New mutations in pediatric brain tumors known as high-grade gliomas (HGGs) have been identified. HGGs most often occur in the youngest patients.

The mutations were identified by the St. Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project. The research was published in Nature Genetics (2014; doi:10.1038/ng.2938).

The discoveries stem from the most comprehensive effort yet to identify the genetic missteps driving these deadly tumors. The results provide desperately needed drug development leads, particularly for agents that target the underlying mutations. This and other studies show these mutations often differ based on patient age. HGGs represent 15% to 20% of brain and spinal tumors in children. Despite aggressive therapy with surgery, radiation, and chemotherapy, long-term survival for HGG patients remains less than 20%.

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The study is one of four published simultaneously in the same issue of Nature Genetics that linked recurring mutations in ACVR1 to cancer for the first time. Pediatric Cancer Genome Project researchers found that ACVR1 was mutated in 32% of 57 patients diagnosed with a subtype of HGG called diffuse intrinsic pontine glioma (DIPG). DIPGs are usually found in children age 5 to 10 years, whereas ACVR1 mutations occurred most frequently in younger-than-average patients. DIPG occurs in the brainstem, which controls vital functions and cannot be surgically removed.

The investigators also identified alterations in NTRK genes that drove tumor development in young HGG patients whose tumors developed outside the brainstem. This study included 10 patients who were age 3 years or younger at diagnosis of such nonbrainstem HGGs. Of those, 40% had tumors with alterations in 1 of 3 NTRK genes and few other changes. The alterations occurred when a segment of the NTRK genes involved in regulating cell division fused with part of another gene.

“These results indicate the NTRK fusion genes might be very potent drivers of cancer development that have the ability to generate tumors with few other mutations,” said cocorresponding author Suzanne Baker, PhD, of St. Jude, in Memphis, Tennessee. “We want to see if these tumors might be selectively sensitive to therapies that target the pathways that are disrupted as a result of these fusion genes.”

In this study, researchers analyzed 127 HGGs from 118 pediatric patients, including whole genome sequencing of the complete tumor and normal DNA from 42 patients. More targeted sequencing of additional tumors was conducted to track how instructions encoded in DNA were translated into the proteins that do the work of cells.

The recurring presence of ACVR1 mutations in a subset of DIPG patients was one of the biggest surprises, Baker said. ACVR1 carries instructions for making a protein receptor on the cell membrane. The receptor functions as an on-off switch for the biochemical pathway bone morphogenetic protein (BMP). The pathway helps regulate growth and development of bone and other tissue. Working with zebra fish and mouse brain cells, researchers found evidence that ACVR1 mutations from DIPG resulted in the BMP pathway being inappropriately and permanently switched on.