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Childhood Kidney Cancer Arises From Altered Normal Tissue, Sequencing Study Finds

NEW YORK – The seeds of a childhood kidney cancer can be present even in tissue that appears normal, a new sequencing analysis has found.

While kidney cancer in children is rare, the most common type is Wilms tumor, which mostly affects children under the age of five. Most cases of Wilms tumor can be cured through surgery to remove the afflicted kidney in combination with chemotherapy and possibly radiotherapy.

In adults, cancers are typically thought to arise through premalignant clonal expansion, but it's been unclear whether the process is similar in pediatric cancers. Researchers led by the Wellcome Sanger Institute's Sam Behjati sequenced tumor and normal kidney tissue to find that alterations indicative of disease were present in some normal tissue from patients as well as in tumors, indicating that that these changes affect cells from which Wilms tumors may later arise.

"The discovery of the genetic root of Wilms' tumour signals a shift in our understanding of this particular cancer and childhood cancer more generally," Behjati, who is also a consultant pediatric oncologist at Addenbrooke's Hospital, said in a statement. "Our findings represent a radical departure from how we think about Wilms' tumour because we never expected to find the root of cancer in normal-looking tissue." 

The researchers' work was published today in Science

By sequencing kidney samples from 54 people — including nearly two dozen children with Wilms tumor, the parents of children with Wilms tumor, and others — the researchers constructed phylogenetic trees of tumor development based on the somatic mutations present. For three children with unilateral Wilms tumor, they sampled their tumors, blood, and histologically normal kidney and uncovered mosaic mutations within these samples. As some of these mosaic mutations were found in both normal and tumor kidney tissue — though not in blood — the researchers suspected that these mutations might have undergone clonal expansions within the kidney.

When the researchers folded in additional samples from other Wilms tumor cases, they found these clonal expansions within normal kidney tissue in 61 percent of the 23 cases they examined.  

But when they examined tissues from people without Wilms, they found that these clonal expansions weren't common in normal kidney development. Instead, these expansions within histologically normal tissue were atypical outcomes of renal development that appear to precede development of Wilms tumor.

Nearly 60 percent of these normal kidney tissues with clonal nephrogenesis exhibited hypermethylation of the H19 locus, which typically acts to regulate cell growth and is a known Wilms tumor driver. This hypermethylation was found throughout the clone. This suppression of H19 leads cells to grow more rapidly to create this swathe of pre-malignant cells from which Wilms tumor may then arise.

This alteration appears to arise during kidney development. When the researchers traced back these clonal expansions in patients with bilateral disease, they found that clonal nephrogenesis had to have arisen before the left and right kidney primordia diverged. They noted, though, that the timing of when these expansions may arise in unilateral disease remains unclear.

These swatches of healthy, but altered tissue could potentially be a marker for tissue where Wilms tumor is at a higher risk of recurring and requires monitoring, author Kathy Pritchard-Jones, a professor of pediatric oncology at the University College London Great Ormond Street Institute of Child Health, said in a statement. 

"My hope is that in future we'll be able to develop treatments that focus on these patches of abnormal tissue without having to sacrifice one or both kidneys," she added.