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Genetic mutations responsible for childhood brain tumors identified
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Researchers have identified several gene mutations that cause medulloblastoma, the most common childhood brain tumor.
Medulloblastoma originates in the cerebellum and affects about 250 children a year in the United States. Treatment involves the surgical removal of the tumor combined with chemotherapy and radiation.
More than one-third of patients with medulloblastoma die of the disease within 5 years of diagnosis, and those who survive often experience lasting adverse effects, Trevor J. Pugh, PhD, assistant laboratory director for the Center for Personalized Genetic Medicine at Harvard Medical School, and colleagues wrote in a research paper.
“Identifying and understanding the genetic events that drive these tumors are critical for the development of more effective diagnostic, prognostic and therapeutic strategies,” Pugh and colleagues wrote.
The paper appeared online in Nature, along with two companion studies. The research is part of an ongoing push to identify generic errors in pediatric brain tumors.
Researchers are beginning to analyze the diverse genetic landscape of medulloblastoma at the molecular level, Yoon-Jae Cho, MD, assistant professor of neurology and neurological sciences at Stanford University and co-author of the companion studies, said in a press release.
Within the past 2 years, researchers have divided medulloblastoma into four subgroups — SHH, WNT, Group 3 and Group 4 — based on gene expression profiles and DNA copy number variations.
Researchers used whole-exome hybrid capture and deep sequencing to extract DNA from 92 medullolastoma tumors. They compared DNA from the tumors with DNA from matched blood samples from the same patients. The researchers identified 12 point mutations driven primarily by structural variation at statistically significant frequencies.
Medulloblastomas have low mutation rates, with a median non-silent mutation per megabase of 0.35, according to the analysis.
Researchers were able to categorize tumors according to their mutations, although no single tumor carried all 12 mutations.
Mutations included previously known mutated genes CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. CTNNB1 and PTCH1 were the two most significantly mutated genes.
Recurrent somatic mutations were newly identified in an RNA helicase gene called DDX3X, which is often concurrent with CTNB1 mutations and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1, according to the researchers’ findings.
“The results reflect two emerging genetic themes seen throughout childhood tumors,” Scott Pomeroy, MD, neurologist-in-chief in the F.M. Kirby Neurology Center at Boston Children’s Hospital, said in a press release. “First, very low mutation rates, much lower than those seen in adult tumors, and second, the importance of mutations in genes that regulate the function of the cell’s growth pathways but which aren’t direct components of those pathways.”
DDX3X mutations have been identified in other tumor types, such as chronic lymphocytic leukemia and head and neck tumors, according to the research paper.
Mutant DDX3X is important in medulloblastoma tumors because it makes powerful gene expressions of a TCF promoter and enhances cell viability when combined with the protein beta-catenin.
“Not only do we now know how to stratify medulloblastomas genomically, we have a firm grasp of what gene mutations drive each molecular subtype,” Pomeroy said in the press release. “For the first time, we will be able to classify and treat medulloblastoma based on molecular typing, providing the best therapy with the fewest long-term consequences.”
Future studies designed to analyze how mutant DDX3X functions with beta-catenin should provide additional insights and open potential avenues for novel therapies, the researchers concluded.
Disclosure: Dr. Cho has served on an advisory board for Novartis.
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