New Study Uncovers Underlying Mechanisms in Wilms Tumor

A study shows that microRNA depresses PLAG1, causing tumor growth in Wilms tumors.

It may be possible to combat Wilms tumor in a whole new way. Researchers connected two previously unrelated insights about the formation of this type of pediatric kidney cancer and uncovered the means by which this cancer continues to grow. In the journal Genes and Development, they report on potential new targets for more effective treatments in the future.

Wilms tumor, the most common type of kidney cancer in children, is treated with surgery, radiation, and chemotherapy. While this combination is effective for many patients, there are numerous adverse effects, and a cure remains elusive for those with aggressive disease.

“As oncologists, we are increasingly used to thinking about cancers from a genomic perspective. For both adult and childhood cancers, it’s now clear that each major cancer type is made up of different molecular subclasses with distinct mutation spectrum and oncogenic mechanisms,” said study investigator James Amatruda, MD, associate professor of pediatrics, molecular biology, and internal medicine at the University of Texas Southwestern Medical Center in Dallas.

Amatruda and colleagues found that a major molecular subclass, characterized by mutations in the microRNA pathway, exhibits overexpression of the PLAG1 gene. He said PLAG1 in turn appears to spur tumor growth by dysregulating IGF2. “This was surprising, but quite interesting as it connects microRNA biogenesis mutations to other previously discovered mechanisms driving IGF2 expression in Wilms tumor,” Amatruda told Cancer Network.

The researchers investigated the function of the DIS3L2 gene, which is mutated in some Wilms tumors and whose loss of function causes Perlman syndrome (a rare lethal disease in newborns). This syndrome is associated with a high risk of Wilms tumor. Previous work suggested that DIS3L2 might prevent Wilms tumor formation through its ability to regulate microRNA levels. However, using genetically engineered mice lacking DIS3L2, the researchers found that loss of this gene had no effect on microRNA. Instead, it led to an increase in IGF2 expression.

“The convergence of multiple mechanisms of Wilms tumorigenesis on IGF2 highlights the importance of this signaling pathway in childhood kidney cancer, and points to possible therapeutic targets,” said Amatruda.

The researchers found that the microRNA-PLAG1IGF2 axis acts through the mammalian target of rapamycin (mTOR) pathway to promote growth. Amatruda said inhibitors of IGF2 and mTOR currently are in clinical development and could have activity against Wilms tumors

Kidney cancer expert James Hsieh, MD, PhD, of Siteman Cancer Center and a professor of medicine at Washington University School of Medicine in St. Louis, said these new findings may have significant clinical implications. “The identification of mTOR as a key downstream signal is likely to have significant impact on clinical management of Wilms tumors with PLAG1 molecular signature since mTOR complex 1 inhibitors everolimus and temsirolimus are among the 13 FDA-approved agents for metastatic kidney cancer,” Hsieh told Cancer Network.