Researchers Implicate BRAF Gene in Low-grade Pediatric Brain Tumors

02/1/2009

A novel duplication in chromosome 7q34 led to the identification of BRAF as a gene that may play a role in the initiation of pediatric low-grade brain tumors, according to a Children’s Hospital study. This finding may aid in the development of targeted therapy for children with these tumors.

Jaclyn Biegel, Ph.D., Division of Human Genetics, led the study, published in the October 2008 online version of Brain Pathology.

Investigators analyzed DNA from 28 pediatric low-grade brain tumors using high-density genome-wide arrays. They identified a novel duplication in chromosome band 7q34 in 20 of the 28 tumors. Further positional cloning and sequencing analysis demonstrated a novel BRAF fusion gene in these tumors. A smaller subset of tumors also revealed mutations in the BRAF oncogene.

“Until this point, studies of low-grade brain tumors have failed to identify a consistent pattern of genetic abnormalities that could be used to identify a diagnosis and determine a prognosis,” says Dr. Biegel. Low-grade brain tumors typically arise in the first 20 years of life and account for nearly 30 percent of tumors of the central nervous system in children. These tumors do not typically become malignant; however, they can recur as a more aggressive type of brain tumor. Although the prognosis for most children with low-grade brain tumors is favorable, many suffer from functional impairments caused by the treatment or the tumor itself.

Surgery is the preferred method for treating slow-growing tumors, but depending on the location of the tumor, it is not always feasible. Standard chemotherapy is not an ideal treatment for benign tumors because it kills both cancerous and normal cells. By detecting abnormalities in the BRAF gene, investigators have identified a potential target for effective therapies in children with low-grade brain tumors. Drugs that target the BRAF gene have been developed and are currently in clinical trials in adult patients with melanoma. Similar inhibitors could be used to treat children who have brain tumors that demonstrate abnormalities in the BRAF gene.

Ongoing studies in both children and adults are in progress to define the spectrum of brain tumors that may carry an alteration in the BRAF gene. In vitro studies have also been undertaken to identify the mechanism by which the BRAF gene can cause a cell to become cancerous.

The National Institutes of Health and the Neurosurgery Research and Education Foundation provided support for the study. Dr. Biegel’s co-authors were Angela Sievert, M.D.; Eric Jackson, M.D.; Xiaowu Gai, Ph.D.; Hakon Hakonarson, M.D., Ph.D.; Alexander Judkins, M.D.; Adam Resnick, Ph.D.; Leslie Sutton, M.D.; Phillip Storm, M.D.; and Tamim Shaikh, Ph.D.