In a Dutch study reported in the Journal of Clinical Oncology, Janna A. Hol, MD, and colleagues found that (epi)genetic predisposing factors could be identified in one-third of children diagnosed with Wilms tumor.
As stated by the investigators, “Wilms tumor is associated with (epi)genetic predisposing factors affecting a growing number of Wilms tumor predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of Wilms tumor predisposing (epi)genetic factors.”
Janna A. Hol, MD
Study Details
In the study, all children diagnosed with Wilms tumor in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Data were collected on phenotypic and disease characteristics, and diagnostic tests were performed. If no genetic predisposition was identified on diagnostic testing, germline whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered.
Key Findings
Among 128 identified patients, 126 were evaluated. Among the 126 patients, (epi)genetic predisposing factors were identified in 42 (33%); factors were identified through molecular diagnosis in blood-derived DNA in 26 patients, assessment of normal kidney-derived DNA in 12, and on the basis of clinical diagnosis of BWSp alone in 4.
Constitutional, heterozygous DIS3L2 variants were identified as a predisposing factor in five patients (4%), with four of the tumors harboring a second somatic hit. A diagnosis of BWSp was made in 20 patients (16%), with 4 additional patients without BWSp (3%) having chromosome 11p15 methylation defects in normal kidney tissue. Additional findings included WT1-related syndromes in 10 patients (8%), and Fanconi anemia, neurofibromatosis type 1, and a pathogenic REST variant in 1 patient each.
Assessment for adult cancer disposition genes in 56 patients with available whole-exome sequencing data revealed likely pathogenic variants in 5 (9%), including variants in BRCA2, PMS2, CHEK2, RNASEL, and MUTYH.
Several candidate Wilms tumor predisposition genes were identified (eg, USP45, MTA1), but their relevance requires further investigation. Of 31 genes identified with verified de novo variants, no variant occurred in more than one patient.
The investigators concluded, “(Epi)genetic Wilms tumor predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with Wilms tumor. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.”
Marjolijn C.J. Jongmans, PhD, of the Princess Máxima Center for Pediatric Oncology, Utrecht, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Stichting Kinderen Kankervij (Foundation KiKa). For full disclosures of the study authors, visit ascopubs.org.
