“Now that we understand the signature mutation in these common pediatric tumors, we can think about designing treatments that alter the pathway that gene controls,” says David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology. “That’s important because right now we have few treatments tailored to this tumor type.”
Gutmann normally studies the tumors, known as pilocytic astrocytomas, in the context of neurofibromatosis 1 (NF1), an inherited condition that is one of the most common tumor predisposition syndromes. But pilocytic astrocytomas also occur sporadically in patients who do not have the NF1 mutation at a rate of about 2-3 new cases per 100,000 children per year. Symptoms from these tumors can include headache, nausea, vomiting, problems with balance and visual impairment.
To learn whether either condition could shed light on the other, Gutmann’s team performed detailed genetic and genomic analyses of tumor samples from 70 patients with sporadic pilocytic astrocytomas and nine patients with NF1. The results appear in the Nov. 1 issue of Neurology.
An early lead linking the sporadic tumors to changes in a gene called HIPK2 in a small region of chromosome 7 didn’t pan out, but it led the researchers to the nearby BRAF gene, which previously had been linked to other cancers.
“BRAF was a particularly enticing target because the signaling pathway that it controls is also controlled by neurofibromin, the protein made by the gene that is mutated in patients with NF1,” says Gutmann, who is director of the Washington University Neurofibromatosis Center. “This finding is exciting, since a number of drugs are known to inhibit this pathway, some of which are already being tested for their ability to control the growth of other cancers.”
Analysis showed that 42 of the 70 patients with sporadic pilocytic astrocytomas had alterations in the BRAF gene, while none of the NF1 patients did.
Further study revealed that the second half of the altered BRAF protein fuses to another gene in the same region of chromosome 7. BRAF normally regulates cell growth, but when its protein fuses with the other gene, BRAF becomes overactive, causing increased growth that culminates in astrocytoma development.
Other than standard chemotherapy, there are currently no treatments that target the specific molecular alterations in pilocytic astrocytoma. Surgery is sometimes used to remove the tumors, but they frequently arise in surgically inaccessible regions of the brain like the optic nerve and brainstem. Moreover, radiation treatment can lead to long-term cognitive deficits.
To further understand how BRAF is linked to cell growth, Gutmann and his colleagues are working to create a model of sporadic low-grade astrocytoma in mice as well as to determine exactly how BRAF regulates cell growth. Their group previously developed a mouse model of NF1-associated optic glioma.
Yu J, Deshmukh H, Gutmann RJ, Emnett RJ, Rodriguez FJ, Watson MA, Nagarajan R, Gutmann DH. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology, Nov. 1, 2009.
Funding from the Brain Tumor Society, the Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital and the National Cancer Institute supported this research.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.