Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q

Andrew J. Murphy (), Changde Cheng, Justin Williams, Timothy I. Shaw, Emilia M. Pinto, Karissa Dieseldorff-Jones, Jack Brzezinski, Lindsay A. Renfro, Brett Tornwall, Vicki Huff, Andrew L. Hong, Elizabeth A. Mullen, Brian Crompton, Jeffrey S. Dome, Conrad V. Fernandez, James I. Geller, Peter F. Ehrlich, Heather Mulder, Ninad Oak, Jamie Maciezsek, Carolyn M. Jablonowski, Andrew M. Fleming, Prahalathan Pichavaram, Christopher L. Morton, John Easton, Kim E. Nichols, Michael R. Clay, Teresa Santiago, Jinghui Zhang, Jun Yang, Gerard P. Zambetti, Zhaoming Wang, Andrew M. Davidoff and Xiang Chen ()
Additional contact information
Andrew J. Murphy: St. Jude Children’s Research Hospital
Changde Cheng: St. Jude Children’s Research Hospital
Justin Williams: St. Jude Children’s Research Hospital
Timothy I. Shaw: St. Jude Children’s Research Hospital
Emilia M. Pinto: St. Jude Children’s Research Hospital
Karissa Dieseldorff-Jones: St. Jude Children’s Research Hospital
Jack Brzezinski: The Hospital for Sick Children
Lindsay A. Renfro: Keck School of Medicine of University of Southern California
Brett Tornwall: Children’s Oncology Group Statistics and Data Center
Vicki Huff: The University of Texas MD Anderson Cancer Center
Andrew L. Hong: Emory University School of Medicine
Elizabeth A. Mullen: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School
Brian Crompton: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School
Jeffrey S. Dome: George Washington University School of Medicine and Health Sciences
Conrad V. Fernandez: IWK Health Center and Dalhousie University
James I. Geller: University of Cincinnati
Peter F. Ehrlich: University of Michigan
Heather Mulder: St. Jude Children’s Research Hospital
Ninad Oak: St. Jude Children’s Research Hospital
Jamie Maciezsek: St. Jude Children’s Research Hospital
Carolyn M. Jablonowski: St. Jude Children’s Research Hospital
Andrew M. Fleming: St. Jude Children’s Research Hospital
Prahalathan Pichavaram: St. Jude Children’s Research Hospital
Christopher L. Morton: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Kim E. Nichols: St. Jude Children’s Research Hospital
Michael R. Clay: University of Colorado Anschutz
Teresa Santiago: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Jun Yang: St. Jude Children’s Research Hospital
Gerard P. Zambetti: St. Jude Children’s Research Hospital
Zhaoming Wang: St. Jude Children’s Research Hospital
Andrew M. Davidoff: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.

Date: 2023
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DOI: 10.1038/s41467-023-43730-0

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