NEW YORK – Roughly one in every three children with a type of kidney cancer known as Wilms tumor, or nephroblastoma, carry germline alterations implicated in hereditary cancer risk, new research suggests — findings that have prompted more widespread genetic testing for Dutch children with the condition.
"On the basis of our research, all children with a Wilms tumor in the Netherlands are now offered extensive genetic diagnostics," senior and corresponding author Marjolijn Jongmans, a clinical geneticist at University Medical Center Utrecht, said in a statement. "Children are tested for changes in the most important genes that are currently known, including the genes that emerged from our study."
As they reported in the Journal of Clinical Oncology on Tuesday, investigators at University Medical Center Utrecht, the Princess Máxima Center for Pediatric Oncology, and elsewhere analyzed genetic and epigenetic features in 126 children treated for Wilms tumor in the Netherlands from 2015 to 2020 using targeted diagnostic testing; tests for chromosome 11 genetic or DNA methylation changes linked to a Wilms tumor-related overgrowth syndrome called Beckwith-Wiedemann spectrum; or parent-child germline exome sequencing.
The team's findings pointed to genetic or epigenetic hereditary cancer susceptibility in 42 Wilms tumor cases. Several Wilms tumor cases involving children carried risky germline variants affecting one copy of the DIS3L2 gene as well as additional somatic mutations falling in the same gene in kidney tumor samples, for example.
Still other cases involved genetic or epigenetic changes implicated in Beckwith-Wiedemann spectrum or other Wilms tumor-related syndromes or risky changes affecting genes linked to everything from Fanconi anemia or neurofibromatosis type 1 to adult cancer risk.
A dozen of the susceptibility variants turned up by analyzing DNA from normal kidney samples, the researchers explained, while another 26 cancer risk variants could also be detected by blood DNA testing. Such patterns can help to distinguish between cancer predisposition variants that are inherited from a child's parents and those that arose in the germline during development.
"Sometimes the predisposition is only found in kidney tissue, and not in blood. Then we know that siblings do not have an increased risk of developing a Wilms tumor," co-first author Janna Hol, a physician affiliated with the Princess Máxima Center for Pediatric Oncology, said in a statement. "If the hereditary predisposition does come from one or both parents, siblings can get a genetic test. They are then screened extra carefully."
Based on these and other findings, the authors argued that children with Wilms tumor should have targeted genetic testing if they show clinical features linked to a known (epi)genetic condition, whereas testing for Beckwith-Wiedemann spectrum and/or exome sequencing may prove beneficial for other children with the kidney tumor.
"(Epi)genetic [Wilms tumor] predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3 percent of patients with [Wilms tumor]," the authors reported. "On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist."