Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Children’s Oncology Group AREN18B5-Q
-
Published:2023-12-18
Issue:1
Volume:14
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Murphy Andrew J.ORCID, Cheng ChangdeORCID, Williams Justin, Shaw Timothy I.ORCID, Pinto Emilia M.ORCID, Dieseldorff-Jones KarissaORCID, Brzezinski Jack, Renfro Lindsay A., Tornwall Brett, Huff Vicki, Hong Andrew L.ORCID, Mullen Elizabeth A.ORCID, Crompton BrianORCID, Dome Jeffrey S.ORCID, Fernandez Conrad V.ORCID, Geller James I., Ehrlich Peter F., Mulder HeatherORCID, Oak NinadORCID, Maciezsek Jamie, Jablonowski Carolyn M., Fleming Andrew M.ORCID, Pichavaram Prahalathan, Morton Christopher L., Easton JohnORCID, Nichols Kim E.ORCID, Clay Michael R., Santiago Teresa, Zhang JinghuiORCID, Yang JunORCID, Zambetti Gerard P.ORCID, Wang ZhaomingORCID, Davidoff Andrew M.ORCID, Chen XiangORCID
Abstract
AbstractDeveloping 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute American Lebanese Syrian Associated Charities St. Baldrick's Foundation American Pediatric Surgical Association Foundation Jay Grosfeld Scholarship American Cancer Society
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference65 articles.
1. Davidoff, A. M. Wilms tumor. Adv. Pediatr. 59, 247–67 (2012). 2. Knudson, A. G. & Strong, L. C. Mutation and cancer: A model for Wilms’ tumor of the kidney. J. Natl. Cancer Inst. 48, 313–24 (1972). 3. Spreafico, F. et al. Wilms tumour. Nat. Rev. Dis. Prim. 7, 75 (2021). 4. Beckwith, J. B., Kiviat, N. B. & Bonadio, J. F. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr. Pathol. 10, 1–36 (1990). 5. Chernin, G. et al. Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin. J. Am. Soc. Nephrol. 5, 1655–62 (2010).
|
|