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

Andrew J. Murphy, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. andrew.murphy@stjude.org.
Changde Cheng, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Justin Williams, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Timothy I. Shaw, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Emilia M. Pinto, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Karissa Dieseldorff-Jones, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Jack Brzezinski, Department of Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Lindsay A. Renfro, Children's Oncology Group and Department of Population and Public Health Sciences, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
Brett Tornwall, Children's Oncology Group Statistics and Data Center, Monrovia, CA, USA.
Vicki Huff, Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Andrew L. Hong, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Elizabeth A. Mullen, Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, 02215, USA.
Brian Crompton, Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, 02215, USA.
Jeffrey S. Dome, Center for Cancer and Blood Disorders, Children's National Hospital, Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Conrad V. Fernandez, IWK Health Center and Dalhousie University, Halifax, NS, Canada.
James I. Geller, Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA.
Peter F. Ehrlich, Section of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI, USA.
Heather Mulder, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Ninad Oak, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jamie Maciezsek, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Carolyn M. Jablonowski, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Andrew M. Fleming, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Prahalathan Pichavaram, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Christopher L. Morton, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
John Easton, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Kim E. Nichols, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Michael R. Clay, Department of Pathology, University of Colorado Anschutz, Aurora, CO, USA.
Teresa Santiago, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Jinghui Zhang, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Jun Yang, Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Gerard P. Zambetti, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Zhaoming Wang, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Document Type

Journal Article

Publication Date

12-18-2023

Journal

Nature communications

Volume

14

Issue

1

DOI

10.1038/s41467-023-43730-0

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.

Department

Pediatrics

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