sporadic WT; one had mutations in telomerase-associated genes and the other had mutations in mismatch repair pathway genes. We investigated other known cancer-associated genes affected by CNAs and single nucleotide variants (SNVs) and found BCORL1 mutations in five BWS WT. Cancer-associated pathways, including targets of TP53, CTNNB1, and MYCN, were significantly differentially methylated between BWS WT and NT. Targets of TP53 and CTNNB1 were also differentially methylated between BWS NT and controls. In addition, FOXO-regulated gene promoters were significant when comparing both BWS WT to NT and BWS NT to control methylation. Overall, WES results indicate that BWS WT have similar genomic stability compared to pediatric cancers and sporadic WT, but we did identify two hyper-mutators including a rare mismatch repair defect WT within the cohort. Recurrent mutations in genes associated with sporadic WT, such as TP53, CTNNB1, and MYCN were not present in BWS samples; however, methylation differences were observed in TP53-, CTNNB1- and MYCN-related gene sets. These and other methylation changes in BWS NT and WT may influence the transcriptome in conjunction with 11p15 alterations to promote growth and oncogenesis without coding mutations. Data presented herein suggest one way in which 11p15-altered genomes predispose cells to oncogenic transitions. Further study of non-syndromic WT methylomes as well as BWS NT and WT tissue expression are required to fully understand these effects. Citation Format: Natali Sobel Naveh, Emily Traxler, Snehal Nirgude, Jennifer Kalish. Methylation differences in cancer signaling pathways drive Beckwith-Wiedemann Syndrome Wilms Tumor oncogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6045.