Brain tumors in children have a common cause

When 96 pilocytic astrocytomas were analyzed by whole-genome sequencing, all had MAPK (mitogen-activated protein kinase)-pathway alterations. This indicates that pilocytic astrocytoma is predominantly a single-pathway disease.

Brain cancer is the primary cause of cancer mortality in children. Even in cases when the cancer is cured, young patients suffer from the stress of a treatment that can be harmful to the developing brain.

In a search for new target structures that would create gentler treatments, cancer researchers are systematically analyzing all alterations in the genetic material of these tumors. This is the mission of the PedBrain Tumor network, which was launched in 2010. Led by Professor Stefan Pfister, MD, from the German Cancer Research Center in Heidelberg (Deutsches Krebsforschungszentrum, DKFZ), the PedBrain researchers have now published the results of the first 96 genome analyses of pilocytic astrocytomas in Nature Genetics (2013; doi: 10.1038/ng.2682).

Pilocytic astrocytomas are the most common childhood brain tumors. These tumors usually grow very slowly. However, they are often difficult to access by surgery and cannot be completely removed, which means that they can recur. The disease may thus become chronic and have debilitating effects for affected children.

In previous work, teams of researchers led by Pfister and David Jones, PhD, had already discovered characteristic mutations in a major proportion of pilocytic astrocytomas. All of the changes involved a key cellular signaling pathway known as the MAPK signaling cascade. MAPK signaling regulates numerous basic biological processes such as embryonic development and differentiation as well as the growth and death of cells.

"Aside from MAPK mutations, we do not find any other frequent mutations that could promote cancer growth in the tumors. This is a very clear indication that overactive MAPK signals are necessary for a pilocytic astrocytoma to develop," said study director Pfister. Thus, the disease appears to be a prototype for rare cancers that are based on defects in a single biological signaling process.

In total, the genomes of pilocytic astrocytomas contain far fewer mutations than are found, for example, in medulloblastomas, a much more malignant pediatric brain tumor. This finding is in accordance with the more-benign growth behavior of astrocytomas. The number of mutations increases with the age of the affected individuals.

About one half of pilocytic astrocytomas develop in the cerebellum, and the other half develops in various other brain regions. Cerebellar astrocytomas are genetically even more homogenous than other cases of the disease: In 48 of 49 cases that were studied, the researchers found fusions between the BRAF gene, a central component of the MAPK-signaling pathway, and various other fusion partners.

"The most important conclusion from our results," says study director Stefan Pfister, "is that targeted agents for all pilocytic astrocytomas are potentially available to block an overactive MAPK signaling cascade at various points. We might thus in the future be able to also help children whose tumors are difficult to access by surgery."
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