A research team from Julius-Maximilians-Universität Würzburg (JMU) in Germany, collaborating with the Wellcome Sanger Institute in Cambridge, UK, has made a major breakthrough in understanding Wilms’ tumors—malignant kidney tumors that affect young children. By analyzing samples from the Wilms tumor biobank at JMU, the team systematically decoded the hereditary predispositions for these tumors in a large group of patients. Their findings, published in *Genome Medicine*, pave the way for improved genetic counseling and monitoring of at-risk children.
At the core of the research is the Wilms tumor biobank at JMU’s Biocenter, a valuable resource built over nearly 30 years (1994–2022). It houses samples from around 1,800 affected children, including 20 familial tumors (those occurring in multiple family members) and 109 bilateral tumors (linked to genetic predisposition). “We identified the underlying predisposition in over 90 percent of these cases,” said Dr. Jenny Wegert, lead author and researcher in JMU’s Department of Developmental Biochemistry.
The study shed light on the step-by-step genetic changes driving tumor development, aligning with Alfred Knudsen’s “two-hit hypothesis” proposed over 50 years ago to explain hereditary childhood tumors. Most commonly, mutations in the tumor suppressor gene WT1 were found: an initial inactivation of one WT1 copy in all body cells raises the risk of kidney failure and, in boys, genitourinary malformations. Tumor formation occurs only when the second WT1 copy in kidney cells fails, alongside activation of the growth factor IGF2 (leading to tumor precursors) and, finally, activation of the WNT signaling pathway (triggering malignant growth).
About half of the patients showed genetic changes in the germline (present in all body cells), involving WT1 and other less common genes. A surprising discovery was that around a third of children lacked classic hereditary mutations but had disruptions in “genomic imprinting” of the IGF2 gene. Imprinting, established during embryonic development and not hereditary, means no increased risk for siblings, nor do affected children pass on the predisposition. These children often had “mosaic” cells—some with normal IGF2 imprinting, others with impaired—with tumors forming when additional gene mutations occur in kidney cells with disturbed IGF2 regulation.
“This research shows a significant proportion of childhood kidney tumors have a hereditary component,” noted Professor Manfred Gessler, study leader and chair of Developmental Biochemistry. “This has critical clinical implications: siblings may face higher risk, and patients themselves could develop secondary tumors or early kidney failure.” The study advocates for broad molecular testing of blood and tumor samples from young patients to detect at-risk cases early and ensure close monitoring.
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