Genetic Predisposition to Childhood Kidney Cancer Uncovered

Wilms tumor, also called nephroblastoma, is a rare tumor type, but the most common form of childhood renal cancer, occurring in about one of every 10,000 children. While most of these tumors are thought to arise during embryogenesis, there is a small portion--about 2%--that may have a hereditary component.

Now, in a study published in Nature Genetics, a team of researchers at The Institute of Cancer Research, London, have identified mutations in a gene called RE1-silencing transcription factor (REST) that are linked to a predisposition for Wilms tumor.

Researchers analyzed 24 individuals with Wilms tumor among 12 families by exome sequencing. After identifying mutations in the REST gene, the team sequenced the full coding sequence of the gene in another 38 individuals with familial Wilms tumor among 27 families.

The researchers identified 11 different mutations that inactivate the REST gene among four families with Wilms tumor cases and nine nonfamilial cases. In two tumors, a second mutational event in the gene was uncovered suggesting REST acts as a tumor suppressor gene.

The REST gene encodes a zinc finger transcription factor that functions during embryonic development and neurogenesis.

According to prior studies, families with a predisposition to Wilms tumor have no other incidence of cancer or other clinical features. Other genetic mutations that can predispose individuals to Wilms tumor include mutations in the WT1 gene, as well as autosomal recessive conditions, including mosaic variegated aneuploidy syndrome and certain types of Fanconi anemia.

The mutations in REST identified in the current study appear to abrogate normal REST transcription factor function, resulting in deregulation of development in the embryo. Ten of the 11 mutations were within a domain of the protein that binds DNA and laboratory experiments with the mutated forms of the protein, and showed that these mutations compromise the ability of the REST protein to function in transcriptional repression.

According to the study authors, about 10% of familiar Wilms tumor cases are likely due to a REST gene mutation.

The REST gene has mostly been studied for its function in the repression of neural transcription programs in neural stem cells and other tissue types, and for its ability to prevent neuronal cell identity during development. “Intriguingly, the current study suggests the possibility that REST might have a role in kidney development or earlier in tissue specification,” concluded the study authors.

"Our findings are of immediate value to families, who now have an explanation for why their child got cancer,” said Study leader Professor Nazneen Rahman, Head of Genetics and Epidemiology at The Institute of Cancer Research, London, and Head of Cancer Genetics at The Royal Marsden NHS Foundation Trust, in a news release. “Moreover, we can now do a simple blood test to see which children in the family are at risk of cancer and may benefit from cancer screening, and which have not inherited the mutation and so are not at increased risk of cancer. This kind of information is really valuable for the families of children with cancer."