How genes and imprinting pave the way for cancer microbiologystudy

A research team at the University of Würzburg has gained new insights into the development of kidney tumors in young children. These enable a better risk assessment and could form the basis for targeted screening and improved early detection.

A research team at the Biocenter of Julius-Maximilians-Universität Würzburg (JMU), together with cooperation partners at the Wellcome Sanger Institute in Cambridge (UK), has taken a significant step toward understanding Wilms tumors, malignant kidney tumors in young children.

Using samples from the Wilms tumor biobank, the team was able to systematically decipher the hereditary predisposition for Wilms tumors in a large cohort. The results have now been published in the journal Genome Medicine; they open up new avenues for genetic counseling and monitoring of patients at risk.

A scientific treasure: The Wilms tumor biobank

The biobank for Wilms tumors located at the JMU Biocenter is at the heart of this research. Over a period of almost 30 years (1994 to 2022), samples from around 1,800 affected children have been collected as part of the German Wilms tumor study. These included 20 familial tumors, i.e. tumors that also occurred in parents and/or siblings, as well as 109 bilateral tumors, which are assumed to have a genetic predisposition.

“We were able to identify the underlying predisposition in over 90% of these cases,” explains Dr. Jenny Wegert, a member of staff at the Department of Developmental Biochemistry and lead author of the study.

Gradual tumor development and stereotypical patterns

Over 50 years ago, Alfred Knudsen postulated the so-called “two-hit hypothesis,” which was intended to explain hereditary forms of childhood tumors such as Wilms tumor. The researchers have now been able to demonstrate these gradual genetic changes during tumor development in molecular detail in their study.

Most frequently, they found mutations in WT1, a tumor suppressor gene, where initially one of the two copies of the WT1 gene is inactivated in all body cells. This alone is associated with an increased risk of kidney failure and, in boys, with genitourinary malformations.

However, actual tumor formation only occurs when the second copy of the WT1 gene in kidney cells also fails and the growth factor IGF2 is activated at the same time, leading to the formation of tumor precursors. A final step, the additional activation of the WNT signaling pathway, which controls many growth and differentiation processes, is then responsible for the development of a malignant tumor.

Genomic imprinting disorders as tumor triggers

For around half of the patients, the scientists were able to identify genetic changes in the germline and therefore in all body cells as the likely cause. In addition to WT1, numerous other genes were also affected, but much less frequently.

“One surprising finding, however, was that around a third of the children did not have one of the classic hereditary mutations, but a disturbance of the so-called genomic imprinting of the IGF2 gene,” says Wegert. Imprinting is established during embryonic development and is therefore not hereditary.

“This means that there is no increased risk for siblings and that those affected do not pass on the tumor predisposition,” says the scientist.

Children with this epigenetic predisposition often exhibited “mosaics,” meaning they had cells with normal and cells with impaired IGF2 imprinting side by side. If mutations in other genes occurred in kidney cells with disturbed IGF2 regulation, tumors developed.

Consequence: Genetic screening for patients at risk

“Our new findings impressively demonstrate that a significant proportion of childhood kidney tumors have a hereditary component,” says Professor Manfred Gessler, Chair of Developmental Biochemistry and head of the study.

“This has important consequences for the clinic: in such cases, there is an increased risk for siblings, and the patients themselves can later develop secondary tumors or suffer early kidney failure.”

The study therefore makes a clear case for broad molecular testing of blood and tumor samples from young patients to identify cases with an increased risk at an early stage and ensure close monitoring.