Genomic analysis of bilateral Wilms tumor: a Children’s Oncology Group and St. Jude Children’s Research Hospital study
We aimed to determine the landscape of genetic and epigenetic predisposition for synchronous bilateral Wilms tumor (BWT) formation using samples from 70 patients with BWT from the Children’s Oncology Group and St. Jude Children’s Research Hospital. We performed whole exome or whole genome sequencing, total-strand RNA-seq, and 850K MethylationEPIC Beadchip analysis. We found that 41% of patients evaluated had germline genetic variants in Wilms tumor or pediatric cancer predisposition genes, with WT1 (16%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA-1, BRCA-2, and PALB2 being the most common. WT1 germline variants were strongly associated with paternal uniparental disomy overlapping the 11p15.5 locus and 11p13/WT1 locus in tumor samples and subsequent somatic CTNNB1 variants. Somatic variants were almost never shared between paired synchronous BWT. However, 11p15.5 status (loss of imprinting, loss of heterozygosity, retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant methods of predisposition for BWT formation are germline genetic variants or post-zygotic epigenetic hypermethylation at the 11p15.5 ICR1 locus (loss of imprinting). 11p15.5 status correlates with an overall methylation profile in BWT.
Reference
Andrew J Murphy#, *, Changde Cheng*, Justin Williams, Timothy I Shaw, Emilia M Pinto, Karissa Dieseldorff-Jones, Jack Brzezinski, Lindsay Renfro, Brett Tornwall, Vicki Huff, Andy Hong, Elizabeth Mullen, Brian Crompton, Jim Geller, Peter Ehrlich, Heather Mulder, Janet Partridge, Alfonso Fernandez Gonzalez, Hyea Jin Gil, Carolyn Jablonowski, Andrew Fleming, Prahalathan Pichavaram, John Easton, Kim Nichols, Teresa Santiago, Jinghui Zhang, Jun Yang, Gerard P Zambetti, Zhaoming Wang, Andrew M Davidoff, Xiang Chen#. Genomic analysis of bilateral Wilms tumor: a Children’s Oncology Group and St. Jude Children’s Research Hospital study