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.

The genetic and epigenetic predisposition of bilateral Wilms tumour remains to be investigated. Here, the authors perform multiomics analysis and identify the predominant genetic and epigenetic events associated with bilateral Wilms tumour predisposition.

Details

Title
Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
Author
Murphy, Andrew J. 1   VIAFID ORCID Logo  ; Cheng, Changde 2   VIAFID ORCID Logo  ; Williams, Justin 2 ; Shaw, Timothy I. 2   VIAFID ORCID Logo  ; Pinto, Emilia M. 3   VIAFID ORCID Logo  ; Dieseldorff-Jones, Karissa 2   VIAFID ORCID Logo  ; Brzezinski, Jack 4 ; Renfro, Lindsay A. 5 ; Tornwall, Brett 6 ; Huff, Vicki 7 ; Hong, Andrew L. 8   VIAFID ORCID Logo  ; Mullen, Elizabeth A. 9   VIAFID ORCID Logo  ; Crompton, Brian 10   VIAFID ORCID Logo  ; Dome, Jeffrey S. 11   VIAFID ORCID Logo  ; Fernandez, Conrad V. 12   VIAFID ORCID Logo  ; Geller, James I. 13 ; Ehrlich, Peter F. 14 ; Mulder, Heather 2   VIAFID ORCID Logo  ; Oak, Ninad 15   VIAFID ORCID Logo  ; Maciezsek, Jamie 3 ; Jablonowski, Carolyn M. 16 ; Fleming, Andrew M. 1   VIAFID ORCID Logo  ; Pichavaram, Prahalathan 16 ; Morton, Christopher L. 16 ; Easton, John 2   VIAFID ORCID Logo  ; Nichols, Kim E. 15   VIAFID ORCID Logo  ; Clay, Michael R. 17 ; Santiago, Teresa 3 ; Zhang, Jinghui 2   VIAFID ORCID Logo  ; Yang, Jun 16   VIAFID ORCID Logo  ; Zambetti, Gerard P. 3   VIAFID ORCID Logo  ; Wang, Zhaoming 18   VIAFID ORCID Logo  ; Davidoff, Andrew M. 1   VIAFID ORCID Logo  ; Chen, Xiang 2   VIAFID ORCID Logo 

1  St. Jude Children’s Research Hospital, Department of Surgery, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X); University of Tennessee Health Science Center, Division of Pediatric Surgery, Department of Surgery, Memphis, USA (GRID:grid.267301.1) (ISNI:0000 0004 0386 9246) 
2  St. Jude Children’s Research Hospital, Department of Computational Biology, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
3  St. Jude Children’s Research Hospital, Department of Pathology, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
4  The Hospital for Sick Children, Department of Oncology, Toronto, Canada (GRID:grid.42327.30) (ISNI:0000 0004 0473 9646) 
5  Keck School of Medicine of University of Southern California, Children’s Oncology Group and Department of Population and Public Health Sciences, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
6  Children’s Oncology Group Statistics and Data Center, Monrovia, USA (GRID:grid.428204.8) (ISNI:0000 0000 8741 3510) 
7  The University of Texas MD Anderson Cancer Center, Department of Genetics, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
8  Emory University School of Medicine, Department of Pediatrics, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
9  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, Department of Pediatric Oncology, Boston, USA (GRID:grid.511177.4) 
10  Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, Department of Pediatric Oncology, Boston, USA (GRID:grid.511177.4); Broad Institute of Harvard and MIT, Cambridge, USA (GRID:grid.66859.34) 
11  George Washington University School of Medicine and Health Sciences, Center for Cancer and Blood Disorders, Children’s National Hospital, Department of Pediatrics, Washington, USA (GRID:grid.253615.6) (ISNI:0000 0004 1936 9510) 
12  IWK Health Center and Dalhousie University, Halifax, Canada (GRID:grid.55602.34) (ISNI:0000 0004 1936 8200) 
13  University of Cincinnati, Division of Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA (GRID:grid.24827.3b) (ISNI:0000 0001 2179 9593) 
14  University of Michigan, Section of Pediatric Surgery, C.S. Mott Children’s Hospital, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
15  St. Jude Children’s Research Hospital, Department of Oncology, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
16  St. Jude Children’s Research Hospital, Department of Surgery, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
17  University of Colorado Anschutz, Department of Pathology, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
18  St. Jude Children’s Research Hospital, Department of Computational Biology, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X); St. Jude Children’s Research Hospital, Department of Epidemiology and Cancer Control, Memphis, USA (GRID:grid.240871.8) (ISNI:0000 0001 0224 711X) 
Pages
8006
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-43730-0
ProQuest document ID
2903127615
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.